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Sample records for allogeneic mesenchymal stem

  1. Mesenchymal stem cells avoid allogeneic rejection

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    Murphy J Mary

    2005-07-01

    Full Text Available Abstract Adult bone marrow derived mesenchymal stem cells offer the potential to open a new frontier in medicine. Regenerative medicine aims to replace effete cells in a broad range of conditions associated with damaged cartilage, bone, muscle, tendon and ligament. However the normal process of immune rejection of mismatched allogeneic tissue would appear to prevent the realisation of such ambitions. In fact mesenchymal stem cells avoid allogeneic rejection in humans and in animal models. These finding are supported by in vitro co-culture studies. Three broad mechanisms contribute to this effect. Firstly, mesenchymal stem cells are hypoimmunogenic, often lacking MHC-II and costimulatory molecule expression. Secondly, these stem cells prevent T cell responses indirectly through modulation of dendritic cells and directly by disrupting NK as well as CD8+ and CD4+ T cell function. Thirdly, mesenchymal stem cells induce a suppressive local microenvironment through the production of prostaglandins and interleukin-10 as well as by the expression of indoleamine 2,3,-dioxygenase, which depletes the local milieu of tryptophan. Comparison is made to maternal tolerance of the fetal allograft, and contrasted with the immune evasion mechanisms of tumor cells. Mesenchymal stem cells are a highly regulated self-renewing population of cells with potent mechanisms to avoid allogeneic rejection.

  2. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

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    Sean D. Owens

    2016-01-01

    Full Text Available Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM or adipose tissue derived MSCs (ad-MSCs were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89% were positive for anti-bovine serum albumin (BSA antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection.

  3. Mesenchymal Stem Cells Enhance Allogeneic Islet Engraftment in Nonhuman Primates

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    Berman, Dora M.; Willman, Melissa A.; Han, Dongmei; Kleiner, Gary; Kenyon, Norman M.; Cabrera, Over; Karl, Julie A.; Wiseman, Roger W.; O'Connor, David H.; Bartholomew, Amelia M.; Kenyon, Norma S.

    2010-01-01

    OBJECTIVE To test the graft-promoting effects of mesenchymal stem cells (MSCs) in a cynomolgus monkey model of islet/bone marrow transplantation. RESEARCH DESIGN AND METHODS Cynomolgus MSCs were obtained from iliac crest aspirate and characterized through passage 11 for phenotype, gene expression, differentiation potential, and karyotype. Allogeneic donor MSCs were cotransplanted intraportally with islets on postoperative day (POD) 0 and intravenously with donor marrow on PODs 5 and 11. Recipients were followed for stabilization of blood glucose levels, reduction of exogenous insulin requirement (EIR), C-peptide levels, changes in peripheral blood T regulatory cells, and chimerism. Destabilization of glycemia and increases in EIR were used as signs of rejection; additional intravenous MSCs were administered to test the effect on reversal of rejection. RESULTS MSC phenotype and a normal karyotype were observed through passage 11. IL-6, IL-10, vascular endothelial growth factor, TGF-β, hepatocyte growth factor, and galectin-1 gene expression levels varied among donors. MSC treatment significantly enhanced islet engraftment and function at 1 month posttransplant (n = 8), as compared with animals that received islets without MSCs (n = 3). Additional infusions of donor or third-party MSCs resulted in reversal of rejection episodes and prolongation of islet function in two animals. Stable islet allograft function was associated with increased numbers of regulatory T-cells in peripheral blood. CONCLUSIONS MSCs may provide an important approach for enhancement of islet engraftment, thereby decreasing the numbers of islets needed to achieve insulin independence. Furthermore, MSCs may serve as a new, safe, and effective antirejection therapy. PMID:20622174

  4. Allogeneic Mesenchymal Stem Cells in Combination with Hyaluronic Acid for the Treatment of Osteoarthritis in Rabbits.

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    En-Rung Chiang

    Full Text Available Mesenchymal stem cell (MSC-based therapies may aid in the repair of articular cartilage defects. The purpose of this study was to investigate the effects of intraarticular injection of allogeneic MSCs in an in vivo anterior cruciate ligament transection (ACLT model of osteoarthritis in rabbits. Allogeneic bone marrow-derived MSCs were isolated and cultured under hypoxia (1% O2. After 8 weeks following ACLT, MSCs suspended in hyaluronic acid (HA were injected into the knees, and the contralateral knees were injected with HA alone. Additional controls consisted of a sham operation group as well as an untreated osteoarthritis group. The tissues were analyzed by macroscopic examination as well as histologic and immunohistochemical methods at 6 and 12 weeks post-transplantation. At 6 and 12 weeks, the joint surface showed less cartilage loss and surface abrasion after MSC injection as compared to the tissues receiving HA injection alone. Significantly better histological scores and cartilage content were observed with the MSC transplantation. Furthermore, engraftment of allogenic MSCs were evident in surface cartilage. Thus, injection of the allogeneic MSCs reduced the progression of osteoarthritis in vivo.

  5. Allogeneic Mesenchymal Stem Cells in Combination with Hyaluronic Acid for the Treatment of Osteoarthritis in Rabbits.

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    Chiang, En-Rung; Ma, Hsiao-Li; Wang, Jung-Pan; Liu, Chien-Lin; Chen, Tain-Hsiung; Hung, Shih-Chieh

    2016-01-01

    Mesenchymal stem cell (MSC)-based therapies may aid in the repair of articular cartilage defects. The purpose of this study was to investigate the effects of intraarticular injection of allogeneic MSCs in an in vivo anterior cruciate ligament transection (ACLT) model of osteoarthritis in rabbits. Allogeneic bone marrow-derived MSCs were isolated and cultured under hypoxia (1% O2). After 8 weeks following ACLT, MSCs suspended in hyaluronic acid (HA) were injected into the knees, and the contralateral knees were injected with HA alone. Additional controls consisted of a sham operation group as well as an untreated osteoarthritis group. The tissues were analyzed by macroscopic examination as well as histologic and immunohistochemical methods at 6 and 12 weeks post-transplantation. At 6 and 12 weeks, the joint surface showed less cartilage loss and surface abrasion after MSC injection as compared to the tissues receiving HA injection alone. Significantly better histological scores and cartilage content were observed with the MSC transplantation. Furthermore, engraftment of allogenic MSCs were evident in surface cartilage. Thus, injection of the allogeneic MSCs reduced the progression of osteoarthritis in vivo.

  6. Intraarticular Injection of Allogenic Mesenchymal Stem Cells has a Protective Role for the Osteoarthritis.

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    Yang, Xin; Zhu, Tian-Yue; Wen, Li-Cheng; Cao, Yong-Ping; Liu, Chao; Cui, Yun-Peng; Meng, Zhi-Chao; Liu, Heng

    2015-09-20

    Researchers initially proposed the substitution of apoptotic chondrocytes in the superficial cartilage by injecting mesenchymal stem cells (MSCs) intraarticularly. This effect was termed as bio-resurfacing. Little evidence supporting the treatment of osteoarthritis (OA) by the delivery of a MSC suspension exists. The aim of this study was to investigate the effects of injecting allogenic MSCs intraarticularly in a rat OA model and to evaluate the influence of immobility on the effects of this treatment. We established a rat knee OA model after 4 and 6 weeks and cultured primary bone marrow MSCs. A MSC suspension was injected into the articular space once per week for 3 weeks. A subgroup of knee joints was immobilized for 3 days after each injection, while the remaining joints were nonimmobilized. We used toluidine blue staining, Mankin scores, and TdT-mediated dUTP-biotin nick end labeling staining to evaluate the therapeutic effect of the injections. Comparisons between the therapy side and the control side of the knee joint were made using paired t-test, and comparisons between the immobilized and nonimmobilized subgroups were made using the unpaired t-test. A P value 0.05). Therapy involving the intraarticular injection of allogenic MSCs promoted cartilage repair in a rat arthritis model, and 3-day immobility after injection had little effect on this therapy.

  7. Intraarticular Injection of Allogenic Mesenchymal Stem Cells has a Protective Role for the Osteoarthritis

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    Xin Yang

    2015-01-01

    Full Text Available Background: Researchers initially proposed the substitution of apoptotic chondrocytes in the superficial cartilage by injecting mesenchymal stem cells (MSCs intraarticularly. This effect was termed as bio-resurfacing. Little evidence supporting the treatment of osteoarthritis (OA by the delivery of a MSC suspension exists. The aim of this study was to investigate the effects of injecting allogenic MSCs intraarticularly in a rat OA model and to evaluate the influence of immobility on the effects of this treatment. Methods: We established a rat knee OA model after 4 and 6 weeks and cultured primary bone marrow MSCs. A MSC suspension was injected into the articular space once per week for 3 weeks. A subgroup of knee joints was immobilized for 3 days after each injection, while the remaining joints were nonimmobilized. We used toluidine blue staining, Mankin scores, and TdT-mediated dUTP-biotin nick end labeling staining to evaluate the therapeutic effect of the injections. Comparisons between the therapy side and the control side of the knee joint were made using paired t-test, and comparisons between the immobilized and nonimmobilized subgroups were made using the unpaired t-test. A P value 0.05. Conclusions: Therapy involving the intraarticular injection of allogenic MSCs promoted cartilage repair in a rat arthritis model, and 3-day immobility after injection had little effect on this therapy.

  8. Systemic Administration of Allogeneic Mesenchymal Stem Cells Does Not Halt Osteoporotic Bone Loss in Ovariectomized Rats.

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    Shuo Huang

    Full Text Available Mesenchymal stem cells (MSCs have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1 Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2 Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91. Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn't show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study

  9. Equine allogeneic chondrogenic induced mesenchymal stem cells: A GCP target animal safety and biodistribution study.

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    Broeckx, S Y; Spaas, J H; Chiers, K; Duchateau, L; Van Hecke, L; Van Brantegem, L; Dumoulin, M; Martens, A M; Pille, F

    2017-12-27

    The safety of the intra-articular use of mesenchymal stem cells (MSCs) is scarcely reported. Therefore, the goal of this study was to investigate the safety of a single intra-articular injection with allogeneic chondrogenic induced MSCs combined with equine plasma (=the investigational product: IVP) compared to a saline (0.9% NaCl) placebo control (=control product: CP). Sixteen healthy experimental horses were randomly assigned to receive a single intra-articular injection with either the IVP (n=8) or the CP (n=8) in the left metacarpophalangeal joint. All horses underwent a daily clinical assessment throughout the entire study period of 42days to assess adverse events. Additionally, a local joint assessment and a lameness examination were performed daily during the first two weeks, and weekly the following 4weeks. Blood samples were taken weekly for hematological and biochemical analysis. At the end of the study period, horses of the IVP group were euthanized for a thorough necropsy and to check for biodistribution. Tissue samples of the injected joint were collected for histological examination. In both CP and IVP treated horses a mild transient subjective increase in periarticular temperature and lameness was noted after the intra-articular injection with no significant differences between the treatment groups. No distribution of the cells was found using immunohistochemistry and no ectopic tissue formation or signs of inflammation were found on histology. A single intra-articular injection of allogeneic chondrogenic induced MSCs combined with allogeneic plasma in horses had the same clinical side effects as an intra-articular injection with saline solution. Copyright © 2018 Elsevier Ltd. All rights reserved.

  10. Biodistribution and Immunogenicity of Allogeneic Mesenchymal Stem Cells in a Rat Model of Intraarticular Chondrocyte Xenotransplantation

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    Maribel Marquina

    2017-11-01

    Full Text Available Xenogeneic chondrocytes and allogeneic mesenchymal stem cells (MSC are considered a potential source of cells for articular cartilage repair. We here assessed the immune response triggered by xenogeneic chondrocytes when injected intraarticularly, as well as the immunoregulatory effect of allogeneic bone marrow-derived MSC after systemic administration. To this end, a discordant xenotransplantation model was established by injecting three million porcine articular chondrocytes (PAC into the femorotibial joint of Lewis rats and monitoring the immune response. First, the fate of MSC injected using various routes was monitored in an in vivo imaging system. The biodistribution revealed a dependency on the injection route with MSC injected intravenously (i.v. succumbing early after 24 h and MSC injected intraperitoneally (i.p. lasting locally for at least 5 days. Importantly, no migration of MSC to the joint was detected in rats previously injected with PAC. MSC were then administered either i.v. 1 week before PAC injection or i.p. 3 weeks after to assess their immunomodulatory function on humoral and adaptive immune parameters. Anti-PAC IgM and IgG responses were detected in all PAC-injected rats with a peak at week 2 postinjection and reactivity remaining above baseline levels by week 18. IgG2a and IgG2b were the predominant and long-lasting IgG subtypes. By contrast, no anti-MSC antibody response was detected in the cohort injected with MSC only, but infusion of MSC before PAC injection temporarily augmented the anti-PAC antibody response. Consistent with a cellular immune response to PAC in PAC-injected rats, cytokine/chemokine profiling in serum by antibody array revealed a distinct pattern relative to controls characterized by elevation of multiple markers at week 2, as well as increases in proliferation in draining lymph nodes. Notably, systemic administration of allogeneic MSC under the described conditions did not diminish the immune

  11. De Novo Arteriovenous Malformation Growth Secondary to Implantation of Genetically Modified Allogeneic Mesenchymal Stem Cells in the Brain.

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    Nakamura, Makoto; Samii, Amir; Lang, Josef M; Götz, Friedrich; Samii, Madjid; Krauss, Joachim K

    2016-04-01

    Local biological drug delivery in the brain is an innovative field of medicine that developed rapidly in recent years. Our report illustrates a unique case of de novo development of a cerebral arteriovenous malformation (AVM) after implantation of genetically modified allogeneic mesenchymal stem cells in the brain. A 50-year-old man was included in a prospective clinical study (study ID number CM GLP-1/01, 2007-004516-31) investigating a novel neuroprotective approach in stroke patients to prevent perihematomal neuronal damage. In this study, alginate microcapsules containing genetically modified allogeneic mesenchymal stem cells producing the neuroprotective glucagon-like peptide-1 (GLP-1) were implanted. Three years later, the patient presented with aphasia and a focal seizure due to a new left frontal intracerebral hemorrhage. Angiography revealed a de novo left frontal AVM. The development of an AVM within a period of 3 years after implantation of the glucagon-like peptide-1-secreting mesenchymal stem cells suggests a possible relationship. This case exemplifies that further investigations are necessary to assess the safety of genetically modified cell lines for local biological drug delivery in the brain.

  12. Clinicopathologic findings following intra-articular injection of autologous and allogeneic placentally derived equine mesenchymal stem cells in horses.

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    Carrade, Danielle D; Owens, Sean D; Galuppo, Larry D; Vidal, Martin A; Ferraro, Gregory L; Librach, Fred; Buerchler, Sabine; Friedman, Michael S; Walker, Naomi J; Borjesson, Dori L

    2011-04-01

    The development of an allogeneic mesenchymal stem cell (MSC) product to treat equine disorders would be useful; however, there are limited in vivo safety data for horses. We hypothesized that the injection of self (autologous) and non-self (related allogeneic or allogeneic) MSC would not elicit significant alterations in physical examination, gait or synovial fluid parameters when injected into the joints of healthy horses. Sixteen healthy horses were used in this study. Group 1 consisted of foals (n = 6), group 2 consisted of their dams (n = 5) and group 3 consisted of half-siblings (n = 5) to group 1 foals. Prior to injection, MSC were phenotyped. Placentally derived MSC were injected into contralateral joints and MSC diluent was injected into a separate joint (control). An examination, including lameness evaluation and synovial fluid analysis, was performed at 0, 24, 48 and 72 h post-injection. MSC were major histocompatibility complex (MHC) I positive, MHC II negative and CD86 negative. Injection of allogeneic MSC did not elicit a systemic response. Local responses such as joint swelling or lameness were minimal and variable. Intra-articular MSC injection elicited marked inflammation within the synovial fluid (as measured by nucleated cell count, neutrophil number and total protein concentration). However, there were no significant differences between the degree and type of inflammation elicited by self and non-self-MSC. The healthy equine joint responds similarly to a single intra-articular injection of autologous and allogeneic MSC. This pre-clinical safety study is an important first step in the development of equine allogeneic stem cell therapies.

  13. Mesenchymal Stem Cells May Ameliorate Nephrotic Syndrome Post-Allogeneic Hematopoietic Stem Cell Transplantation-Case Report

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    Xin Zhang

    2017-08-01

    Full Text Available IntroductionBecause of their immunomodulatory and anti-inflammatory effects, mesenchymal stem cells (MSCs have been considered as potential therapeutic agents for treating immune-related or autoimmune diseases, such as graft-versus-host disease (GVHD. Nephrotic syndrome (NS after allogeneic hematopoietic stem cell transplantation (allo-HSCT is an uncommon complication with unclear etiology and pathogenesis. It may be an immune disorder involving immune complex deposition, B cells, regulatory T cells (Tregs, and Th1 cytokines and be a manifestation of chronic GVHD. Corticosteroids and calcium antagonists, alone or in combination, are the most common therapeutic agents in this setting. Rituximab is commonly administered as salvage treatment. However, treatment failure and progressive renal function deterioration has been reported to occur in approximately 20% of patients in a particular cohort.Case presentationWe present a patient who developed NS 10 months after allo-HSCT. After treatment failure with cyclosporine A, prednisone, and rituximab, she achieved a complete response with MSC treatment. The clinical improvement of this patient was accompanied by a decreased B cell population together with an increased frequency of regulatory B cells (Bregs and Tregs after MSC treatment.ConclusionMSCs could modulate NS after allo-HSCT by suppressing B cell proliferation, inducing Tregs and Bregs, and inhibiting inflammatory cytokine production by monocytes and NK cells. Among all these, Bregs might play an important role in ameliorating the NS of this patient.

  14. Tenogenically induced allogeneic mesenchymal stem cells for the treatment of proximal suspensory ligament desmitis in a horse

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    Aurelie eVandenberghe

    2015-10-01

    Full Text Available Suspensory ligament injuries are a common injury in sport horses, especially in competing dressage horses. Because of the poor healing of chronic recalcitrant tendon injuries, this represents a major problem in the rehabilitation of sport horses and often compromises the return to the initial performance level. Stem cells are considered as a novel treatment for different pathologies in horses and humans. Autologous mesenchymal stem cells (MSCs are well known for their use in the treatment of tendinopathies, however, recent studies report a safe use of allogeneic MSCs for different orthopaedic applications in horses. Moreover, it has been reported that predifferentiation of MSCs prior to injection might result in improved clinical outcomes. For all these reasons, the present case report describes the use of allogeneic tenogenically induced peripheral blood-derived MSCs for the treatment of a proximal suspensory ligament injury. During conservative management for 4 months, the horse demonstrated no improvement of a right front lameness with a Grade 2/5 on the AAEP scale and a clear hypo-echoic area detectable in 30% of the cross sectional area. From 4 weeks after treatment, the lameness reduced to an AAEP Grade 1/5 and a clear filling of the lesion could be noticed on ultrasound. At 12 weeks (T4 after the first injection, a second intralesional injection with allogeneic tenogenically induced MSCs and PRP was given and at 4 weeks after the second injection (T5, the horse trotted sound under all circumstances with a close to total fiber alignment. The horse went back to previous performance level at 32 weeks after the first regenerative therapy and is currently still doing so (i.e. 20 weeks later or 1 year after the first stem cell treatment.In conclusion, the present case report demonstrated a positive evolution of proximal suspensory ligament desmitis after treatment with allogeneic tenogenically induced MSCs.

  15. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo

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    Lee, Miyoung; Jeong, Sang Young; Ha, Jueun; Kim, Miyeon; Jin, Hye Jin; Kwon, Soon-Jae [Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874 (Korea, Republic of); Chang, Jong Wook [Research Institute for Future Medicine Stem Cell and Regenerative Medicine Center, Samsung Medical Center, Seoul 137-710 (Korea, Republic of); Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun [Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874 (Korea, Republic of); Kim, Jae-Sung [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-709 (Korea, Republic of); Jeon, Hong Bae, E-mail: jhb@medi-post.co.kr [Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 137-874 (Korea, Republic of)

    2014-04-18

    Highlights: • hUCB-MSCs maintained low immunogenicity even after immune challenge in vitro. • Humanized NSG mice were established using human UCB CD34+ cells. • Repeated intravenous hUCB-MSC injection into mice did not lead to immune responses and adverse events. • Allogeneic hUCB-MSCs maintained low immunogenicity in vitro and in vivo. - Abstract: Evaluation of the immunogenicity of human mesenchymal stem cells (MSCs) in an allogeneic setting during therapy has been hampered by lack of suitable models due to technical and ethical limitations. Here, we show that allogeneic human umbilical cord blood derived-MSCs (hUCB-MSCs) maintained low immunogenicity even after immune challenge in vitro. To confirm these properties in vivo, a humanized mouse model was established by injecting isolated hUCB-derived CD34+ cells intravenously into immunocompromised NOD/SCID IL2γnull (NSG) mice. After repeated intravenous injection of human peripheral blood mononuclear cells (hPBMCs) or MRC5 cells into these mice, immunological alterations including T cell proliferation and increased IFN-γ, TNF-α, and human IgG levels, were observed. In contrast, hUCB-MSC injection did not elicit these responses. While lymphocyte infiltration in the lung and small intestine and reduced survival rates were observed after hPBMC or MRC5 transplantation, no adverse events were observed following hUCB-MSC introduction. In conclusion, our data suggest that allogeneic hUCB-MSCs have low immunogenicity in vitro and in vivo, and are therefore “immunologically safe” for use in allogeneic clinical applications.

  16. Inflammatory effects of autologous, genetically modified autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses.

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    Pigott, J H; Ishihara, A; Wellman, M L; Russell, D S; Bertone, A L

    2013-01-01

    To compare the clinical and inflammatory joint responses to intra-articular injection of bone marrow-derived mesenchymal stem cells (MSC) including autologous, genetically modified autologous, allogeneic, or xenogeneic cells in horses. Six five-year-old Thoroughbred mares had one fetlock joint injected with Gey's balanced salt solution as the vehicle control. Each fetlock joint of each horse was subsequently injected with 15 million MSC from the described MSC groups, and were assessed for 28 days for clinical and inflammatory parameters representing synovitis, joint swelling, and pain. There were not any significant differences between autologous and genetically modified autologous MSC for synovial fluid total nucleated cell count, total protein, interleukin (IL)-6, IL-10, fetlock circumference, oedema score, pain-free range-of-motion, and soluble gene products that were detected for at least two days. Allogeneic and xenogeneic MSC produced a greater increase in peak of inflammation at 24 hours than either autologous MSC group. Genetically engineered MSC can act as vehicles to deliver gene products to the joint; further investigation into the therapeutic potential of this cell therapy is warranted. Intra-articular MSC injection resulted in a moderate acute inflammatory joint response that was greater for allogeneic and xenogeneic MSC than autologous MSC. Clinical management of this response may minimize this effect.

  17. Safety of Allogeneic Canine Adipose Tissue-Derived Mesenchymal Stem Cell Intraspinal Transplantation in Dogs with Chronic Spinal Cord Injury

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    Cláudia Cardoso Maciel Escalhão

    2017-01-01

    Full Text Available This is a pilot clinical study primarily designed to assess the feasibility and safety of X-ray-guided percutaneous intraspinal injection of allogeneic canine adipose tissue-derived mesenchymal stem cells in dogs with chronic spinal cord injury. Six dogs with chronic paraplegia (≥six months were intraparenchymally injected with allogeneic cells in the site of lesion. Cells were obtained from subcutaneous adipose tissue of a healthy dog, cultured to passage 3, labeled with 99mTechnetium, and transplanted into the lesion by percutaneous X-ray-guided injection. Digital X-ray efficiently guided cell injection as 99mTechnetium-labeled cells remained in the injection site for at least 24 hours after transplantation. No adverse effects or complications (infection, neuropathic pain, or worsening of neurological function were observed during the 16-week follow-up period after transplantation. Three animals improved locomotion as assessed by the Olby scale. One animal walked without support, but no changes in deep pain perception were observed. We conclude that X-ray-guided percutaneous intraspinal transplantation of allogeneic cells in dogs with chronic spinal cord injury is feasible and safe. The efficacy of the treatment will be assessed in a new study involving a larger number of animals.

  18. Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial.

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    Vega, Aurelio; Martín-Ferrero, Miguel Angel; Del Canto, Francisco; Alberca, Mercedes; García, Veronica; Munar, Anna; Orozco, Lluis; Soler, Robert; Fuertes, Juan Jose; Huguet, Marina; Sánchez, Ana; García-Sancho, Javier

    2015-08-01

    Osteoarthritis is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. Conventional treatments demonstrate only modest clinical benefits without lesion reversal. Autologous mesenchymal stromal cell (MSC) treatments have shown feasibility, safety, and strong indications for clinical efficacy. We performed a randomized, active control trial to assess the feasibility and safety of treating osteoarthritis with allogeneic MSCs, and we obtain information regarding the efficacy of this treatment. We randomized 30 patients with chronic knee pain unresponsive to conservative treatments and showing radiological evidence of osteoarthritis into 2 groups of 15 patients. The test group was treated with allogeneic bone marrow MSCs by intra-articular injection of 40 × 10(6) cells. The control group received intra-articular hyaluronic acid (60 mg, single dose). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. Feasibility and safety were confirmed and indications of clinical efficacy were identified. The MSC-treated patients displayed significant improvement in algofunctional indices versus the active controls treated with hyaluronic acid. Quantification of cartilage quality by T2 relaxation measurements showed a significant decrease in poor cartilage areas, with cartilage quality improvements in MSC-treated patients. Allogeneic MSC therapy may be a valid alternative for the treatment of chronic knee osteoarthritis that is more logistically convenient than autologous MSC treatment. The intervention is simple, does not require surgery, provides pain relief, and significantly improves cartilage quality.

  19. Preclinical Study of Cell Therapy for Osteonecrosis of the Femoral Head with Allogenic Peripheral Blood-Derived Mesenchymal Stem Cells.

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    Fu, Qiang; Tang, Ning Ning; Zhang, Qian; Liu, Yi; Peng, Jia Chen; Fang, Ning; Yu, Li Mei; Liu, Jin Wei; Zhang, Tao

    2016-07-01

    To explore the value of transplanting peripheral blood-derived mesenchymal stem cells from allogenic rabbits (rPBMSCs) to treat osteonecrosis of the femoral head (ONFH). rPBMSCs were separated/cultured from peripheral blood after granulocyte colony-stimulating factor mobilization. Afterwards, mobilized rPBMSCs from a second passage labeled with PKH26 were transplanted into rabbit ONFH models, which were established by liquid nitrogen freezing, to observe the effect of rPBMSCs on ONFH repair. Then, the mRNA expressions of BMP-2 and PPAR-γ in the femoral head were assessed by RT-PCR. After mobilization, the cultured rPBMSCs expressed mesenchymal markers of CD90, CD44, CD29, and CD105, but failed to express CD45, CD14, and CD34. The colony forming efficiency of mobilized rPBMSCs ranged from 2.8 to 10.8 per million peripheral mononuclear cells. After local transplantation, survival of the engrafted cells reached at least 8 weeks. Therein, BMP-2 was up-regulated, while PPAR-γ mRNA was down-regulated. Additionally, bone density and bone trabeculae tended to increase gradually. We confirmed that local transplantation of rPBMSCs benefits ONFH treatment and that the beneficial effects are related to the up-regulation of BMP-2 expression and the down-regulation of PPAR-γ expression.

  20. The effect of allogenic versus autologue mesenchymal stem cells in bone reconstructio

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    Jensen, Stefan; Overgaard, Søren; Ding, Ming

    2008-01-01

    with allogenic MSC (group#3) proved to have a significant higher mean SFE (Fisher's LSD-test). The other groups (#1 and #2) had a slightly higher mean SFE (Table 2). Discussion and Conclusion: There are shown two interesting things in this minor pilot-study. There is a trend showing, that the use of MSC has...

  1. Tenogenically Induced Allogeneic Peripheral Blood Mesenchymal Stem Cells in Allogeneic Platelet-Rich Plasma: 2-Year Follow-up after Tendon or Ligament Treatment in Horses

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    Charlotte Beerts

    2017-09-01

    Full Text Available Poor healing of tendon and ligament lesions often results in early retirement of sport horses. Therefore, regenerative therapies are being explored as potentially promising treatment for these injuries. In this study, an intralesional injection was performed with allogeneic tenogenically induced mesenchymal stem cells and platelet-rich plasma 5–6 days after diagnosis of suspensory ligament (SL (n = 68 or superficial digital flexor tendon (SDFT (n = 36 lesion. Clinical, lameness and ultrasonographic evaluation was performed at 6 and 12 weeks. Moreover, a survey was performed 12 and 24 months after treatment to determine how many horses were competing at original level and how many were re-injured. At 6 weeks, 88.2% of SL (n = 68 and 97.3% of SDFT lesions (n = 36 demonstrated moderate ultrasonographic improvement. At 12 weeks, 93.1% of SL (n = 29 and 95.5% of SDFT lesions (n = 22 improved convincingly. Moreover, lameness was abolished in 78.6% of SL (n = 28 and 85.7% (n = 7 of SDFT horses at 12 weeks. After 12 months (n = 92, 11.8% of SL and 12.5% of SDFT horses were re-injured, whereas 83.8 of SL and 79.2% of SDFT returned to previous performance level. At 24 months (n = 89 after treatment, 82.4 (SL and 85.7% (SDFT of the horses returned to previous level of performance. A meta-analysis was performed on relevant published evidence evaluating re-injury 24 months after stem cell-based [17.6% of the SL and 14.3% of the SDFT group (n = 89] versus conventional therapies. Cell therapies resulted in a significantly lower re-injury rate of 18% [95% confidence interval (CI, 0.11–0.25] 2 years after treatment compared to the 44% re-injury rate with conventional treatments (95% CI, 0.37–0.51 based on literature data (P < 0.0001.

  2. Anti-Donor Immune Responses Elicited by Allogeneic Mesenchymal Stem Cells and Their Extracellular Vesicles: Are We Still Learning?

    Directory of Open Access Journals (Sweden)

    Paul Lohan

    2017-11-01

    Full Text Available Mesenchymal stromal cells (MSC have been used to treat a broad range of disease indications such as acute and chronic inflammatory disorders, autoimmune diseases, and transplant rejection due to their potent immunosuppressive/anti-inflammatory properties. The breadth of their usage is due in no small part to the vast quantity of published studies showing their ability to modulate multiple immune cell types of both the innate and adaptive immune response. While patient-derived (autologous MSC may be the safer choice in terms of avoiding unwanted immune responses, factors including donor comorbidities may preclude these cells from use. In these situations, allogeneic MSC derived from genetically unrelated individuals must be used. While allogeneic MSC were initially believed to be immune-privileged, substantial evidence now exists to prove otherwise with multiple studies documenting specific cellular and humoral immune responses against donor antigens following administration of these cells. In this article, we will review recent published studies using non-manipulated, inflammatory molecule-activated (licensed and differentiated allogeneic MSC, as well as MSC extracellular vesicles focusing on the immune responses to these cells and whether or not such responses have an impact on allogeneic MSC-mediated safety and efficacy.

  3. Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cells as a Potential Source for Cartilage and Bone Regeneration: An In Vitro Study

    Directory of Open Access Journals (Sweden)

    A. Marmotti

    2017-01-01

    Full Text Available Umbilical cord (UC may represent an attractive cell source for allogeneic mesenchymal stem cell (MSC therapy. The aim of this in vitro study is to investigate the chondrogenic and osteogenic potential of UC-MSCs grown onto tridimensional scaffolds, to identify a possible clinical relevance for an allogeneic use in cartilage and bone reconstructive surgery. Chondrogenic differentiation on scaffolds was confirmed at 4 weeks by the expression of sox-9 and type II collagen; low oxygen tension improved the expression of these chondrogenic markers. A similar trend was observed in pellet culture in terms of matrix (proteoglycan production. Osteogenic differentiation on bone-graft-substitute was also confirmed after 30 days of culture by the expression of osteocalcin and RunX-2. Cells grown in the hypertrophic medium showed at 5 weeks safranin o-positive stain and an increased CbFa1 expression, confirming the ability of these cells to undergo hypertrophy. These results suggest that the UC-MSCs isolated from minced umbilical cords may represent a valuable allogeneic cell population, which might have a potential for orthopaedic tissue engineering such as the on-demand cell delivery using chondrogenic, osteogenic, and endochondral scaffold. This study may have a clinical relevance as a future hypothetical option for allogeneic single-stage cartilage repair and bone regeneration.

  4. Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.

    Science.gov (United States)

    Kol, Amir; Wood, Joshua A; Carrade Holt, Danielle D; Gillette, Jessica A; Bohannon-Worsley, Laurie K; Puchalski, Sarah M; Walker, Naomi J; Clark, Kaitlin C; Watson, Johanna L; Borjesson, Dori L

    2015-04-15

    Intravenous (IV) injection of mesenchymal stem cells (MSCs) is used to treat systemic human diseases and disorders but is not routinely used in equine therapy. In horses, MSCs are isolated primarily from adipose tissue (AT) or bone marrow (BM) and used for treatment of orthopedic injuries through one or more local injections. The objective of this study was to determine the safety and lymphocyte response to multiple allogeneic IV injections of either AT-derived MSCs (AT-MSCs) or BM-derived MSCs (BM-MSCs) to healthy horses. We injected three doses of 25 × 10(6) allogeneic MSCs from either AT or BM (a total of 75 × 10(6) MSCs per horse) into five and five, respectively, healthy horses. Horses were followed up for 35 days after the first MSC infusion. We evaluated host inflammatory and immune response, including total leukocyte numbers, serum cytokine concentration, and splenic lymphocyte subsets. Repeated injection of allogeneic AT-MSCs or BM-MSCs did not elicit any clinical adverse effects. Repeated BM-MSC injection resulted in increased blood CD8(+) T-cell numbers. Multiple BM-MSC injections also increased splenic regulatory T cell numbers compared with AT-MSC-injected horses but not controls. These data demonstrate that multiple IV injections of allogeneic MSCs are well tolerated by healthy horses. No clinical signs or clinico-pathologic measurements of organ toxicity or systemic inflammatory response were recorded. Increased numbers of circulating CD8(+) T cells after multiple IV injections of allogeneic BM-MSCs may indicate a mild allo-antigen-directed cytotoxic response. Safety and efficacy of allogeneic MSC IV infusions in sick horses remain to be determined.

  5. Mesenchymal stem cells provide prophylaxis against acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: A meta-analysis of animal models.

    Science.gov (United States)

    Wang, Li; Zhang, Haiyan; Guan, Lixun; Zhao, Shasha; Gu, Zhenyang; Wei, Huaping; Gao, Zhe; Wang, Feiyan; Yang, Nan; Luo, Lan; Li, Yonghui; Wang, Lili; Liu, Daihong; Gao, Chunji

    2016-09-20

    A meta-analysis of animal models was conducted to evaluate the prophylactic effects of mesenchymal stem cells (MSCs) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation. A total of 50 studies involving 1848 animals were included. The pooled results showed that MSCs significantly reduced aGVHD-associated mortality (risk ratio = 0.70, 95% confidence interval 0.62 to 0.79, P = 2.73×10-9) and clinical scores (standardized mean difference = -3.60, 95% confidence interval -4.43 to -2.76, P = 3.61×10-17). In addition, MSCs conferred robust favorable prophylactic effects on aGVHD across recipient species, MSC doses, and administration times, but not MSC sources. Our meta-analysis showed that MSCs significantly prevented mortality and alleviated the clinical manifestations of aGVHD in animal models. These data support further clinical trials aimed at evaluating the efficacy of using MSCs to prevent aGVHD.

  6. Treatment of faecal incontinence using allogeneic-adipose-derived mesenchymal stem cells: a study protocol for a pilot randomised controlled trial.

    Science.gov (United States)

    Park, Eun Jung; Kang, Jeonghyun; Baik, Seung Hyuk

    2016-02-17

    Faecal incontinence is a distressing condition with recurrent uncontrolled passage of faecal material. Although faecal incontinence may cause psychological depression and social isolation, previous treatments have been limited. Recently, regenerative treatment has been developed using mesenchymal stem cells. Especially, there are possibilities that adipose-tissue-derived stem cells can be effective to treat a degenerated anal sphincter that is causing faecal incontinence. Therefore, this study aimed to investigate the safety and efficacy of using allogeneic-adipose-derived mesenchymal stem cells in the treatment of the anal sphincter of patients with faecal incontinence. This study is a randomised, prospective, dose escalation, placebo-controlled, single-blinded, single-centre trial with two parallel groups. The safety test is performed by an injection of allogeneic-adipose-derived mesenchymal stem cells (ALLO-ASCs) into the anal sphincter with dose escalation (3 × 10(7), 6 × 10(7) and 9 × 10(7) cells, sequentially). After confirming the safety of the stem cells, an efficacy test is performed by this dose in the experimental group. The experimental group will receive ALLO-ASCs mixed with fibrin glue into the anal sphincter, and the placebo group will receive 0.9% normal saline injection mixed with fibrin glue. The primary end point is to assess the safety of ALLO-ASCs after the injection into the anal sphincter, and the secondary end point is to compare the efficacy of ALLO-ASC injection with fibrin glue in patients with faecal incontinence. The study protocol was approved by the Ministry of Food and Drug Safety and the Ministry of Health & Welfare, in the Republic of Korea. The informed consent form was approved by the institutional review board of Gangnam Severance Hospital (IRB approval number 3-2014-0271). Dissemination of the results will be presented at a conference and in peer-reviewed publications. NCT02384499; Pre-results. Published by the BMJ

  7. Intracoronary Administration of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction.

    Science.gov (United States)

    Bobi, Joaquim; Solanes, Núria; Fernández-Jiménez, Rodrigo; Galán-Arriola, Carlos; Dantas, Ana Paula; Fernández-Friera, Leticia; Gálvez-Montón, Carolina; Rigol-Monzó, Elisabet; Agüero, Jaume; Ramírez, José; Roqué, Mercè; Bayés-Genís, Antoni; Sánchez-González, Javier; García-Álvarez, Ana; Sabaté, Manel; Roura, Santiago; Ibáñez, Borja; Rigol, Montserrat

    2017-05-03

    Autologous adipose tissue-derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post-myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long-term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance. Thirty-eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow-ups were performed at short (2 days after acute myocardial infarction vehicle-treated, n=10; ATMSCs-treated, n=9) or long term (60 days after acute myocardial infarction vehicle-treated, n=7; ATMSCs-treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs-treated animals (48.6±6% versus 55.9±5.7% in vehicle; P =0.017); enhancement of the reparative process with up-regulated vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and stromal-derived factor-1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle; P =0.016). In long-term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day-7 and day-60 cardiac magnetic resonance studies in ATMSCs-treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days; P =0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days; P =0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs-treated animals (118±18 versus 92.4±24.3 vessels/mm 2 in vehicle; P =0.045). Cardiac magnetic resonance-measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point. In this porcine acute myocardial infarction model, allogeneic ATMSCs-based therapy was associated with increased cardioprotective and reparative

  8. Clinical follow-up of horses treated with allogeneic equine mesenchymal stem cells derived from umbilical cord blood for different tendon and ligament disorders.

    Science.gov (United States)

    Van Loon, Vic J F; Scheffer, Carmen J W; Genn, Herman J; Hoogendoorn, Arie C; Greve, Jan W

    2014-01-01

    Mesenchymal stem cells (MSCs) offer promise as therapeutic aids in the repair of tendon and ligament disorders in sport horses. Equine allogeneic MSCs derived from umbilical cord blood (eUCB-MSCs) can be obtained in a minimally invasive fashion with successful propagation of MSCs. The objective of this study was to determine the applicability and therapeutic effect of eUCB-MSCs on tendinitis of the superficial digital flexor tendon, desmitis of the suspensory ligament, tendinitis of the deep digital flexor tendon, and desmitis of the inferior check ligament in clinical cases. A retrospective clinical study was performed. At two equine clinics, 52 warmblood horses were treated with cultured eUCB-MSCs between 2009 and 2012. About 2-10 × 10(6) cells per lesion were administered. When a lesion was treated twice, the total amount could run up to 20 × 10(6) cells. Pearson's chi-squared test was used to compare the effect of the injured structure on the success rate, as well as the effect of the age of the horse. Based on repeated examinations, 40 horses (77%) returned to work on the same or a higher level based on information provided by the owner. Neither the injured structure nor the age of the horse had a statistically significant influence on the result. Overall, the results of treatment of some tendon and ligament injuries with eUCB-MSCs in clinical cases are promising.

  9. Comparison of the osteogenic potentials of autologous cultured osteoblasts and mesenchymal stem cells loaded onto allogeneic cancellous bone granules.

    Science.gov (United States)

    Kim, Seok-Jung; Chung, Yang-Guk; Lee, Yun-Kyoung; Oh, Il-Whan; Kim, Yong-Sik; Moon, Young-Seok

    2012-02-01

    We compared the bone regeneration potentials of autologous cultured osteoblasts and of bone-marrow-derived autologous MSCs in combination with allogeneic cancellous bone granules in a rabbit radial defect model. Radial shaft defects over 15 mm were made in 26 New Zealand white rabbits. The animals underwent insertion of allogeneic cancellous bone granules containing autologous osteoblasts into right-side defects (the experimental group) and of allogeneic cancellous bone granules with autologous MSCs into left-side defects (the control group). To quantitatively assess bone regeneration, radiographic evaluations as well as BMD and BMC measurements were performed 3, 6, 9 and 12 weeks post-implantation and histology as well as micro-CT image analysis were performed at 6 and 12 weeks. Radiographic evaluations 3 weeks post-implantation showed that the experimental group had a higher mean bone quantity index (p bone volume and surface area than the control sides (p bone formation in the experimental group. This in vivo study demonstrates that a combination of autologous osteoblasts and small-sized, allogeneic cancellous bone granules leads to more rapid bone regeneration than autologous MSCs and small-sized, allogeneic cancellous bone granules.

  10. Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons

    NARCIS (Netherlands)

    de Windt, Tommy S; Vonk, Lucienne A; Slaper-Cortenbach, Ineke C M; van den Broek, Marcel P H; Nizak, Razmara; van Rijen, Mattie H P; de Weger, Roel A; Dhert, Wouter J A; Saris, Daniel B F

    Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have

  11. Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.

    Science.gov (United States)

    Berglund, A K; Schnabel, L V

    2017-07-01

    Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Experimental controlled study. Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. This study examined MSC death in vitro only and utilized antisera from a small number of horses. The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death. © 2016 The

  12. Effects and safety of allogenic mesenchymal stem cell intravenous infusion in active ankylosing spondylitis patients who failed NSAIDs: a 20-week clinical trial.

    Science.gov (United States)

    Wang, Peng; Li, Yuxi; Huang, Lin; Yang, Jiewen; Yang, Rui; Deng, Wen; Liang, Biling; Dai, Lie; Meng, Qingqi; Gao, Liangbin; Chen, Xiaodong; Shen, Jun; Tang, Yong; Zhang, Xin; Hou, Jingyi; Ye, Jichao; Chen, Keng; Cai, Zhaopeng; Wu, Yanfeng; Shen, Huiyong

    2014-01-01

    Our objective was to evaluate the feasibility, safety, and efficacy of intravenous (IV) infusion of allogenic mesenchymal stem cells (MSCs) in ankylosing spondylitis (AS) patients who are refractory to or cannot tolerate the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). AS patients enrolled in this study received four IV infusions of MSCs on days 0, 7, 14, and 21. The percentage of ASAS20 responders (the primary endpoint) at the fourth week and the mean ASAS20 response duration (the secondary endpoint) were used to assess treatment response to MSC infusion and duration of the therapeutic effects. Ankylosing Spondylitis Disease Activity Score Containing C-reactive Protein (ASDAS-CRP) and other preestablished evaluation indices were also adopted to evaluate the clinical effects. Magnetic resonance imaging (MRI) was performed to detect changes of bone marrow edema in the spine. The safety of this treatment was also evaluated. Thirty-one patients were included, and the percentage of ASAS20 responders reached 77.4% at the fourth week, and the mean ASAS20 response duration was 7.1 weeks. The mean ASDAS-CRP score decreased from 3.6 ± 0.6 to 2.4 ± 0.5 at the fourth week and then increased to 3.2 ± 0.8 at the 20th week. The average total inflammation extent (TIE) detected by MRI decreased from 533,482.5 at baseline to 480,692.3 at the fourth week (p > 0.05) and 400,547.2 at the 20th week (p < 0.05). No adverse effects were noted. IV infusion of MSCs is a feasible, safe, and promising treatment for patients with AS.

  13. Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: Clinical and laboratory outcomes.

    Science.gov (United States)

    Pérez-Merino, E M; Usón-Casaús, J M; Zaragoza-Bayle, C; Duque-Carrasco, J; Mariñas-Pardo, L; Hermida-Prieto, M; Barrera-Chacón, R; Gualtieri, M

    2015-12-01

    Mesenchymal stem cells (MSCs) have shown immunomodulatory and anti-inflammatory effects in experimental colitis, and promising clinical results have been obtained in humans with Crohn's disease and ulcerative colitis. The aim of this study was to determine the safety and feasibility of adipose tissue-derived MSC (ASC) therapy in dogs with inflammatory bowel disease (IBD). Eleven dogs with confirmed IBD received one ASC intravascular (IV) infusion (2 × 10(6) cells/kg bodyweight). The outcome measures were clinical response based on percentage reduction of the validated Clinical Inflammatory Bowel Disease Activity Index (CIBDAI) and Canine Chronic Enteropathy Clinical Activity Index (CCECAI), as well as normalisation of C-reactive protein (CRP), albumin, folate and cobalamin serum concentrations at day 42 post-treatment. The Wilcoxon test was used to compare variables before and after treatment. No acute reaction to ASC infusion and no side effects were reported during follow-up in any dog. Six weeks post-treatment, the CIBDAI and CCECAI decreased significantly and albumin, cobalamin and folate concentrations increased substantially. Differences in CRP concentrations pre- and post-treatment were not significant (P = 0.050). Clinical remission (defined by a reduction of initial CIBDAI and CCECAI >75%) occurred in 9/11 dogs at day 42. The two remaining dogs showed a partial response with reduction percentages of 69.2% and 71.4%. In conclusion, a single IV infusion of allogeneic ASCs was well tolerated and appeared to produce clinical benefits in dogs with severe IBD. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Combined transplantation of autologous hematopoietic stem cells and allogenic mesenchymal stem cells increases T regulatory cells in systemic lupus erythematosus with refractory lupus nephritis and leukopenia.

    Science.gov (United States)

    Wang, Q; Qian, S; Li, J; Che, N; Gu, L; Wang, Q; Liu, Y; Mei, H

    2015-10-01

    Autologous hematopoietic stem cell (HSC) and mesenchymal stem cell (MSC) transplantation is currently being evaluated as a novel treatment for autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we report a case of autologous HSC transplantation combined with MSCs in a 25-year-old severe SLE patient with multiple life-threatening complications and refractory to conventional cyclophosphamide (CYC) therapy. After being pretreated with CYC, fludarabine and antithymocyte globulin, the patient was transplanted with autologous CD34+HSCs and MSCs by intravenous infusion. Hematopoietic regeneration was observed on day 12 thereafter. After HSC and MSC transplantation, the patient's clinical symptoms caused by SLE were remitted, and the SLEDAI score decreased. Moreover, CD4+CD25+FoxP3+Treg cells increased in peripheral blood mononuclear cells (PBMCs) after transplantation. This result suggests that the combined transplantation of HSCs and MSCs may reset the adaptive immune system to re-establish self-tolerance in SLE. A 36-month follow-up showed that the clinical symptoms remained in remission. Although a longer follow-up is required for assessing the long-term efficacy, our present results suggest that the combined transplantation of HSCs and MSCs may be a novel and effective therapy for refractory SLE. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  15. Kidney dysfunction after allogeneic stem cell transplantation

    NARCIS (Netherlands)

    Kersting, S.

    2008-01-01

    Allogeneic stem cell transplantation (SCT) is a widely accepted approach for malignant and nonmalignant hematopoietic diseases. Unfortunately complications can occur because of the treatment, leading to treatment-related mortality. We studied kidney dysfunction after allogeneic SCT in 2 cohorts of

  16. Allogeneic Peripheral Blood Stem Cell Harvest

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Allogeneic Peripheral Blood Stem Cell Harvest. Mobilization protocol. G-CSF 10 mcg/Kg / day for 5 days. Pheresis. Cobe Spectra; Haemonetics mcs+. Enumeration. CD34 counts; Cfu-GM assays.

  17. Human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Abdallah, Basem; Kassem, Moustapha

    2008-01-01

    Mesenchymal stem cells (MSC) are a group of clonogenic cells present among the bone marrow stroma and capable of multilineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. Due to their ease of isolation and their differentiation potential, MSC are being...... introduced into clinical medicine in variety of applications and through different ways of administration. Here, we discuss approaches for isolation, characterization and directing differentiation of human mesenchymal stem cells (hMSC). An update of the current clinical use of the cells is also provided....

  18. Modified Masquelet technique using allogeneic umbilical cord-derived mesenchymal stem cells for infected non-union femoral shaft fracture with a 12 cm bone defect: A case report.

    Science.gov (United States)

    Dilogo, Ismail Hadisoebroto; Primaputra, Muhammad Rizqi Adhi; Pawitan, Jeanne Adiwinata; Liem, Isabella Kurnia

    2017-01-01

    Non-union due to large bone loss often causes significant long-term morbidity. We incorporate the use of allogeneic umbilical cord-derived mesenchymal stem cells (UC-MSCs) as part of the diamond concept of regenerative medicine in a case of infected non-union fracture. We reported a 54-year-old female patient presenting with pain on the right thigh. She was previously diagnosed with a closed fracture of the right femoral shaft and underwent four surgeries before finally being referred to Dr. Cipto Mangunkusumo General Hospital with infected non-union of the right femoral shaft. The patient was treated with a combination of UC-MSCs, bone morphogenetic protein-2 (BMP-2), Hydroxyapatite (HA), and mechanical stabilization using Masquelet Technique. The combination of allogeneic MSCs, BMP2, HA, and Masquelet Technique was successful in creating new bone with no apparent side effects. Bone loss might be caused by external factors (true defects), or structural loss of the existing bone. The combination of allogeneic UC-MSCs, BMP-2, HA and an induced membrane technique pioneered by Masquelet allowed for faster regeneration process and more optimal bone healing. This paper aims to assess and compare the result of such procedures with the previous four surgeries done to the patient, which did not yield satisfactory results. The application of allogeneic UC-MSC, BMP-2, HA and Masquelet technique as proposed in the diamond concept is a viable method in treating critical-sized bone defect and provides an effective way to overcome non-union caused by large defect. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial.

    Science.gov (United States)

    Díez-Tejedor, Exuperio; Gutiérrez-Fernández, María; Martínez-Sánchez, Patricia; Rodríguez-Frutos, Berta; Ruiz-Ares, Gerardo; Lara, Manuel Lara; Gimeno, Blanca Fuentes

    2014-01-01

    Few studies have evaluated the possible beneficial effect of the administration of stem cells in the early stages of stroke. Intravenous administration of allogeneic mesenchymal stem cells (MSCs) from adipose tissue in patients with acute stroke could be a safe therapy for promoting neurovascular unit repair, consequently supporting better functional recovery. We aim to assess the safety and efficacy of MSC administration and evaluate its potential as a treatment for cerebral protection and repair. A Phase IIa, prospective, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Twenty patients presenting acute ischemic stroke will be randomized in a 1:1 proportion to treatment with allogeneic MSCs from adipose tissue or to placebo (or vehicle) administered as a single intravenous dose within the first 2 weeks after the onset of stroke symptoms. The patients will be followed up for 2 years. Primary outcomes for safety analysis: adverse events (AEs) and serious AEs; neurologic and systemic complications, and tumor development. Secondary outcomes for efficacy analysis: modified Rankin Scale; NIHSS; infarct size; and biochemical markers of brain repair (vascular endothelial growth factor, brain-derived neurotrophic factor, and matrix metalloproteinases 9). To our knowledge, this is the first, phase II, pilot clinical trial to investigate the safety and efficacy of intravenous administration of allogeneic MSCs from adipose tissue within the first 2 weeks of stroke. In addition, its results will help us define the best criteria for a future phase III study. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  20. Mesenchymal Stem Cells

    DEFF Research Database (Denmark)

    Horwood, Nicole J.; Dazzi, Francesco; Zaher, Walid

    2012-01-01

    Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth...... and differentiation of hematopoietic stem cells (HSC) and hematopoiesis. These cells have been described as important immunoregulators due to their ability to suppress T cells proliferation. MSC can also directly contribute to tissue repair by migrating to sites of injury and providing a source of cells...

  1. Allogenic banking of dental pulp stem cells for innovative therapeutics.

    Science.gov (United States)

    Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

    2015-08-26

    Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.

  2. Human bone marrow-derived mesenchymal stem cells | Nasef ...

    African Journals Online (AJOL)

    Mesenchymal stem cells (MSCs) have elicited a great clinical interest, particularly in the areas of regenerative medicine and induction of tolerance in allogeneic transplantation. Previous reports demonstrated the feasibility of transplanting MSCs, which generates new prospects in cellular therapy. Recently, injection of ...

  3. Mesenchymal Stem Cells

    DEFF Research Database (Denmark)

    Horwood, Nicole J.; Dazzi, Francesco; Zaher, Walid

    2012-01-01

    and differentiation of hematopoietic stem cells (HSC) and hematopoiesis. These cells have been described as important immunoregulators due to their ability to suppress T cells proliferation. MSC can also directly contribute to tissue repair by migrating to sites of injury and providing a source of cells......Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth...... for differentiation and/or providing bystander support for resident stromal cells. This chapter discusses the cellular and molecular properties of MSC, the mechanisms by which they can modulate immune responses and the clinical applications of MSC in disorders such as graft-versus-host disease and aplastic anaemia...

  4. Bilateral Transplantation of Allogenic Adult Human Bone Marrow-Derived Mesenchymal Stem Cells into the Subventricular Zone of Parkinson’s Disease: A Pilot Clinical Study

    Directory of Open Access Journals (Sweden)

    N. K. Venkataramana

    2012-01-01

    Full Text Available The progress of PD and its related disorders cannot be prevented with the medications available. In this study, we recruited 8 PD and 4 PD plus patients between 5 to 15 years after diagnosis. All patients received BM-MSCs bilaterally into the SVZ and were followed up for 12 months. PD patients after therapy reported a mean improvement of 17.92% during “on” and 31.21% during “off” period on the UPDRS scoring system. None of the patients increased their medication during the follow-up period. Subjectively, the patients reported clarity in speech, reduction in tremors, rigidity, and freezing attacks. The results correlated with the duration of the disease. Those patients transplanted in the early stages of the disease (less than 5 years showed more improvement and no further disease progression than the later stages (11–15 years. However, the PD plus patients did not show any change in their clinical status after stem cell transplantation. This study demonstrates the safety of adult allogenic human BM-MSCs transplanted into the SVZ of the brain and its efficacy in early-stage PD patients.

  5. Effect of Allogeneic Bone Marrow-mesenchymal Stem Cells (BM-MSCs) to Accelerate Burn Healing of Rat on the Expression of Collagen Type I and Integrin α2β1.

    Science.gov (United States)

    Revilla, Gusti; Darwin, Eryati; Yanwirasti; Rantam, Fedik A

    Burn is a public health problem, it causes physical disability even death. Treatment of burn wound has been conducted in various ways, but the satisfactory healing has not been provided. Bone marrow-derived mesenchymal stem cells (BM-MSCs) treatment is one of attempt to burn recovery, accelerate wound healing and angiogenesis. This study aimed to investigate the effect of allogeneic BM-MSC treatment on the expression of collagen type I and integrin α2β1 in burn skin tissue of rat observed on day 14. Twelve Wistar rats divided into two groups, control group (injected with phospate buffer solution) and treatment group (injected with BM-MSC). Rat was anaesthetized with xylazine and ketamine (ratio 1:1), fur of rat's back was shaved and full thickness burn was made by boiling plate in hot water for 30 min and patched on the back for 20 min. The burns were covered by tegaderm film and elastomult haft. Antalgin as an analgetic was injected to rats during observation process. Burns of rat was observed on day 14. In this study one-way analysis of variance test and Tukey as a further test were analyzed. The results showed that the healing time of allogeneic BM-MSC treatment on burn skin tissue rats was faster, the thickness of collagen type I in burn skin tissue of rats was thicker (0.977 μm) than controls (0.475 μm) and statistically demonstrated significant differences (p = 0.000). The average percentage of integrin α2β1 expression was higher (2.94%) than control group (2.34%), but the differences were not statistically significant (p = 0.176). The study concluded that BM-MSC treatment was able to accelerate the healing process of burns by increasing the thickness of the collagen and the percentage of integrin α2β1, thus accelerated the cell migration involved during wound healing.

  6. Allogeneic adipose stem cell therapy in acute myocardial infarction.

    Science.gov (United States)

    Rigol, Montserrat; Solanes, Núria; Roura, Santiago; Roqué, Mercè; Novensà, Laura; Dantas, Ana Paula; Martorell, Jaume; Sitges, Marta; Ramírez, José; Bayés-Genís, Antoni; Heras, Magda

    2014-01-01

    Stem cell therapy offers a promising approach to reduce the long-term mortality rate associated with heart failure after acute myocardial infarction (AMI). To date, in vivo translational studies have not yet fully studied the immune response to allogeneic adipose tissue-derived mesenchymal stem cells (ATMSCs). We analysed the immune response and the histological and functional effects of allogeneic ATMSCs in a porcine model of reperfused AMI and determine the effect of administration timing. Pigs that survived AMI (24/26) received intracoronary administration of culture medium after reperfusion (n = 6), ATMSCs after reperfusion (n = 6), culture medium 7 days after AMI (n = 6) or ATMSCs 7 days after AMI (n = 6). At 3-week follow-up, cardiac function, alloantibodies and histological analysis were evaluated. Administration of ATMSCs after reperfusion and 7 days after AMI resulted in similar rates of cell engraftment; some of those cells expressed endothelial, smooth muscle and cardiomyogenic cell lineage markers. Delivery of ATMSCs after reperfusion compared with that performed at 7 days was more effective in increasing: vascular density (249 ± 64 vs. 161 ± 37 vessels/mm2; P < 0.01), T lymphocytes (1 ± 0.4 vs. 0.4 ± 0.3% of area CD3(+) ; P < 0.05) and expression of vascular endothelial growth factor (VEGF; 32 ± 7% vs. 20 ± 4% of area VEGF(+) ; P < 0.01). Allogeneic ATMSC-based therapy did not change ejection fraction but generated alloantibodies. The present study is the first to demonstrate that allogeneic ATMSCs elicit an immune response and, when administered immediately after reperfusion, are more effective in increasing VEGF expression and neovascularization. © 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

  7. Allogenicity & immunogenicity in regenerative stem cell therapy.

    Science.gov (United States)

    Charron, Dominique

    2013-11-01

    The development of regenerative medicine relies in part on the capacity of stem cells to differentiate into specialized cell types and reconstitute tissues and organs. The origin of the stem cells matters. While autologous cells were initially the preferred ones the need for "off the shelf" cells is becoming prevalent. These cells will be immediately available and they originate from young non diseased individuals. However their allogenicity can be viewed as a limitation to their use. Recent works including our own show that allogenicity of stem cell can be viewed as on one hand detrimental leading to their elimination and on the other hand beneficial through a paracrine effect that can induce a local tissue regenerative effect from endogenous stem cells. Also their immune modulatory capacity can be harnessed to favor regeneration. Therefore the immune phenotype of stem cells is an important criteria to be considered before their clinical use. Immuno monitoring of the consequences of their in vivo injection needs to be taken into account. Transplantation immunology knowledge will be instrumental to enable the development of safe personalized regenerative stem cell therapy.

  8. Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

    Energy Technology Data Exchange (ETDEWEB)

    Tsuno, Hiroaki [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Yoshida, Toshiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nogami, Makiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Orthopedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Koike, Chika; Okabe, Motonori [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Noto, Zenko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Arai, Naoya; Noguchi, Makoto [Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nikaido, Toshio, E-mail: tnikaido@med.u-toyama.ac.jp [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan)

    2012-12-01

    Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAM{alpha} cells and induced to osteogenic status-their in vivo osteogenesis was subsequently investigated in rats. It was found that HAM{alpha} cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAM{alpha} cells. The expression of osteocalcin mRNA was increased in HAM{alpha} cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAM{alpha} cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: Black-Right-Pointing-Pointer Human amniotic mesenchymal cells include cells (HAM{alpha} cells) that have the properties of MSCs. Black-Right-Pointing-Pointer HAM{alpha} cells have excellent osteogenic differentiation potential. Black-Right-Pointing-Pointer Osteogenic differentiation ability of HAM{alpha} was amplified by calcium phosphate scaffolds. Black-Right-Pointing-Pointer HAM{alpha} cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

  9. Allogeneic Stem Cells Alter Gene Expression and Improve Healing of Distal Limb Wounds in Horses

    OpenAIRE

    Textor, Jamie A.; Clark, Kaitlin C.; Walker, Naomi J.; Aristizobal, Fabio A.; Kol, Amir; LeJeune, Sarah S.; Bledsoe, Andrea; Davidyan, Arik; Gray, Sarah N.; Bohannon‐Worsley, Laurie K.; Woolard, Kevin D.; Borjesson, Dori L.

    2017-01-01

    Abstract Distal extremity wounds are a significant clinical problem in horses and humans and may benefit from mesenchymal stem cell (MSC) therapy. This study evaluated the effects of direct wound treatment with allogeneic stem cells, in terms of gross, histologic, and transcriptional features of healing. Three full‐thickness cutaneous wounds were created on each distal forelimb in six healthy horses, for a total of six wounds per horse. Umbilical cord‐blood derived equine MSCs were applied to...

  10. Complications of allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Arnaout, Karim; Patel, Nihar; Jain, Maneesh; El-Amm, Joelle; Amro, Farah; Tabbara, Imad A

    2014-08-01

    Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.

  11. Human bone marrow-derived mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Lopez M

    2007-01-01

    Full Text Available Mesenchymal stem cells (MSCs have elicited a great clinical interest, particularly in the areas of regenerative medicine and induction of tolerance in allogeneic transplantation. Previous reports demonstrated the feasibility of transplanting MSCs, which generates new prospects in cellular therapy. Recently, injection of MSCs induced remission of steroid-resistant acute graft-versus-host disease (GVHD. This review summarizes the knowledge and possible future clinical uses of MSCs.

  12. Human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Aldahmash, Abdullah; Zaher, Walid; Al-Nbaheen, May

    2012-01-01

    Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self......-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number...

  13. Allogeneic amniotic membrane-derived mesenchymal stromal cell transplantation in a porcine model of chronic myocardial ischemia

    Directory of Open Access Journals (Sweden)

    Kimura M

    2012-01-01

    Full Text Available Introduction. Amniotic membrane contains a multipotential stem cell population and is expected to possess the machinery to regulate immunological reactions. We investigated the safety and efficacy of allogeneic amniotic membrane-derived mesenchymal stromal cell (AMSC transplantation in a porcine model of chronic myocardial ischemia as a preclinical trial. Methods. Porcine AMSCs were isolated from amniotic membranes obtained by cesarean section just before delivery and were cultured to increase their numbers before transplantation. Chronic myocardial ischemia was induced by implantation of an ameroid constrictor around the left circumflex coronary artery. Four weeks after ischemia induction, nine swine were assigned to undergo either allogeneic AMSC transplantation or normal saline injection. Functional analysis was performed by echocardiography, and histological examinations were carried out by immunohistochemistry 4 weeks after AMSC transplantation. Results. Echocardiography demonstrated that left ventricular ejection fraction was significantly improved and left ventricular dilatation was well attenuated 4 weeks after AMSC transplantation. Histological assessment showed a significant reduction in percentage of fibrosis in the AMSC transplantation group. Injected allogeneic green fluorescent protein (GFP-expressing AMSCs were identified in the immunocompetent host heart without the use of any immunosuppressants 4 weeks after transplantation. Immunohistochemistry revealed that GFP colocalized with cardiac troponin T and cardiac troponin I. Conclusions. We have demonstrated that allogeneic AMSC transplantation produced histological and functional improvement in the impaired myocardium in a porcine model of chronic myocardial ischemia. The transplanted allogeneic AMSCs survived without the use of any immunosuppressants and gained cardiac phenotype through either their transdifferentiation or cell fusion.

  14. Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro

    NARCIS (Netherlands)

    Vonk, Lucienne A.; van Dooremalen, Sanne F.J.; Liv, Nalan; Klumperman, Judith; Coffer, Paul J.; Saris, Daniël B.F.; Lorenowicz, Magdalena J.

    2018-01-01

    Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available. Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA. Increasing evidence suggests that therapeutic efficacy of MSC

  15. In vitro and in vivo neurogenic potential of mesenchymal stem cells ...

    Indian Academy of Sciences (India)

    Particularly, mesenchymal stem cells (MSCs) are a great tool in regenerative medicine because of their lack of tumorogenicity, immunogenicity and ability to perform immunomodulatory as well as anti-inflammatory functions. Numerous studies have investigated the role of MSCs in tissue repair and modulation of allogeneic ...

  16. Interaction between adipose tissue-derived mesenchymal stem cells and regulatory T-cells

    NARCIS (Netherlands)

    A.U. Engela (Anja); C.C. Baan (Carla); A. Peeters (Anna); W. Weimar (Willem); M.J. Hoogduijn (Martin)

    2013-01-01

    textabstractMesenchymal stem cells (MSCs) exhibit immunosuppressive capabilities, which have evoked interest in their application as cell therapy in transplant patients. So far it has been unclear whether allogeneic MSCs and host regulatory T-cells (Tregs) functionally influence each other. We

  17. Systematic Nutritional Support in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

    Science.gov (United States)

    Fuji, Shigeo; Einsele, Hermann; Savani, Bipin N; Kapp, Markus

    2015-10-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) has become an established treatment modality for various hematological diseases. However, in allogeneic HSCT, patients often suffer from severe gastrointestinal complications caused by the conditioning regimen and acute/chronic graft-versus-host disease, which requires support by multidisciplinary nutritional support teams (NST). In addition, pretransplantation nutritional status can affect the clinical outcome after allogeneic HSCT. Therefore, it is important to refer the patient to a NST when becoming aware of nutritional problems before allogeneic HSCT. It is also important to follow nutritional status over the long term, as patients often suffer from various nutritional problems, such as malnutrition and metabolic syndrome, even late after allogeneic HSCT. In summary, NST can contribute to the improvement of nutritional status and possibly prognosis at every stage before and after allogeneic HSCT. Here, we aim to give a comprehensive overview of current understanding about nutritional support in allogeneic HSCT and try to provoke a constructive discussion to stimulate further investigation. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results from a Clinical Trial for Safety and Proof-of-Concept with 7 Years of Extended Follow-Up.

    Science.gov (United States)

    Park, Yong-Beom; Ha, Chul-Won; Lee, Choong-Hee; Yoon, Young Cheol; Park, Yong-Geun

    2017-02-01

    Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Patients with Kellgren-Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell-based medicinal product (a composite of culture-expanded allogeneic hUCB-MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7-year extended follow-up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12-week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow-up. The histological findings at 1 year showed hyaline-like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment-emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell-based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees. Stem Cells Translational Medicine 2017;6:613-621. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  19. Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

    Directory of Open Access Journals (Sweden)

    Ichim Thomas E

    2010-11-01

    Full Text Available Abstract Cellular therapy for spinal cord injury (SCI is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI.

  20. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Xiaomei Chen

    Full Text Available Mesenchymal stem cells (MSCs have been broadly used experimentally in various clinical contexts. The addition of MSCs to initial steroid therapy for acute graft-versus-host disease (aGVHD may improve patient outcomes. However, investigations regarding prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD remain controversial. We thus conducted a systematic review and meta-analysis of published clinical trials to determine possible prognostic factors affecting the efficacy of MSCs in treating steroid-refractory aGVHD.Clinical trials using MSC therapy for steroid-refractory aGVHD were identified by searching PubMed and EMBASE databases. A total of 6,963 citations were reviewed, and 13 studies met the inclusion criteria. A total of 301 patients from thirteen studies were included. Of these, 136 patients showed a complete response (CR, and 69 patients displayed a partial (PR or mixed response (MR. In total, 205 patients exhibited overall response (ORR. Patients with skin steroid-refractory aGVHD showed a better clinical response than gastrointestinal (CR: odds ratio [OR] = 1.93, 95% confidence interval [95%CI]: 1.05-3.57, p < 0.05 and liver (CR: OR = 2.30, 95%CI: 1.12-4.69, p < 0.05, and ORR: OR = 2.93, 95%CI: 1.06-8.08, p < 0.05 steroid-refractory aGVHD. Those with grade II steroid-refractory aGVHD exhibited a better clinical response following MSC therapy than recipients with grade III-IV (CR: OR = 3.22, 95%CI: 1.24-8.34, p < 0.05. Completion therapy may improve the CR but reduce ORR compared with induction therapy (CR: OR = 0.20, 95%CI: 0.09-0.44, p < 0.05; ORR: OR = 2.18, 95%CI: 1.17-4.05, p = 0.01. There was also a trend towards a better clinical response in children compared with adults (CR: OR = 2.41, 95%CI: 1.01-5.73, p = 0.05.Age, skin involvement, lower aGVHD grade, and the number of infusions are the main prognostic factors affecting the efficacy of MSC therapy for steroid-refractory aGVHD.

  1. Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood‐Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results from a Clinical Trial for Safety and Proof‐of‐Concept with 7 Years of Extended Follow‐Up

    Science.gov (United States)

    Park, Yong‐Beom; Lee, Choong‐Hee; Yoon, Young Cheol; Park, Yong‐Geun

    2016-01-01

    Abstract Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood‐derived mesenchymal stem cells (hUCB‐MSCs). Patients with Kellgren‐Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell‐based medicinal product (a composite of culture‐expanded allogeneic hUCB‐MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7‐year extended follow‐up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12‐week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow‐up. The histological findings at 1 year showed hyaline‐like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment‐emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell‐based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees. Stem Cells Translational Medicine 2017;6:613–621 PMID:28191757

  2. Allogeneic stem cell transplantation for myelodysplastic syndromes: critical for cure?

    NARCIS (Netherlands)

    Witte, T.J.M. de

    2011-01-01

    Allogeneic stem cell transplantation (SCT) is the treatment of choice for young patients (age

  3. Ocular findings after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Tabbara, Khalid F; Al-Ghamdi, Ahmad; Al-Mohareb, Fahad; Ayas, Mouhab; Chaudhri, Naeem; Al-Sharif, Fahad; Al-Zahrani, Hazzaa; Mohammed, Said Y; Nassar, Amr; Aljurf, Mahmoud

    2009-09-01

    To study the incidence, causes, and outcome of major ocular complications in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Retrospective, noncomparative, observational clinical study. The study included a total of 620 patients who underwent allogeneic HSCT in the period from 1997 to 2007 at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Allogeneic HSCT. Patients with ocular complications were referred to the ophthalmology division for complete ophthalmologic examination, including visual acuity, tonometry, Schirmer test, biomicroscopy, and dilated ophthalmoscopy. Laboratory investigations were performed whenever indicated. The incidence and causes of major ocular complications after allogeneic HSCT were determined. Visual acuity at 1 year after allogeneic HSCT was recorded. Major ocular complications occurred in 80 (13%) of 620 patients who underwent allogeneic HSCT. There were 36 male patients (45%) and 44 female patients (55%) with a mean age of 29 years and an age range of 9 to 65 years. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate in 69 patients, and cyclosporine, methotrexate and corticosteroids, or mycophenolate mofetil in 11 patients. The most frequently encountered ocular complications were chronic GVHD, dry eye syndrome without GVHD, corneal ulcers, cataract, glaucoma, cytomegalovirus retinitis, fungal endophthalmitis, and acquisition of allergic conjunctivitis from atopic donors. There was no correlation between the pattern of ocular complications and the transplanted stem cell source. Best-corrected visual acuity (BCVA) at 1 year after transplantation was less than 20/200 in 13 patients (16%), less than 20/50 in 17 patients (21%), and better than 20/50 in 50 patients (63%). Ocular complications are common in patients undergoing allogeneic HSCT. Early recognition and prompt treatment are important. The author(s) have no proprietary or commercial

  4. Allogeneic split-skin grafting in stem cell transplanted patients

    DEFF Research Database (Denmark)

    Olsen, Jan Kyrre Berg; Vindeløv, Lars; Schmidt, G.

    2008-01-01

    -Hodgkin's lymphoma of the patient. Pre-BMT human leucocyte antigen (HLA)-typing had revealed identity between the donor and the recipient, who were siblings (not twins). Complete donor chimaerism was achieved. The recipient developed severe cGvHD with ichthyosis-like dryness and scleroderma. A folliculitis evolved......). Allogeneic skin grafts are known to be acutely rejected. Successful allogeneic STSG has only been reported in sporadic cases of identical twins (isotransplantation). This case is the first to demonstrate what works in theory: the immune system of a stem cell transplanted patient with 100% or mixed stable...

  5. Characteristics of mouse adipose tissue-derived stem cells and therapeutic comparisons between syngeneic and allogeneic adipose tissue-derived stem cell transplantation in experimental autoimmune thyroiditis.

    Science.gov (United States)

    Choi, Eun Wha; Shin, Il Seob; Park, So Young; Yoon, Eun Ji; Kang, Sung Keun; Ra, Jeong Chan; Hong, Sung Hwa

    2014-01-01

    Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic) or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissue-derived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations.

  6. Mesenchymal stem cells in regenerative rehabilitation.

    Science.gov (United States)

    Nurkovic, Jasmin; Dolicanin, Zana; Mustafic, Fahrudin; Mujanovic, Rifat; Memic, Mensur; Grbovic, Vesna; Skevin, Aleksandra Jurisic; Nurkovic, Selmina

    2016-06-01

    [Purpose] Regenerative medicine and rehabilitation contribute in many ways to a specific plan of care based on a patient's medical status. The intrinsic self-renewing, multipotent, regenerative, and immunosuppressive properties of mesenchymal stem cells offer great promise in the treatment of numerous autoimmune, degenerative, and graft-versus-host diseases, as well as tissue injuries. As such, mesenchymal stem cells represent a therapeutic fortune in regenerative medicine. The aim of this review is to discuss possibilities, limitations, and future clinical applications of mesenchymal stem cells. [Subjects and Methods] The authors have identified and discussed clinically and scientifically relevant articles from PubMed that have met the inclusion criteria. [Results] Direct treatment of muscle injuries, stroke, damaged peripheral nerves, and cartilage with mesenchymal stem cells has been demonstrated to be effective, with synergies seen between cellular and physical therapies. Over the past few years, several researchers, including us, have shown that there are certain limitations in the use of mesenchymal stem cells. Aging and spontaneous malignant transformation of mesenchymal stem cells significantly affect the functionality of these cells. [Conclusion] Definitive conclusions cannot be made by these studies because limited numbers of patients were included. Studies clarifying these results are expected in the near future.

  7. Allogeneic stem cell transplantation in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Natasha Ali

    2012-11-01

    Full Text Available We report a case series of 12 patients with acute myeloid leukemia who underwent allogeneic stem cell transplant with a matched related donor. Male to female ratio was 1:1. The main complication post-transplant was graft-versus-host disease (n=7 patients. Transplant-related mortality involved one patient; cause of death was multi-organ failure. After a median follow up of 36.0±11.3 months, overall survival was 16%.

  8. Therapeutic Potential of Mesenchymal Stem Cells in Regenerative Medicine

    Directory of Open Access Journals (Sweden)

    Devang M. Patel

    2013-01-01

    Full Text Available Mesenchymal stem cells (MSCs are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation into both mesenchymal and nonmesenchymal lineages. The intrinsic properties of these cells make them an attractive candidate for clinical applications. MSCs are of keen interest because they can be isolated from a small aspirate of bone marrow or adipose tissues and can be easily expanded in vitro. Moreover, their ability to modulate immune responses makes them an even more attractive candidate for regenerative medicine as allogeneic transplant of these cells is feasible without a substantial risk of immune rejection. MSCs secrete various immunomodulatory molecules which provide a regenerative microenvironment for a variety of injured tissues or organ to limit the damage and to increase self-regulated tissue regeneration. Autologous/allogeneic MSCs delivered via the bloodstream augment the titers of MSCs that are drawn to sites of tissue injury and can accelerate the tissue repair process. MSCs are currently being tested for their potential use in cell and gene therapy for a number of human debilitating diseases and genetic disorders. This paper summarizes the current clinical and nonclinical data for the use of MSCs in tissue repair and potential therapeutic role in various diseases.

  9. Mesenchymal dental stem cells in regenerative dentistry.

    Science.gov (United States)

    Rodríguez-Lozano, Francisco-Javier; Insausti, Carmen-Luisa; Iniesta, Francisca; Blanquer, Miguel; Ramírez, María-del-Carmen; Meseguer, Luis; Meseguer-Henarejos, Ana-Belén; Marín, Noemí; Martínez, Salvador; Moraleda, José-María

    2012-11-01

    In the last decade, tissue engineering is a field that has been suffering an enormous expansion in the regenerative medicine and dentistry. The use of cells as mesenchymal dental stem cells of easy access for dentist and oral surgeon, immunosuppressive properties, high proliferation and capacity to differentiate into odontoblasts, cementoblasts, osteoblasts and other cells implicated in the teeth, suppose a good perspective of future in the clinical dentistry. However, is necessary advance in the known of growth factors and signalling molecules implicated in tooth development and regeneration of different structures of teeth. Furthermore, these cells need a fabulous scaffold that facility their integration, differentiation, matrix synthesis and promote multiple specific interactions between cells. In this review, we give a brief description of tooth development and anatomy, definition and classification of stem cells, with special attention of mesenchymal stem cells, commonly used in the cellular therapy for their trasdifferentiation ability, non ethical problems and acceptable results in preliminary clinical trials. In terms of tissue engineering, we provide an overview of different types of mesenchymal stem cells that have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHEDs), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs), and stem cells from apical papilla (SCAPs), growth factors implicated in regeneration teeth and types of scaffolds for dental tissue regeneration.

  10. Circulating mesenchymal stem cells and their clinical implications

    Directory of Open Access Journals (Sweden)

    Liangliang Xu

    2014-01-01

    Full Text Available Circulating mesenchymal stem cells (MSCs is a new cell source for tissue regeneration and tissue engineering. The characteristics of circulating MSCs are similar to those of bone marrow-derived MSCs (BM-MSCs, but they exist at a very low level in healthy individuals. It has been demonstrated that MSCs are able to migrate to the sites of injury and that they have some distinct genetic profiles compared to BM-MSCs. The current review summaries the basic knowledge of circulating MSCs and their potential clinical applications, such as mobilizing the BM-MSCs into circulation for therapy. The application of MSCs to cure a broad spectrum of diseases is promising, such as spinal cord injury, cardiovascular repair, bone and cartilage repair. The current review also discusses the issues of using of allogeneic MSCs for clinical therapy.

  11. Modified Masquelet technique using allogeneic umbilical cord-derived mesenchymal stem cells for infected non-union femoral shaft fracture with a 12 cm bone defect: A case report

    Directory of Open Access Journals (Sweden)

    Ismail Hadisoebroto Dilogo

    2017-01-01

    Conclusion: The application of allogeneic UC-MSC, BMP-2, HA and Masquelet technique as proposed in the diamond concept is a viable method in treating critical-sized bone defect and provides an effective way to overcome non-union caused by large defect.

  12. Inactivated Mesenchymal Stem Cells Maintain Immunomodulatory Capacity

    NARCIS (Netherlands)

    Luk, Franka; de Witte, Samantha F. H.; Korevaar, Sander S.; Roemeling, Marieke; Franquesa, Marcella; Strini, Tanja; van den Engel, Sandra; Gargesha, Madhusudhana; Roy, Debashish; Dor, Frank J. M. F.; Horwitz, Edwin M.; de Bruin, Ron W. F.; Betjes, Michiel G. H.; Baan, Carla C.; Hoogduijn, Martin J.

    2016-01-01

    Mesenchymal stem cells (MSC) are studied as a cell therapeutic agent for treatment of various immune diseases. However, therapy with living culture-expanded cells comes with safety concerns. Furthermore, development of effective MSC immunotherapy is hampered by lack of knowledge of the mechanisms of

  13. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine.

    Science.gov (United States)

    Murphy, Matthew B; Moncivais, Kathryn; Caplan, Arnold I

    2013-11-15

    Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.

  14. Allogeneic stem cell transplantation for myelodysplastic syndromes: critical for cure?

    Science.gov (United States)

    de Witte, Theo

    2011-06-01

    Allogeneic stem cell transplantation (SCT) is the treatment of choice for young patients (age ≤ 55 years) with myelodysplastic syndromes (MDS) characterized by poor-risk or intermediate-risk cytogenetics, who have a histocompatible related or unrelated donor. For patients who lack an human leukocyte antigen-compatible donor, autologous SCT, or chemotherapy may be good alternatives for those with MDS and with good-risk cytogenetic characteristics. Iron toxicity is an underestimated cause of hematopoietic stem cell transplantation (HSCT) treatment-related mortality. The pathogenesis, diagnosis, and monitoring of iron-induced organ damage are currently topics of investigation. Prospective studies on the prevention or treatment of iron toxicity before HSCT and/or after HSCT are necessary. Copyright © 2011. Published by Elsevier Inc.

  15. Umbilical cord as a mesenchymal stem cell source for treating joint pathologies.

    Science.gov (United States)

    Arufe, Maria Carmen; De la Fuente, Alexandre; Fuentes, Isaac; Toro, Francisco Javier De; Blanco, Francisco Javier

    2011-06-18

    Articular cartilage disorders and injuries often result in life-long chronic pain and compromised quality of life. Regrettably, the regeneration of articular cartilage is a continuing challenge for biomedical research. One of the most promising therapeutic approaches is cell-based tissue engineering, which provides a healthy population of cells to the injured site but requires differentiated chondrocytes from an uninjured site. The use of healthy chondrocytes has been found to have limitations. A promising alternative cell population is mesenchymal stem cells (MSCs), known to possess excellent proliferation potential and proven capability for differentiation into chondrocytes. The "immunosuppressive" property of human MSCs makes them an important candidate for allogeneic cell therapy. The use of allogeneic MSCs to repair large defects may prove to be an alternative to current autologous and allogeneic tissue-grafting procedures. An allogeneic cell-based approach would enable MSCs to be isolated from any donor, expanded and cryopreserved in allogeneic MSC banks, providing a readily available source of progenitors for cell replacement therapy. These possibilities have spawned the current exponential growth in stem cell research in pharmaceutical and biotechnology communities. Our objective in this review is to summarize the knowledge about MSCs from umbilical cord stroma and focus mainly on their applications for joint pathologies.

  16. Mesenchymal stem cells for cartilage repair in osteoarthritis.

    Science.gov (United States)

    Gupta, Pawan K; Das, Anjan K; Chullikana, Anoop; Majumdar, Anish S

    2012-07-09

    Osteoarthritis (OA) is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extracellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived 'mesenchymal stem cells' or 'mesenchymal stromal cells', with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. BMSCs can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local microenvironment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. This review broadly describes the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.

  17. Central nervous system infection following allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Hanajiri, Ryo; Kobayashi, Takeshi; Yoshioka, Kosuke; Watanabe, Daisuke; Watakabe, Kyoko; Murata, Yutaka; Hagino, Takeshi; Seno, Yasushi; Najima, Yuho; Igarashi, Aiko; Doki, Noriko; Kakihana, Kazuhiko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2017-03-01

    Here, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years. Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection. A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10-1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n=6), enterococcus (n=2), staphylococcus (n=2), streptococcus (n=2), varicella zoster virus (n=1), cytomegalovirus (n=1), John Cunningham virus (n=1), adenovirus (n=1), and Toxoplasma gondii (n=1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p=.02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p=.04). Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  18. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

    2016-01-01

    The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

  19. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria

    Science.gov (United States)

    de Latour, Régis Peffault; Schrezenmeier, Hubert; Bacigalupo, Andrea; Blaise, Didier; de Souza, Carmino A.; Vigouroux, Stephane; Willemze, Roelf; Terriou, Louis; Tichelli, Andre; Mohty, Mohamad; de Guibert, Sophie; Marsh, Judith C.; Passweg, Jakob; Yves Mary, Jean; Socié, Gerard

    2012-01-01

    Background In the era of eculizumab, identifying patients with paroxysmal nocturnal hemoglobinuria who may benefit from allogeneic stem cell transplantation is challenging. Design and Methods We describe the characteristics and overall survival of 211 patients transplanted for paroxysmal nocturnal hemoglobinuria in 83 EBMT centers from 1978 to 2007. Next, we conducted a comparison with a cohort of 402 non-transplanted patients with paroxysmal nocturnal hemoglobinuria diagnosed between 1950 and 2005 in 92 French centers. We compared the occurrence of complications (i.e. thromboembolism and aplastic anemia) using either an individual or a stratum-matching procedure. Results After a median follow-up of 5 years, the 5-year overall survival rate ± standard error (%) was 68±3 in the transplanted group (54±7 in the case of thromboembolism, 69±5 in the case of aplastic anemia without thromboembolism and 86±6 in the case of recurrent hemolytic anemia without thromboembolism or aplastic anemia). Only thromboembolism as the indication for transplantation was associated with worse outcome (P=0.03). We identified 24 pairs of transplanted and non-transplanted patients with thromboembolism for the matched comparison, with worse overall survival for the transplanted patients (hazard ratio=10.0; 95% confidence interval, 1.3-78.1; P=0.007). This was confirmed by the global matching procedure (P=0.03). As regards aplastic anemia without thromboembolism, 30 pairs were identified for the matched comparison. It was not observed that transplanted patients had a significantly worse overall survival (hazard ratio=4.0; 95% confidence interval, 0.9-18.9; P=0.06). A global matching procedure was not feasible. Conclusions Allogeneic stem cell transplantation is probably not a suitable treatment option for life-threatening thromboembolism in paroxysmal nocturnal hemoglobinuria. PMID:22689687

  20. Assessment of the regenerative potential of allogeneic periodontal ligament stem cells in a rodent periodontal defect model.

    Science.gov (United States)

    Han, J; Menicanin, D; Marino, V; Ge, S; Mrozik, K; Gronthos, S; Bartold, P M

    2014-06-01

    The complex microenvironment of the periodontal wound creates many challenges associated with multitissue regeneration of periodontal lesions. Recent characterization of mesenchymal stem cell-like populations residing in periodontal ligament tissues has shown that these cells exhibit features of postnatal stem cells. Despite these advances, a lack of consistency in design of preclinical studies and a limited study of allogeneic transplantation applications has restricted our understanding of their clinical utility in the treatment of periodontal disease. The aim of this study was to assess the regenerative potential of allogeneic periodontal ligament stem cells (PDLSCs) in a rat periodontal fenestration defect mode and to identify an optimal end time-point suitable for quantitative assessment of tissue regeneration. Periodontal fenestration defects, created in Sprague Dawley rats, were treated with allogeneic PDLSCs seeded onto Gelfoam(®) (Absorbable gelatin sponge; Pharmacia Corporation, Kalamazoo, MI, USA) or with Gelfoam(®) alone, or remained untreated. Experimental rats were killed at 7, 14, 21 or 28 d after surgery and the tissues were processed for immunohistochemical and histomorphometric examination. Defects treated with PDLSCs showed significantly greater percentage bone fill and length of new bone bridge compared with the untreated group or the group treated with Gelfoam(®) alone on days 14 and 21. Similarly, a statistically significant difference was achieved within specimens retrieved on day 21 for analysis of regeneration of cementum/periodontal ligament (PDL)-like structures. The present investigation shows that allogeneic PDLSCs have a marked ability to repair periodontal defects by forming bone, PDL and cementum-like tissue in vivo. The results suggest that treatment periods of 14 and 21 d are optimal end time-points for quantitative assessment of periodontal regeneration within the rodent fenestration-defect model utilized in the present study

  1. Mesenchymal Stem Cells for the Treatment of Skin Diseases

    Directory of Open Access Journals (Sweden)

    Toshio Hasegawa

    2017-08-01

    Full Text Available Mesenchymal stem cell (MSC-based therapy involving both autologous and allogeneic MSCs shows great promise in treating several conditions. MSCs promote wound healing, and can differentiate into multiple cell lineages, including keratinocytes. Therefore, MSCs can be used for the treatment of congenital or acquired skin defects. Because of their immunomodulatory properties, MSCs may be useful for the treatment of inflammatory and autoimmune skin diseases. In particular, MSCs might be effective for the treatment of large vitiligo lesions as immunosuppressant or cultured grafts. MSCs can also be a novel cell source for regenerating hair in the treatment of scarring alopecia and androgenic alopecia. MSCs might also be an effective treatment for alopecia areata, which is associated with autoimmunity. Stem cell therapies with topical administration of MSCs and bone marrow transplantation were shown to alleviate recessive dystrophic epidermolysis bullosa in both animal models and human subjects. In addition to cell transplantation, the mobilization of endogenous MSCs has been attempted for skin regeneration. Overall, this review highlights the great potential of MSCs for the treatment of skin diseases in the near future.

  2. Mesenchymal stem cells induce dermal fibroblast responses to injury

    International Nuclear Information System (INIS)

    Smith, Andria N.; Willis, Elise; Chan, Vincent T.; Muffley, Lara A.; Isik, F. Frank; Gibran, Nicole S.; Hocking, Anne M.

    2010-01-01

    Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.

  3. Differential effect of conditioning regimens on cytokine responses during allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Andersen, J; Heilmann, C; Jacobsen, N

    2006-01-01

    The purpose of this study was to characterize cytokine responses during conditioning in patients undergoing allogeneic stem cell transplantation (SCT) with the aim to identify which markers that may reliably reflect inflammatory activity during conditioning. We investigated inflammatory and anti...

  4. ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Worel, Nina

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for a variety of malignant and non-malignant hematological and congenital diseases. Due to the fact that the human leukocyte antigen system is inherited independently of the blood group system, approximately 40-50% of all HSCTs are performed across the ABO blood group barrier. The expected immune-hematological consequences after transplantation of an ABO-mismatched stem cell graft are immediate and delayed hemolytic complications due to presence of isohemagglutinins or passenger lymphocyte syndrome. The risks of these complications can partially be prevented by graft manipulation and appropriate transfusion support. Dependent on the kind of ABO mismatch, different effects on engraftment have been observed, e.g. delayed red blood cell recovery and pure red cell aplasia. Data on incidence of acute graft-versus-host disease (GVHD), non-relapse mortality, relapse, and overall survival are inconsistent as most studies include limited patient numbers, various graft sources, and different conditioning and GVHD prophylaxis regimens. This makes it difficult to detect a consistent effect of ABO-mismatched transplantation in the literature. However, knowledge of expectable complications and close monitoring of patients helps to detect problems early and to treat patients efficiently, thus reducing the number of fatal or life-threatening events caused by ABO-mismatched HSCT.

  5. SIGNALING PATHWAYS ASSOCIATED WITH VX EXPOSURE IN MESENCHYMAL STEM CELLS

    Science.gov (United States)

    2017-09-01

    administrative support. iv  Blank v  CONTENTS 1. INTRODUCTION...M.J.; Cheng, A.; Genever, P.G. Functional Nicotinic and Muscarinic Receptors on Mesenchymal Stem Cells. Stem Cells Dev. 2009, 18, 103–112. 12

  6. Mesenchymal Stem Cells as a Potent Cell Source for Bone Regeneration

    Directory of Open Access Journals (Sweden)

    Elham Zomorodian

    2012-01-01

    Full Text Available While small bone defects heal spontaneously, large bone defects need surgical intervention for bone transplantation. Autologous bone grafts are the best and safest strategy for bone repair. An alternative method is to use allogenic bone graft. Both methods have limitations, particularly when bone defects are of a critical size. In these cases, bone constructs created by tissue engineering technologies are of utmost importance. Cells are one main component in the manufacture of bone construct. A few cell types, including embryonic stem cells (ESCs, adult osteoblast, and adult stem cells, can be used for this purpose. Mesenchymal stem cells (MSCs, as adult stem cells, possess characteristics that make them good candidate for bone repair. This paper discusses different aspects of MSCs that render them an appropriate cell type for clinical use to promote bone regeneration.

  7. Functionality testing of stem cell grafts to predict infectious complications after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Nilsson, J; Granrot, I; Mattsson, J; Omazic, B; Uhlin, M; Thunberg, S

    2017-07-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a routine clinical procedure performed to treat patients with haematological malignancies, primary immune deficiencies or metabolic disorders. Infections during lymphopenia after allogeneic HSCT are associated with high mortality and morbidity. Typical infectious agents are Epstein-Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus and fungi. The study aim was to evaluate whether measurement of the responses of antigen-specific T-cells, recognizing infectious pathogens would correlate to protective functions in the stem cell recipient post-transplant. Twenty-one grafts were analysed by flow cytometry and cells were stimulated in vitro with relevant infectious antigens, followed by evaluation of T-cell proliferation and cytokine production. Results were compared to the recipients' clinical records 1-year post-transplantation. We show that an extensive repertoire of transferred antigen-specific T-cells from allogeneic donor grafts against infectious agents, involved in post-transplant infections, are linked to an absence of infectious complications for the recipient up-to 1-year post-transplant. The protective effect was associated with antigen-specific T-cell proliferation and IL-1β secretion. Our results suggest that assaying T-cell function before HSCT could determine individual risks for infectious complications and thus aid in clinical decision-making regarding prophylactic and pre-emptive anti-infective therapy. © 2017 International Society of Blood Transfusion.

  8. T cell reconstitution in allogeneic haematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kielsen, K; Jordan, K K; Uhlving, H H

    2015-01-01

    Infections and acute graft-versus-host disease (aGVHD) are major causes of treatment-related mortality and morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). Both complications depend on reconstitution of the T-lymphocyte population based on donor T cells. Although...... it is well established that Interleukin-7 (IL-7) is a cytokine essential for de novo T cell development in the thymus and homoeostatic peripheral expansion of T cells, associations between circulating levels of IL-7 and T cell reconstitution following HSCT have not been investigated previously. We...... in patients treated with anti-thymocyte globulin (ATG) compared with those not treated with ATG (P = 0.0079). IL-7 levels at day +7 were negatively associated with T cell counts at day +30 to +60 (at day +60: CD3(+) : β = -10.6 × 10(6) cells/l, P = 0.0030; CD8(+) : β = -8.4 × 10(6) cells/l, P = 0.061; CD4...

  9. Mesenchymal stem cells for cartilage regeneration in osteoarthritis.

    Science.gov (United States)

    Kristjánsson, Baldur; Honsawek, Sittisak

    2017-09-18

    Osteoarthritis (OA) is a slowly progressive disease where cartilage of the synovial joint degenerates. It is most common in the elderly where patients experience pain and reduce physical activity. In combination with lack of conventional treatment, patients are often left with no other choices than arthroplasty. Over the last years, multipotent stromal cells have been used in efforts to treat OA. Mesenchymal stem/progenitor cells (MSCs) are stromal cells that can differentiate into bone, fat, and cartilage cells. They reside within bone marrow and fat. MSCs can also be found in synovial joints where they affect the progression of OA. They can be isolated and proliferated in an incubator before being applied in clinical trials. When it comes to treatment, emphasis has hitherto been on autologous MSCs, but allogenic cells from healthy donors are emerging as another source of the cells. The first adaptations of MSCs revolved in the use of cell-rich matrix, delivered as invasive surgical procedure, which resulted in production of hyaline cartilage and fibrocartilage. However, the demand for less invasive delivery of cells has prompted the use of direct intra-articular injections, wherein a large amount of suspended cells are implanted in the cartilage defect.

  10. Activation and Differentiation of Mesenchymal Stem Cells.

    Science.gov (United States)

    Mishra, Pravin J; Banerjee, Debabrata

    2017-01-01

    Mesenchymal stem cells (MSCs) are multipotent cells and exhibit two main characteristics that define stem cells: self-renewal and differentiation. MSCs can migrate to sites of injury, inflammation, and tumor. Moreover, MSCs undergo myofibroblast like differentiation, including increased production of α-SMA in response to transforming growth factor-β (TGF-β), a growth factor commonly secreted by tumor cells to evade immune surveillance. Based on our previous finding hMSCs become activated and resemble carcinoma-associated myofibroblasts upon prolonged exposure to conditioned medium from MDAMB231 human breast cancer cells. Here, we show that keratinocyte conditioned medium (KCM) induces differentiation of MSCs to resemble dermal myofibroblast like cells using immunofluorescence techniques demonstrating punctate vinculin staining, and F-actin filaments.

  11. Viability of mesenchymal stem cells during electrospinning

    Directory of Open Access Journals (Sweden)

    G. Zanatta

    2012-02-01

    Full Text Available Tissue engineering is a technique by which a live tissue can be re-constructed and one of its main goals is to associate cells with biomaterials. Electrospinning is a technique that facilitates the production of nanofibers and is commonly used to develop fibrous scaffolds to be used in tissue engineering. In the present study, a different approach for cell incorporation into fibrous scaffolds was tested. Mesenchymal stem cells were extracted from the wall of the umbilical cord and mononuclear cells from umbilical cord blood. Cells were re-suspended in a 10% polyvinyl alcohol solution and subjected to electrospinning for 30 min under a voltage of 21 kV. Cell viability was assessed before and after the procedure by exclusion of dead cells using trypan blue staining. Fiber diameter was observed by scanning electron microscopy and the presence of cells within the scaffolds was analyzed by confocal laser scanning microscopy. After electrospinning, the viability of mesenchymal stem cells was reduced from 88 to 19.6% and the viability of mononuclear cells from 99 to 8.38%. The loss of viability was possibly due to the high viscosity of the polymer solution, which reduced the access to nutrients associated with electric and mechanical stress during electrospinning. These results suggest that the incorporation of cells during fiber formation by electrospinning is a viable process that needs more investigation in order to find ways to protect cells from damage.

  12. Allogeneic Stem Cells Alter Gene Expression and Improve Healing of Distal Limb Wounds in Horses

    Science.gov (United States)

    Textor, Jamie A.; Clark, Kaitlin C.; Walker, Naomi J.; Aristizobal, Fabio A.; Kol, Amir; LeJeune, Sarah S.; Bledsoe, Andrea; Davidyan, Arik; Gray, Sarah N.; Bohannon‐Worsley, Laurie K.; Woolard, Kevin D.

    2017-01-01

    Abstract Distal extremity wounds are a significant clinical problem in horses and humans and may benefit from mesenchymal stem cell (MSC) therapy. This study evaluated the effects of direct wound treatment with allogeneic stem cells, in terms of gross, histologic, and transcriptional features of healing. Three full‐thickness cutaneous wounds were created on each distal forelimb in six healthy horses, for a total of six wounds per horse. Umbilical cord‐blood derived equine MSCs were applied to each wound 1 day after wound creation, in one of four forms: (a) normoxic‐ or (b) hypoxic‐preconditioned cells injected into wound margins, or (c) normoxic‐ or (d) hypoxic‐preconditioned cells embedded in an autologous fibrin gel and applied topically to the wound bed. Controls were one blank (saline) injected wound and one blank fibrin gel‐treated wound per horse. Data were collected weekly for 6 weeks and included wound surface area, thermography, gene expression, and histologic scoring. Results indicated that MSC treatment by either delivery method was safe and improved histologic outcomes and wound area. Hypoxic‐preconditioning did not offer an advantage. MSC treatment by injection resulted in statistically significant increases in transforming growth factor beta and cyclooxygenase‐2 expression at week 1. Histologically, significantly more MSC‐treated wounds were categorized as pro‐healing than pro‐inflammatory. Wound area was significantly affected by treatment: MSC‐injected wounds were consistently smaller than gel‐treated or control wounds. In conclusion, MSC therapy shows promise for distal extremity wounds in horses, particularly when applied by direct injection into the wound margin. stem cells translational medicine 2018;7:98–108 PMID:29063737

  13. Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: a concise review.

    Science.gov (United States)

    Vonk, Lucienne A; de Windt, Tommy S; Slaper-Cortenbach, Ineke C M; Saris, Daniël B F

    2015-05-15

    The evolution of articular cartilage repair procedures has resulted in a variety of cell-based therapies that use both autologous and allogeneic mesenchymal stromal cells (MSCs). As these cells are increasingly available and show promising results both in vitro and in vivo, cell-based strategies, which aim to improve ease of use and cost-effectiveness, are progressively explored. The use of MSCs in cartilage repair makes it possible to develop single-stage cell-based therapies. However, true single-stage procedures rely on one intervention, which will limit cell sources to fraction concentrates containing autologous MSCs or culture-expanded allogeneic MSCs. So far, it seems both autologous and allogeneic cells can safely be applied, but clinical studies are still ongoing and little information on clinical outcome is available. Further development of cell-based therapies may lead to clinical-grade, standardized, off-the-shelf products with easy handling for orthopedic surgeons. Although as of yet no preclinical or clinical studies are ongoing which explore the use of induced pluripotent stem cells for cartilage repair, a good manufacturing practice-grade induced pluripotent stem cell line might become the basis for such a product in the future, providing that cell fate can be controlled. The use of stem cells in clinical trials brings along new ethical issues, such as proper controls and selecting primary outcome measures. More clinical trials are needed to estimate detailed risk-benefit ratios and trials must be carefully designed to minimize risks and burdens for patients while choosing outcome measures that allow for adequate comparison with results from similar trials. In this review, we discuss the different aspects of new stem cell-based treatments, including safety and ethical issues, as well as provide an overview of current clinical trials exploring these approaches and future perspectives.

  14. Lymph node tuberculosis after allogeneic haematopoietic stem cell transplantation: an atypical presentation of an uncommon complication.

    Science.gov (United States)

    Martín-Sánchez, Guillermo; Drake-Pérez, Marta; Rodriguez, José Luis; Yañez, Lucrecia; Insunza, Andrés; Richard, Carlos

    2015-01-01

    Mycobacterium tuberculosis infections are uncommon complications in the haematopoietic stem cell post-transplant period. Most cases are reactivations of latent infections affecting the lung. We present an atypical case of isolated lymph node tuberculosis after an allogeneic haematopoietic stem cell transplantation, which highlights the importance of having a high suspicion index, even in non-endemic countries.

  15. Allogeneic stem cell transplantation for thalassemia major in India

    Directory of Open Access Journals (Sweden)

    Vikram Mathews

    2017-12-01

    Full Text Available Allogeneic stem cell transplantation (allo-SCT is the only currently available curative treatment for thalassemia major. Since it was first done in 1981, several thousand patients have benefited from it and it is now possible to offer this treatment in different parts of the world with good results. With better risk stratification and supportive care, the results of allo-SCT are now very good even in high risk patients who have significant iron overload related organ dysfunction. The improvements have mainly been in the conditioning strategies with less toxic myeloablation and management of the complications of SCT. However, several challenges remain. Transplant related complications still cause significant morbidity and mortality. There is data to show that the results of transplantation as best if done in well transfused and chelated patients <7 years of age. As only a third of the patients will have a matched related donor, there is need for investigating SCT with alternative donors. Experience with SCT for thalassemia major from matched unrelated donors or haplo-identical donors is still limited but needs further exploration. Adequate management needs to be provided post-SCT for all pre-existing complications particularly iron chelation to prevent further organ dysfunction. Systematic follow-up is needed to measure long term outcomes. The biggest challenges in India are the cost of this treatment and access to centres capable of providing this treatment. With greater support from the government, health insurance and philanthropic programs, there has been a rapid increase in the number of SCTs for thalassemia major in India. The number centres providing this treatment are also increasing making this curative treatment more widely available in India.

  16. Potential clinical applications of adult human mesenchymal stem cell (Prochymal® therapy

    Directory of Open Access Journals (Sweden)

    Patel AN

    2011-11-01

    Full Text Available Amit N Patel, Jorge GenoveseUniversity of Utah School of Medicine, Salt Lake City, UT, USAAbstract: In vitro, in vivo animal, and human clinical data show a broad field of application for mesenchymal stem cells (MSCs. There is overwhelming evidence of the usefulness of MSCs in regenerative medicine, tissue engineering, and immune therapy. At present, there are a significant number of clinical trials exploring the use of MSCs for the treatment of various diseases, including myocardial infarction and stroke, in which oxygen suppression causes widespread cell death, and others with clear involvement of the immune system, such as graft-versus-host disease, Crohn's disease, and diabetes. With no less impact, MSCs have been used as cell therapy to treat defects in bone and cartilage and to help in wound healing, or in combination with biomaterials in tissue engineering development. Among the MSCs, allogeneic MSCs have been associated with a regenerative capacity due to their unique immune modulatory properties. Their immunosuppressive capability without evidence of immunosuppressive toxicity at a global level define their application in the treatment of diseases with a pathogenesis involving uncontrolled activity of the immune system. Until now, the limitation in the number of totally characterized autologous MSCs available represents a major obstacle to their use for adult stem cell therapy. The use of premanufactured allogeneic MSCs from controlled donors under optimal conditions and their application in highly standardized clinical trials would lead to a better understanding of their real applications and reduce the time to clinical translation.Keywords: regeneration, immunomodulation, tissue engineering, allogeneic, mesenchymal stem cells

  17. Mesenchymal stem cell therapy for nonmusculoskeletal diseases: emerging applications.

    Science.gov (United States)

    Kuo, Tom K; Ho, Jennifer H; Lee, Oscar K

    2009-01-01

    Mesenchymal stem cells are stem/progenitor cells originated from the mesoderm and can different into multiple cell types of the musculoskeletal system. The vast differentiation potential and the relative ease for culture expansion have established mesenchymal stem cells as the building blocks in cell therapy and tissue engineering applications for a variety of musculoskeletal diseases, including repair of fractures and bone defects, cartilage regeneration, treatment of osteonecrosis of the femoral head, and correction of genetic diseases such as osteogenesis imperfect. However, research in the past decade has revealed differentiation potentials of mesenchymal stem cells beyond lineages of the mesoderm, suggesting broader applications than originally perceived. In this article, we review the recent developments in mesenchymal stem cell research with respect to their emerging properties and applications in nonmusculoskeletal diseases.

  18. Characterization and therapeutic application of canine adipose mesenchymal stem cells to treat elbow osteoarthritis.

    Science.gov (United States)

    Kriston-Pál, Éva; Czibula, Ágnes; Gyuris, Zoltán; Balka, Gyula; Seregi, Antal; Sükösd, Farkas; Süth, Miklós; Kiss-Tóth, Endre; Haracska, Lajos; Uher, Ferenc; Monostori, Éva

    2017-01-01

    Visceral adipose tissue (AT) obtained from surgical waste during routine ovariectomies was used as a source for isolating canine mesenchymal stem cells (MSCs). As determined by cytofluorimetry, passage 2 cells expressed MSC markers CD44 and CD90 and were negative for lineage-specific markers CD34 and CD45. The cells differentiated toward osteogenic, adipogenic, and chondrogenic directions. With therapeutic aims, 30 dogs (39 joints) suffering from elbow dysplasia (ED) and osteoarthritis (OA) were intra-articularly transplanted with allogeneic MSCs suspended in 0.5% hyaluronic acid (HA). A highly significant improvement was achieved without any medication as demonstrated by the degree of lameness during the follow-up period of 1 y. Control arthroscopy of 1 transplanted dog indicated that the cartilage had regenerated. Histological analysis of the cartilage biopsy confirmed that the regenerated cartilage was of hyaline type. These results demonstrate that transplantation of allogeneic adipose tissue-derived mesenchymal stem cells (AT-MSCs) is a novel, noninvasive, and highly effective therapeutic tool in treating canine elbow dysplasia.

  19. Mesenchymal stem cells in multiple sclerosis - translation to clinical trials.

    Science.gov (United States)

    Dulamea, A

    2015-01-01

    Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterized by an aberrant activation of the immune system and combining demyelination with neurodegeneration. Studies on experimental models of multiple sclerosis revealed immunomodulatory and immunosuppressive properties of mesenchymal stem cells. Clinical trials using mesenchymal stem cells therapy in multiple sclerosis patients showed tolerability, safety on short term, some immunomodulatory properties reducing the Th1 proinflammatory response and the inflammatory MRI parameters. The author reviews the data about experimental studies and clinical trials using mesenchymal stem cells for the treatment of multiple sclerosis.

  20. Analysis of the results of allogeneic hematopoietic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair

    Directory of Open Access Journals (Sweden)

    Ye. V. Kuzmich

    2015-01-01

    Full Text Available HLA matching of the donor / recipient pair is a major factor associated with the outcome of allogeneic stem cell transplantation. In the presentstudy we analyzed the risk of severe acute graft-versus-host disease, graft failure, 2.year overall survival of the patients after allogeneic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair.

  1. Mesenchymal Stem Cells: Angels or Demons?

    Directory of Open Access Journals (Sweden)

    Rebecca S. Y. Wong

    2011-01-01

    Full Text Available Mesenchymal stem cells (MSCs have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment.

  2. Treatment of osteoarthritis with mesenchymal stem cells.

    Science.gov (United States)

    Wang, Wen; Cao, Wei

    2014-06-01

    Osteoarthritis (OA) is one of the most prevalent joint diseases with prominent symptoms affecting the daily life of millions of middle aged and elderly people. Despite this, there are no successful medical interventions that can prevent the progressive destruction of OA joints. The onset of pathological changes in OA is associated with deviant activity of mesenchymal stem cells (MSCs), the multipotent precursors of connective tissue cells that reside in joints. Current therapies for OA have resulted in poor clinical outcomes without repairing the damaged cartilage. Intra-articular delivery of culture-expanded MSCs has opened new avenues of OA treatment. Pre-clinical and clinical trials demonstrated the feasibility, safety, and efficacy of MSC therapy. The Wnt/β-catenin, bone morphogenetic protein 2, Indian hedgehog, and Mitogen-activated protein kinase signaling pathways have been demonstrated to be involved in OA and the mechanism of action of MSC therapies.

  3. Mesenchymal stem cell therapy for laryngotracheal stenosis

    DEFF Research Database (Denmark)

    Jakobsen, Kathrine Kronberg; Grønhøj, Christian; Jensen, David H

    2017-01-01

    studies addressing the effect of MSC therapy on the airway. We assessed effect on inflammation, fibrosis, and MSC as a component in tissue engineering for treating defects in the airway. RESULTS: We identified eleven studies (n = 256 animals) from eight countries evaluating the effect of MSCs......BACKGROUND: Laryngotracheal stenosis (LTS) can be either congenital or acquired. Laryngeal stenosis is most often encountered after prolonged intubation. The mechanism for stenosis following intubation is believed to be hypertrophic scarring. Mesenchymal stem cells (MSCs) therapy has shown...... promising results in regenerative medicine. We aimed to systematically review the literature on MSC therapy for stenosis of the conductive airways. METHODS: PubMed, EMBASE, Google Scholar and the Cochrane Library were systematically searched from January 1980-January 2017 with the purpose of identifying all...

  4. Receptor control in mesenchymal stem cell engineering

    Science.gov (United States)

    Dalby, Matthew J.; García, Andrés J.; Salmeron-Sanchez, Manuel

    2018-03-01

    Materials science offers a powerful tool to control mesenchymal stem cell (MSC) growth and differentiation into functional phenotypes. A complex interplay between the extracellular matrix and growth factors guides MSC phenotypes in vivo. In this Review, we discuss materials-based bioengineering approaches to direct MSC fate in vitro and in vivo, mimicking cell-matrix-growth factor crosstalk. We first scrutinize MSC-matrix interactions and how the properties of a material can be tailored to support MSC growth and differentiation in vitro, with an emphasis on MSC self-renewal mechanisms. We then highlight important growth factor signalling pathways and investigate various materials-based strategies for growth factor presentation and delivery. Integrin-growth factor crosstalk in the context of MSC engineering is introduced, and bioinspired material designs with the potential to control the MSC niche phenotype are considered. Finally, we summarize important milestones on the road to MSC engineering for regenerative medicine.

  5. Effects of Hypoxia and Chitosan on Equine Umbilical Cord-Derived Mesenchymal Stem Cells

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    D. J. Griffon

    2016-01-01

    Full Text Available Chitosan opens new perspectives in regenerative medicine as it enhances the properties of mesenchymal stem cells (MSCs through formation of spheroids. Hypoxia has also been proposed to enhance stemness and survival of MSCs after in vivo implantation. These characteristics are relevant to the development of an off-the-shelf source of allogenic cells for regenerative therapy of tendinopathies. Umbilical cord-derived MSCs (UCM-MSCs offer an abundant source of immature and immunoprivileged stem cells. In this study, equine UCM-MSCs (eqUCM-MSCs conditioned for 3 and 7 days on chitosan films at 5% oxygen were compared to eqUCM-MSCs under standard conditions. Equine UCM-MSCs formed spheroids on chitosan but yielded 72% less DNA than standard eqUCM-MSCs. Expression of Sox2, Oct4, and Nanog was 4 to 10 times greater in conditioned cells at day 7. Fluorescence-labeled cells cultured for 7 days under standard conditions or on chitosan films under hypoxia were compared in a bilateral patellar tendon defect model in rats. Fluorescence was present in all treated tendons, but the modulus of elasticity under tension was greater in tendons treated with conditioned cells. Chitosan and hypoxia affected cell yield but improved the stemness of eqUCM-MSCs and their contribution to the healing of tissues. Given the abundance of allogenic cells, these properties are highly relevant to clinical applications and outweigh the negative impact on cell proliferation.

  6. Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

    Directory of Open Access Journals (Sweden)

    Bart eVaes

    2012-11-01

    Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

  7. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    DEFF Research Database (Denmark)

    Nicolini, Franck Emmanuel; Basak, Grzegorz W; Soverini, Simona

    2011-01-01

    T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow......) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL(T315I) mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors....

  8. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission

    DEFF Research Database (Denmark)

    Nagler, Arnon; Rocha, Vanderson; Labopin, Myriam

    2013-01-01

    Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable bioavailabil......Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable...

  9. A Prospective, Randomized, Masked and Placebo-Controlled Efficacy Study of Intraarticular Allogeneic Adipose Stem Cells for the Treatment of Osteoarthritis in Dogs

    Directory of Open Access Journals (Sweden)

    Robert J Harman

    2016-09-01

    Full Text Available Osteoarthritis (OA is a degenerative joint disease with a high prevalence in dogs. Mesenchymal stem cells have been used to treat humans, dogs, and horses with OA. This report describes a prospective, randomized, blinded, and placebo-controlled clinical efficacy study of intraarticular allogeneic adipose stem cells for the treatment of dogs with osteoarthritis. Health assessments and measurements of pain and activity impairment were performed at baseline and at selected time points through day 60. The primary outcome variable was the owner Client-Specific Outcome Measurement (CSOM and secondary measures included veterinary pain on manipulation, veterinary global score, and owner global score. The dogs were treated with either a saline placebo or a single dose of allogeneic adipose-derived mesenchymal stem cells in either one or two joints. Seventy-four dogs were statistically analyzed for efficacy outcomes. Success in the primary outcome variable, CSOM, was statistically improved in the treated dogs compared to the placebo dogs (79.2% versus 55.4%, p=0.029. The veterinary pain on manipulation score (92.8% versus 50.2%, p=0.017 and the veterinary global score (86.9% versus 30.8%, p= 0.009 were both statistically improved in treated dogs compared to placebo. There was no detected significant difference between treated and placebo dogs in the incidence of adverse events or negative health findings. Allogeneic adipose-derived stem cell treatment was shown to be efficacious compared to placebo. This large study of dogs also provides valuable animal clinical safety and efficacy outcome data to our colleagues developing human stem cell therapy.

  10. Glucocorticoids induce autophagy in rat bone marrow mesenchymal stem cells

    DEFF Research Database (Denmark)

    Wang, L.; Fan, J.; Lin, Y. S.

    2015-01-01

    and their responses to diverse stimuli, however, the role of autophagy in glucocorticoidinduced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy...

  11. Labeling and Imaging Mesenchymal Stem Cells with Quantum Dots

    Science.gov (United States)

    Mesenchymal stem cells (MSCs) are multipotent cells with the potential to differentiate into bone, cartilage, adipose and muscle cells. Adult derived MSCs are being actively investigated because of their potential to be utilized for therapeutic cell-based transplantation. Methods...

  12. Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation

    Science.gov (United States)

    2012-02-01

    10-1-0927 TITLE: Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation...immunosuppression. Bone Marrow Derived Mesenchymal stem cells (BM-MSCs) are pluripotent cells, capable of differentiation along multiple mesenchymal lineages into...As part of implemented transition from University of Pittsburgh to Johns Hopkins University, we optimized our mesenchymal stem cell (MSC) isolation

  13. Mesenchymal stem cells in synovial fluid increase after meniscus injury.

    Science.gov (United States)

    Matsukura, Yu; Muneta, Takeshi; Tsuji, Kunikazu; Koga, Hideyuki; Sekiya, Ichiro

    2014-05-01

    Although relatively uncommon, spontaneous healing from a meniscus injury has been observed even within the avascular area. This may be the result of the existence of mesenchymal stem cells in synovial fluid. The purpose of this study was to investigate whether mesenchymal stem cells existed in the synovial fluid of the knee after meniscus injury. Synovial fluid was obtained from the knees of 22 patients with meniscus injury just before meniscus surgery and from 8 volunteers who had no history of knee injury. The cellular fraction of the synovial fluid was cultured for 14 days followed by analysis for multilineage potential and presentation of surface antigens characteristic of mesenchymal stem cells. Colony-forming efficiency and proliferation potential were also compared between the two groups. Cells with characteristics of mesenchymal stem cells were observed in the synovial fluid of injured knees to a much greater degree than in uninjured knees. The colony-forming cells derived from the synovial fluid of the knee with meniscus injury had multipotentiality and surface epitopes identical to mesenchymal stem cells. The average number of colony formation, obtained from 1 mL of synovial fluid, in meniscus-injured knees was 250, higher than that from healthy volunteers, which was 0.5 (p < 0.001). Total colony number per synovial fluid volume was positively correlated with the postinjury period (r = 0.77, p < 0.001). Mesenchymal stem cells were found to exist in synovial fluid from knees after meniscus injury. Mesenchymal stem cells were present in higher numbers in synovial fluid with meniscus injury than in normal knees. Total colony number per synovial fluid volume was positively correlated with the postinjury period. Our current human study and previous animal studies suggest the possibility that mesenchymal stem cells in synovial fluid increase after meniscus injury contributing to spontaneous meniscus healing.

  14. Retrospective analysis of fluoroquinolone prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Simondsen, Katherine A; Reed, Michael P; Mably, Mary S; Zhang, Yang; Longo, Walter L

    2013-12-01

    Patients undergoing allogeneic hematopoietic stem cell transplant are at a high risk for infection-related mortality in the immediate post-transplantation phase. Prophylaxis with a fluoroquinolone is now recommended to reduce this risk with the stipulation that surveillance for increased fluoroquinolone resistance Clostridium difficile associated diarrhea be conducted. We conducted a retrospective chart review of 48 patients who underwent an allogeneic hematopoietic stem cell transplant and received a fluoroquinolone for prophylaxis and 48 patients who underwent an allogeneic hematopoietic stem cell transplant who did not receive a fluoroquinolone for prophylaxis. All patients received the same standard antifungal, antiviral and anti-pneumocystis prophylaxis. Patients receiving fluoroquinolone prophylaxis had a lower incidence of febrile neutropenia than those not receiving prophylaxis, though the difference was not found to be statistically significant (83% vs. 67%, p = 0.098). Similar non-significant improvements in the number of positive cultures recovered during an episode of febrile neutropenia and antimicrobial days were noted. No significant increase in fluoroquinolone resistance, Clostridium difficile associated diarrhea, or in methicillin resistant Staphylococcus aureus infections were noted. Our single institution experience with fluoroquinolone prophylaxis for allogeneic hematopoietic stem cell transplant patients supports continuation of this practice. Expansion to autologous hematopoietic stem cell transplant patients may be appropriate based on guideline recommendations and our institution-specific experience with fluoroquinolone prophylaxis.

  15. Application of mesenchymal stem cells in paediatrics

    Directory of Open Access Journals (Sweden)

    Wawryk-Gawda Ewelina

    2017-09-01

    Full Text Available Mesenchymal stem cells (MSC were described by Friedenstein in the 1970s as being a group of bone marrow non-hematopoietic cells that are the source of fibroblasts. Since then, knowledge about the therapeutic potential of MSCs has significantly increased. MSCs are currently used for the treatment of many diseases, both in adults and children. MSCs are used successfully in the case of autoimmune diseases, including rheumatic diseases, diabetes mellitus type 1, gastroenterological and neurological diseases. Moreover, treatment of such organ disorders as damage or hypoxia through application of MSC therapy has shown to be satisfactory. In addition, there are some types of congenital disorders, including osteogenesis imperfecta and Spinal Muscular Atrophy, that may be treated with cellular therapy. Most studies showed no other adverse effects than fever. Our study is an analysis that particularly focuses on the registered trials and results of MSCs application to under 18 patients with acute, chronic, recurrent, resistance and corticosteroids types of Graft-versus-Host Disease (GvHD. Stem cells currently play an important role in the treatment of many diseases. Long-term studies conducted on animals have shown that cell therapy is both effective and safe. The number of indications for use of these cells in the course of treatment of people is constantly increasing. The results of subsequent studies provide important data justifying the application of MSCs in the course of treatment of many diseases whose treatment is ineffective when utilizing other approaches.

  16. Mesenchymal Stem Cells: Application for Immunomodulation and Tissue Repair

    DEFF Research Database (Denmark)

    Horwood, Nicole J.; Dazzi, Francesco; Zaher, Walid

    2012-01-01

    Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth and diffe......Mesenchymal stem cells (MSC) are stem cell populations present among the bone marrow stroma and a number of other tissues that are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. MSC provide supportive stroma for growth...

  17. Defining human mesenchymal stem cell efficacy in vivo

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    Lennon Donald P

    2010-10-01

    Full Text Available Abstract Allogeneic human mesenchymal stem cells (hMSCs can suppress graft versus host disease (GvHD and have profound anti-inflammatory and regenerative capacity in stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of disease. There is significant clinical hMSC variability in efficacy and the ultimate response in vivo. The challenge in hMSC based therapy is defining the efficacy of hMSC in vivo. Models which may provide insight into hMSC bioactivity in vivo would provide a means to distinguish hMSCs for clinical utility. hMSC function has been described as both regenerative and trophic through the production of bioactive factors. The regenerative component involves the multi-potentiality of hMSC progenitor differentiation. The secreted factors generated by the hMSCs are milieu and injury specific providing unique niches for responses in vivo. These bioactive factors are anti-scarring, angiogenic, anti-apoptotic as well as regenerative. Further, from an immunological standpoint, hMSC's can avoid host immune response, providing xenographic applications. To study the in vivo immuno-regulatory effectiveness of hMSCs, we used the ovalbumin challenge model of acute asthma. This is a quick 3 week in vivo pulmonary inflammation model with readily accessible ways of measuring effectiveness of hMSCs. Our data show that there is a direct correlation between the traditional ceramic cube score to hMSCs attenuation of cellular recruitment due to ovalbumin challenge. The results from these studies verify the in vivo immuno-modulator effectiveness of hMSCs and support the potential use of the ovalbumin model as an in vivo model of hMSC potency and efficacy. Our data also support future directions toward exploring hMSCs as an alternative therapeutic for the treatment of airway inflammation associated with asthma.

  18. Autologous Mesenchymal Stem Cells in Chronic Stroke

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    Ashu Bhasin

    2011-12-01

    Full Text Available Background: Cell transplantation is a ‘hype and hope’ in the current scenario. It is in the early stage of development with promises to restore function in chronic diseases. Mesenchymal stem cell (MSC transplantation in stroke patients has shown significant improvement by reducing clinical and functional deficits. They are feasible and multipotent and have homing characteristics. This study evaluates the safety, feasibility and efficacy of autologous MSC transplantation in patients with chronic stroke using clinical scores and functional imaging (blood oxygen level-dependent and diffusion tensor imaging techniques. Methods: Twelve chronic stroke patients were recruited; inclusion criteria were stroke lasting 3 months to 1 year, motor strength of hand muscles of at least 2, and NIHSS of 4–15, and patients had to be conscious and able to comprehend. Fugl Meyer (FM, modified Barthel index (mBI, MRC, Ashworth tone grade scale scores and functional imaging scans were assessed at baseline, and after 8 and 24 weeks. Bone marrow was aspirated under aseptic conditions and expansion of MSC took 3 weeks with animal serum-free media (Stem Pro SFM. Six patients were administered a mean of 50–60 × 106 cells i.v. followed by 8 weeks of physiotherapy. Six patients served as controls. This was a non-randomized experimental controlled trial. Results: Clinical and radiological scanning was normal for the stem cell group patients. There was no mortality or cell-related adverse reaction. The laboratory tests on days 1, 3, 5 and 7 were also normal in the MSC group till the last follow-up. The FM and mBI showed a modest increase in the stem cell group compared to controls. There was an increased number of cluster activation of Brodmann areas BA 4 and BA 6 after stem cell infusion compared to controls, indicating neural plasticity. Conclusion: MSC therapy aiming to restore function in stroke is safe and feasible. Further randomized controlled trials are needed

  19. Reduction of acute rejection by bone marrow mesenchymal stem cells during rat small bowel transplantation.

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    Yang Yang

    Full Text Available Bone marrow mesenchymal stem cells (BMMSCs have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats.Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control, isogeneically transplanted rats (BN-BN and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg cells were assessed at each time point.Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF-α, and interferon (IFN-γ while upregulating IL-10 and transforming growth factor (TGF-β expression and increasing Treg levels.BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation.

  20. Allogeneic hematopoietic stem cell transplantation as immunotherapy : B lymphocytes versus leukemia

    NARCIS (Netherlands)

    Gillissen, M.A.

    2018-01-01

    Research described in this thesis focuses on the role of B lymphocytes in graft versus leukemia responses following allogeneic hematopoietic stem cell transplantation (HSCT) as treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Acute myeloid leukemia (AML) and high-risk

  1. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation

    Science.gov (United States)

    Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-r...

  2. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Jordan, Karina; Pontoppidan, Peter; Uhlving, Hilde Hylland

    2017-01-01

    Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immun...

  3. Unrelated allogeneic stem-cell transplantation in adult patients – 10-year experience

    Directory of Open Access Journals (Sweden)

    Jožef Pretnar

    2012-12-01

    Conclusion: Unrelated allogeneic stem-cell transplantation is suitable for acute myeloblastic leukemias with unfavorable risk factors. However, results in acute lymphoblastic leukemia are worse. Unrelated transplantation is not efficient as salvage treatment for patients with recurrent disease after autologous transplantation or chemotherapy- resistant relapse.

  4. Physiological problems in patients undergoing autologous and allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Sevgisun Kapucu

    2014-01-01

    Full Text Available Objective: Stem cell transplantation is usually performed in an effort to extend the patient′s life span and to improve their quality of life. This study was conducted to determine the postoperative physiological effects experienced by patients who had undergone autologous and allogeneic stem cell transplantation. Methods: The research is a descriptive study conducted with a sample of 60 patients at Stem Cell Transplantation Units in Ankara. Percentile calculation and chi-square tests were used to evaluate the data. Results: When a comparison was made between patients who had undergone allogeneic Hematopoietic stem cell transplantation (HSCT and those who had undergone autologous HSCT, results indicated that problems occurred more often for the allogeneic HSCT patients. The problems included: Digestion (94.3%, dermatological (76.7%, cardiac and respiratory (66.7%, neurological (66.7%, eye (56.7%, infections (26.7% and Graft Versus Host Disease (5 patients. Furthermore, the problems with pain (50%, numbness and tingling (40%, and speech disorders (3 patients were observed more often in autologous BMT patients. Conclusion: Autologous and allogeneic patients experienced most of physical problems due to they receive high doses of chemotherapy. Therefore, it is recommended that an interdisciplinary support team approach should be usedtohelp reduce and manage the problems that may arise during patient care.

  5. Nutritional risk in allogeneic stem cell transplantation: rationale for a tailored nutritional pathway.

    Science.gov (United States)

    Aoyama, Takashi; Imataki, Osamu; Mori, Keita; Yoshitsugu, Kanako; Fukaya, Masafumi; Okamura, Ikue; Enami, Terukazu; Tatara, Raine; Ikeda, Takashi

    2017-04-01

    Hematopoietic stem cell transplantation carries nutrition-related risks. Therefore, nutritional therapy needs to be initiated before transplantation even takes place. We assessed nutritional risk among patients who underwent allogeneic stem cell transplantation. We assessed nutrient supply (calorie supply and protein supply) by chart review. Assessments were made from the pretreatment phase of transplantation to after the end of parenteral nutrition in 51 patients who underwent allogeneic stem cell transplantation at Shizuoka Cancer Center between 2007 and 2012. We compared nutrition-related adverse events and parameters between two groups: those in whom % loss of body weight was ≥7.5 and those in whom % loss of body weight was stem cell transplantation to ameliorate body weight loss associated with nutrition-related adverse events.

  6. Allogeneic hematopoietic stem cell transplantations in acute lymphoblastic leukemia in children and adolescents

    OpenAIRE

    Styczyński, Jan; Dębski, Robert; Krenska, Anna; Czyżewski, Krzysztof; Dembna, Ewa; Irga, Ninela; Szalewska, Magdalena; Adamkiewicz-Drożyńska, Elżbieta; Płonowski, Marcin; Leszczyńska, Elżbieta; Krawczuk-Rybak, Maryna; Żyromska, Agnieszka; Drzewiecka, Barbara; Majewska, Karolina; Windorbska, Wiesława

    2012-01-01

    Background. ALL is the most common indication for allogeneic hematopoietic stem cell transplantation (allo- HSCT) in children. Objective. The analysis of results of therapy in children and adolescents treated for ALL with allo-HSCT. Patients and methods. A total number of 41 patients undergoing allo-HSCT due to ALL between 2003 and 2012. In 17 patients HSCT was performed from related donor and in 24 from unrelated donor. A source of hematopoietic stem cells was peripheral blood in 21 patients...

  7. Telomere stability and telomerase in mesenchymal stem cells

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Graakjaer, Jesper; Kølvrå, Steen

    2008-01-01

    Telomeres are repetitive genetic material that cap and thereby protect the ends of chromosomes. Each time a cell divides, telomeres get shorter. Telomere length is mainly maintained by telomerase. This enzyme is present in high concentrations in the embryonic stem cells and in fast growing...... embryonic cells, and declines with age. It is still unclear to what extent there is telomerase in adult stem cells, but since these are the founder cells of cells of all the tissues in the body, understanding the telomere dynamics and expression of telomerase in adult stem cells is very important....... In the present communication we focus on telomere expression and telomere length in stem cells, with a special focus on mesenchymal stem cells. We consider different mechanisms by which stem cells can maintain telomeres and also focus on the dynamics of telomere length in mesenchymal stem cells, both the overall...

  8. Mesenchymal Stem Cells in Tissue Repair

    Directory of Open Access Journals (Sweden)

    Amy M DiMarino

    2013-09-01

    Full Text Available The advent of mesenchymal stem cell (MSC based therapies for clinical therapeutics has been an exciting and new innovation for the treatment of a variety of diseases associated with inflammation, tissue damage and subsequent regeneration and repair. Application-based ability to measure MSC potency and fate of the cells post-MSC therapy are the variables that confound the use of MSCs therapeutics in human diseases. An evaluation of MSC function and applications with attention to detail in the preparation as well as quality control (QC and quality assurance (QA are only as good as the assays that are developed. In vivo measures of efficacy and potency require an appreciation of the overall pathophysiology of the model and standardization of outcome measures. The new concepts of how MSC’s participate in the tissue regeneration and wound repair process and further, how this is impacted by estimates of efficacy and potency Are important new topics. In this regard,,, this chapter will review some of the in vitro and in vivo assays for MSC function and activity and their application to the clinical arena.

  9. Chemokine Receptor Signatures in Allogeneic Stem Cell Transplantation

    Science.gov (United States)

    2015-08-01

    is a potentially effective strategy to reduce graft-versus-host disease (GVHD) after allogeneic HSCT without compromising the graft-versus-leukemia...to review data, to discuss ongoing experiments and for didactic sessions. I participated in weekly meetings and other scientific activities by the...institutional trial that tests novel strategies in GvHD prevention (BMT-CTN 1203). During the 2nd year of the award this multi-center clinical trial

  10. Mesenchymal stem cells: biological characteristics and potential clinical applications

    DEFF Research Database (Denmark)

    Kassem, Moustapha

    2004-01-01

    Mesenchymal stem cells (MSC) are clonogenic, non-hematpoietic stem cells present in the bone marrow and are able to differentiate into multiple mesoderm-type cell lineages, for example, osteoblasts, chondrocytes, endothelial-cells and also non-mesoderm-type lineages, for example, neuronal...

  11. Mesenchymal stem cells: cell biology and potential use in therapy

    DEFF Research Database (Denmark)

    Kassem, Moustapha; Kristiansen, Malthe; Abdallah, Basem M

    2004-01-01

    Mesenchymal stem cells are clonogenic, non-haematopoietic stem cells present in the bone marrow and are able to differentiate into multiple mesoderm-type cell lineages e.g. osteoblasts, chondrocytes, endothelial-cells and also non-mesoderm-type lineages e.g. neuronal-like cells. Several methods...

  12. [Differentiation of mesenchymal stem cells of adipose tissue].

    Science.gov (United States)

    Salyutin, R V; Zapohlska, K M; Palyanytsya, S S; Sirman, V M; Sokolov, M F

    2015-03-01

    Experimental investigation were conducted with the objective to determine a stem cells, capacity to differentiate in adipogenic direction, if they were obtained from adipose tissue. The investigation results have witnessed, that the cells, obtained from adipose tissue, are capable for a tissue-speciphic differentiation in osteogenic, chondrogenic, and, principally--in adipogenic direction, what confirms a multypotent nature of mesenchymal stem cells of adipose tissue. Adipose tissue constitutes an alternative to the bone marrow, as a source of multipotent mesenchymal stem cells, which may be applied in further investigations, concerning determination of their defense possibility for the transplanted autologous adipose tissue from the tissue resorption, made in a lipophiling way.

  13. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies.

    Science.gov (United States)

    Liu, Jun; Zhong, Jiang F; Zhang, Xi; Zhang, Cheng

    2017-01-31

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the cornerstone in treatment of hematological malignancies. However, relapse of the hematological disease after allo-HSCT remains a challenge and is associated with poor long-term survival. Chimeric antigen receptor redirected T cells (CAR-T cells) can lead to disease remission in patients with relapsed/refractory hematological malignancies. However, the therapeutic window for infusion of CAR-T cells post allo-HSCT and its efficacy are debatable. In this review, we first discuss the use of CAR-T cells for relapsed cases after allo-HSCT. We then review the toxicities and the occurrence of graft-versus-host disease in relapsed patients who received CAR-T cells post allo-HSCT. Finally, we review clinical trial registrations and the therapeutic time window for infusion of CAR-T cells post allo-HSCT. The treatment of allogeneic CAR-T cells is beneficial for patients with relapsed B cell malignancies after allo-HSCT with low toxicities and complications. However, multicenter clinical trials with larger sample sizes should be performed to select the optimal therapeutic window and confirm its efficacy.

  14. Immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells.

    Science.gov (United States)

    Zhang, Hao; Tao, Yanling; Liu, Haihui; Ren, Saisai; Zhang, Bin; Chen, Hu

    2017-07-01

    Bone marrow derived mesenchymal stem cells (MSCs) play a critical role in immune modulation. However, immunomodulatory function of whole human umbilical cord derived mesenchymal stem cells (UC-MSCs) remains unclear. In this study, UC-MSCs were separated from whole umbilical cord using a single enzyme digestion. UC-MSCs (CD73 + , CD90 + , CD105 + , and CD34 - , CD45 - , HLA-DR - ) were differentiated into adipocytes, osteocytes and chondrocytes in vitro under specific stimulatory environments. UC-MSCs suppressed umbilical cord blood lymphocyte proliferation stimulated by mitogen, and ELISA showed that the secretion of INF-γ was downregulated, and the secretion of IL-4 was upregulated, with CD8 + T cells markedly decreased and CD4 + T cells changed lightly. Moreover, the infusion of UC-MSCs in recipient mice transplanted with donor bone marrow cells ameliorated acute graft-versus host disease (aGVHD) and extended survival. In conclusion, UC-MSCs might negatively modulate immunoreactions, and have application potential in the treatment of aGVHD caused by allogeneic stem cells transplantation. Copyright © 2017. Published by Elsevier Ltd.

  15. Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT.

    Science.gov (United States)

    Konuma, Takaaki; Ooi, Jun; Takahashi, Satoshi; Tomonari, Akira; Tsukada, Nobuhiro; Kato, Seiko; Sato, Aki; Monma, Fumihiko; Kasahara, Senji; Uchimaru, Kaoru; Iseki, Tohru; Tojo, Arinobu; Asano, Shigetaka

    2009-06-01

    There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100mg/m(2) and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT.

  16. Kaposi Sarcoma After Allogeneic Hematopoietic Stem Cell Transplant: A Rare Complication.

    Science.gov (United States)

    Ramzi, Mani; Vojdani, Reza; Haghighinejad, Hourvash

    2018-01-02

    Kaposi sarcoma is a multicentric angioproliferative neoplasm of lymphatic endothelium-derived cells. Although this malignancy is relatively frequent after solid-organ transplant, it is extremely rare after bone marrow transplantation. Allogeneic stem cell transplantation is associated with severe prolonged immunosuppression; however, a few cases of Kaposi sarcoma after hematopoietic stem cell transplant were previously reported. Here, we report a case of Kaposi sarcoma after haploidentical allogeneic hematopoietic stem cell transplant. The patient was a known case of acute myelogenous leukemia and underwent transplant after relapse. Four months posttransplant, she presented with 3 dark blue or purplish small nodules on her face above the upper lip. Histopathologic study confirmed Kaposi sarcoma. Serum antibody against human herpes virus type 8 was positive. After discontinuation of immunosuppressive medication and cryotherapy for local control, Kaposi sarcoma skin nodules healed with residual pigmented skin lesions. The patient is currently in complete remission for Kaposi sarcoma and cured from acute myelogenous leukemia 36 months after stem cell transplant. Only 14 cases of Kaposi sarcoma after hematopoietic cell transplant have been previously reported in the literature (11 after allogeneic and 3 after autologous hematopoietic stem cell transplant). According to our knowledge from literature review, this case is the first report of Kaposi sarcoma after a haploidentical HLA match transplant.

  17. Allogeneic adipose-derived stem cells promote survival of fat grafts in immunocompetent diabetic rats.

    Science.gov (United States)

    Zhang, Jun; Bai, Xiaozhi; Zhao, Bin; Wang, Yunchuan; Su, Linlin; Chang, Peng; Wang, Xujie; Han, Shichao; Gao, Jianxin; Hu, Xiaolong; Hu, Dahai; Liu, Xiaoyan

    2016-05-01

    Autologous adipose-derived stem cells (ADSCs) can protect fat grafts in cell-assisted lipotransfer (CAL). However, diabetes alters the intrinsic properties of ADSCs and impairs their function so that they lack these protective effects. We investigate whether allogeneic ADSCs from healthy donors could protect fat grafts in immunocompetent diabetic rats. Syngeniec adipose tissues and ADSCs were derived from diabetic Lewis (LEW) rats, whereas allogeneic ADSCs were from healthy brown-Norway rats. A grafted mixture containing 0.7 ml granule fat and 0.3 ml 6 × 10(6) allogeneic/syngeneic ADSCs was injected subcutaneously on the skulls of diabetic LEW rats. Fat samples were harvested to evaluate the levels of injury and vascularization as shown by perilipin A, CD34 and VEGF at 14 days. The immune response was evaluated with a lymphocytotoxicity test and the CD4/CD8 ratio in peripheral blood at 14 days. The volume retention of fat grafts was measured at 3 months. Healthy allogeneic ADSCs increased the expression levels of perilipin A, CD34 and VEGF at 14 days. The volume retention of fat grafts was improved by allogeneic ADSCs at 3 months. ADSCs were demonstrated to have low immunogenicity by the lymphocyte proliferation test and immunophenotype including MHC and co-stimulatory markers. The lymphocytotoxicity test and CD4/CD8 ratio indicated no obvious immune response elicited by allogeneic ADSCs. Thus, healthy allogeneic ADSCs can promote the survival of fat grafts in this immunocompetent diabetic rat model, with little or no obvious immune rejection.

  18. Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Whangbo, J; Ritz, J; Bhatt, A

    2017-02-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota.

  19. The effects of allogenic stem cells in a murine model of hind limb diabetic ischemic tissue

    Directory of Open Access Journals (Sweden)

    Jesús Álvarez García

    2017-08-01

    Full Text Available Background Diabetes is one of the major risk factors for peripheral arterial disease. In patients in whom surgery cannot be performed, cell therapy may be an alternative treatment. Since time is crucial for these patients, we propose the use of allogenic mesenchymal cells. Methods We obtained mesenchymal cells derived from the fat tissue of a healthy Sprague-Dawley rat. Previous diabetic induction with streptozotocin in 40 male Sprague-Dawley rats, ligation plus left iliac and femoral artery sections were performed as a previously described model of ischemia. After 10 days of follow-up, macroscopic and histo-pathological analysis was performed to evaluate angiogenic and inflammatory parameters in the repair of the injured limb. All samples were evaluated by the same blind researcher. Statistical analysis was performed using the SPSS v.11.5 program (P < 0.05. Results Seventy percent of the rats treated with streptozotocin met the criteria for diabetes. Macroscopically, cell-treated rats presented better general and lower ischemic clinical status, and histologically, a better trend towards angiogenesis, greater infiltration of type 2 macrophages and a shortening of the inflammatory process. However, only the inflammatory variables were statistically significant. No immunological reaction was observed with the use of allogeneic cells. Discussion The application of allogeneic ASCs in a hind limb ischemic model in diabetic animals shows no rejection reactions and a reduction in inflammatory parameters in favor of better repair of damaged tissue. These results are consistent with other lines of research in allogeneic cell therapy. This approach might be a safe, effective treatment option that makes it feasible to avoid the time involved in the process of isolation, expansion and production of the use of autologous cells.

  20. Allogeneic hematopoietic stem cell transplantation for Chediak-Higashi syndrome.

    Science.gov (United States)

    Umeda, Katsutsugu; Adachi, Souichi; Horikoshi, Yasuo; Imai, Kohsuke; Terui, Kiminori; Endo, Mikiya; Mitsui, Tetsuo; Kato, Keisuke; Koh, Katsuyoshi; Kajiwara, Ryosuke; Ito, Rieko; Otsuka, Yoshitoshi; Inoue, Masami; Ishii, Eiichi; Yabe, Hiromasa

    2016-03-01

    The clinical outcome of allogeneic HSCT was retrospectively analyzed in eight patients with CHS. In total, six of these eight patients are alive. Four of five patients transplanted with MAC achieved prompt engraftment, and three of the four patients, including two patients with AP before transplant, are alive without disease. In contrast, three patients transplanted with RIC without active AP disease achieved prompt engraftment and survive long term. RIC-HSCT might be an alternative treatment for CHS similar to other types of HLH, at least for patients without active AP disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials.

    Science.gov (United States)

    Wang, Li-Tzu; Ting, Chiao-Hsuan; Yen, Men-Luh; Liu, Ko-Jiunn; Sytwu, Huey-Kang; Wu, Kenneth K; Yen, B Linju

    2016-11-04

    Human mesenchymal stem cells (MSCs) are multilineage somatic progenitor/stem cells that have been shown to possess immunomodulatory properties in recent years. Initially met with much skepticism, MSC immunomodulation has now been well reproduced across tissue sources and species to be clinically relevant. This has opened up the use of these versatile cells for application as 3rd party/allogeneic use in cell replacement/tissue regeneration, as well as for immune- and inflammation-mediated disease entities. Most surprisingly, use of MSCs for in immune-/inflammation-mediated diseases appears to yield more efficacy than for regenerative medicine, since engraftment of the exogenous cell does not appear necessary. In this review, we focus on this non-traditional clinical use of a tissue-specific stem cell, and highlight important findings and trends in this exciting area of stem cell therapy.

  2. Mesenchymal stem cell-mediated functional tooth regeneration in swine.

    Directory of Open Access Journals (Sweden)

    Wataru Sonoyama

    2006-12-01

    Full Text Available Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla. Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

  3. Specific Factors Influence the Success of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Thissiane L. Gonçalves

    2009-01-01

    Full Text Available Successful hematopoietic stem cell transplantation (HSCT, both autologous and allogeneic, requires a rapid and durable engraftment, with neutrophil (>500/µL and platelet (>20,000/µL reconstitution. Factors influencing engraftment after autologous or allogeneic HSCT were investigated in 65 patients: 25 autologous peripheral stem cell transplantation (PBSCT and 40 allogeneic bone marrow transplantation (BMT patients. The major factor affecting engraftment was the graft source for HSCT. Neutrophil and platelet recovery were more rapid in autologous PBSCT than in allogeneic BMT [neutrophil occurring in median on day 10.00 (09.00/11.00 and 19.00 (16.00/23.00 and platelet on day 11.00 (10.00/13.00 and 21.00 (18.00/25.00, respectively; p < 0.0001]. The type of disease also affected engraftment, where multiple myeloma (MM and lymphoma showed faster engraftment when compared with leukemia, syndrome myelodysplastic (SMD and aplastic anemia (AA and MM presented the best overall survival (OS in a period of 12 months. Other factors included the drug used in the conditioning regimen (CR, where CBV, melphalan (M-200 and FluCy showed faster engraftment and M-200 presented the best OS, in a period of 12 months and age, where 50–59 years demonstrated faster engraftment. Sex did not influence neutrophil and platelet recovery.

  4. Some aspects of allogeneic stem cell transplantation in patients with myelodysplastic syndrome: advances and controversy

    Directory of Open Access Journals (Sweden)

    Blau O

    2014-12-01

    Full Text Available Olga Blau, Igor Wolfgang Blau Department of Hematology, Oncology and Tumor Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany Abstract: Myelodysplastic syndrome (MDS is a heterogeneous group of myeloid disorders. MDS remains a disease of elderly patients; moreover, the incidence of high risk MDS is proportionally greater in elderly patients, with increased frequency of secondary acute myeloid leukemia, as well as adverse cytogenetic abnormalities. Allogeneic stem cell transplantation is a therapeutic approach with known curative potential for patients with MDS that allows the achievement of long-term disease control. Numerous controversies still exist regarding transplantation in MDS: timing of transplantation, disease status at transplantation and comorbidity, conditioning intensity, pretransplant therapy, and stem cell source. Various transplant modalities of different intensities and alternative donor sources are now in use. Current advances in transplant technology are allowing the consideration of older patients. This should result in a greater number of older patients benefiting from this potentially curative treatment modality. Despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reduced early mortality, transplant numbers in MDS patients have significantly increased. Moreover, recent new developments with innovative drugs, including hypomethylating agents, have extended the therapeutic alternatives for MDS patients. Hypomethylating agents allow the delay of allogeneic stem cell transplantation by serving as an effective and well-tolerated means to reduce disease burden. Keywords: myelodysplastic syndrome, allogeneic stem cell transplantation, reduced-intensity conditioning

  5. Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer

    Directory of Open Access Journals (Sweden)

    Yue Cao

    2017-01-01

    Full Text Available Mesenchymal stem cells (MSCs, an ideal cell source for regenerative therapy with no ethical issues, play an important role in diabetic foot ulcer (DFU. Growing evidence has demonstrated that MSCs transplantation can accelerate wound closure, ameliorate clinical parameters, and avoid amputation. In this review, we clarify the mechanism of preclinical studies, as well as safety and efficacy of clinical trials in the treatment of DFU. Bone marrow-derived mesenchymal stem cells (BM-MSCs, compared with MSCs derived from other tissues, may be a suitable cell type that can provide easy, effective, and cost-efficient transplantation to treat DFU and protect patients from amputation.

  6. Microencapsulation of Hepatocytes and Mesenchymal Stem Cells for Therapeutic Applications.

    Science.gov (United States)

    Meier, Raphael P H; Montanari, Elisa; Morel, Philippe; Pimenta, Joël; Schuurman, Henk-Jan; Wandrey, Christine; Gerber-Lemaire, Sandrine; Mahou, Redouan; Bühler, Leo H

    2017-01-01

    Encapsulated hepatocyte transplantation and encapsulated mesenchymal stem cell transplantation are newly developed potential treatments for acute and chronic liver diseases, respectively. Cells are microencapsulated in biocompatible semipermeable alginate-based hydrogels. Microspheres protect cells against antibodies and immune cells, while allowing nutrients, small/medium size proteins and drugs to diffuse inside and outside the polymer matrix. Microencapsulated cells are assessed in vitro and designed for experimental transplantation and for future clinical applications.Here, we describe the protocol for microencapsulation of hepatocytes and mesenchymal stem cells within hybrid poly(ethylene glycol)-alginate hydrogels.

  7. Age-related characteristics of multipotent human nasal inferior turbinate-derived mesenchymal stem cells.

    Directory of Open Access Journals (Sweden)

    Se Hwan Hwang

    Full Text Available BACKGROUND AND OBJECTIVES: Multipotent mesenchymal stem cells (MSCs represent a promising cell-based therapy for a number of degenerative conditions. Understanding the effect of aging on MSCs is crucial for both autologous therapy development and allogenic donors in older subjects whom degenerative diseases typically afflict. In this study, we investigated the influence of donor age on the characteristics, proliferation, and differentiation potential of in vitro cultures of multipotent human turbinated mesenchymal stem cells (hTMSCs from patients of various age groups. SUBJECTS AND METHODS: Twelve patients comprised the four age groups: (I 60 years. Inferior turbinate tissues were discarded from patients undergoing partial turbinectomy. After isolating hTMSCs, the expression of the hTMSC surface markers CD14, CD19, CD34, CD73, CD90, CD105, and HLA-DR was assessed by FACS analysis, and cell proliferation was assessed using a cell counting kit (CCK-8. The differentiation potential of hTMSCs was evaluated in osteogenic media by histology and determination of osteoblastic gene expression. RESULTS: FACS analysis revealed that hTMSCs were negative for CD14, CD19, CD34, and HLA-DR, and positive for CD73, CD90, and CD105, representing a characteristic MSC phenotype, and showed no significant differences among the age groups. Cellular proliferation and osteogenic differentiation potential of hTMSCs also showed no significant differences among the age groups. CONCLUSIONS: We conclude that donor age does not affect the characteristics, proliferation, and osteogenic differentiation potential of hTMSCs. Donor age may be excluded as a criterion in the guidelines for clinical use of the autologous or allogenic transplantation of hTMSCs.

  8. Stem cell factor supports migration in canine mesenchymal stem cells.

    Science.gov (United States)

    Enciso, Nathaly; Ostronoff, Luciana L K; Mejías, Guillermo; León, Leticia G; Fermín, María Luisa; Merino, Elena; Fragio, Cristina; Avedillo, Luis; Tejero, Concepción

    2018-03-01

    Adult Mesenchymal Stem Cells (MSC) are cells that can be defined as multipotent cells able to differentiate into diverse lineages, under appropriate conditions. These cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Initially discovered in bone marrow, MSC can now be isolated from a wide spectrum of adult and foetal tissues. Studies to evaluate the therapeutic potential of these cells are based on their ability to arrive to damaged tissues. In this paper we have done a comparative study analyzing proliferation, surface markers and OCT4, SOX9, RUNX2, PPARG genes expression in MSC cells from Bone marrow (BMMSC) and Adipose tissue (ASC). We also analyzed the role of Stem Cell Factor (SCF) on MSC proliferation and on ASCs metalloproteinases MMP-2, MMP-9 secretion. Healthy dogs were used as BMMSC donors, and ASC were collected from omentum during elective ovariohysterectomy surgery. Both cell types were cultured in IMDM medium with or without SCF, 10% Dog Serum (DS), and incubated at 38 °C with 5% CO2. Growth of BMMSCs and ASCs was exponential until 25-30 days. Flow citometry of MSCs revealed positive results for CD90 and negative for CD34, CD45 and MCH-II. Genes were evaluated by RT-PCR and metalloproteinases by zymografy. Our findings indicate morphological and immunological similarities as well as expression of genes from both origins on analyzed cells. Furthermore, SCF did not affect proliferation of MSCs, however it up-regulated MMP-2 and MMP-9 secretion in ASCs. These results suggest that metalloproteinases are possibly essential molecules pivoting migration.

  9. [Virus infection in children after allogenic stem cell transplantation ].

    Science.gov (United States)

    Rybka, Katarzyna; Turkiewicz, Dominik

    2003-01-01

    Allogenic hematopoietic cell transplantation (alloHCT) is the treatment of choice for various pediatric malignancies and nonmalignant diseases. The most prominent complication of allotransplantation is graft vs host disease (GvHD). The treatment of GvHD influence negatively function of immune system and increase risk of bacterial, fungal and viral infections. Clinical symptoms of viral infection may mimic GvHD and lead to inappropriate treatment. Human cytomegalovirus (CMV, Herpesviridae) has been recognized as most important viral pathogen after alloHCT. Increasing number of procedures, especially from alternative donors, requiring more intensive immunosuppression, led to identification more viral pathogens causing transplant related mortality and morbidity. Among them are adenoviruses (ADV, Adenoviridae), BK and JC viruses (Papovaviridae) and human herpes virus 6 (HHV-6, Herpesviridae). Frequency of complications caused by those pathogens is higher in children then in adults.

  10. Lichen striatus occurring after allogenic peripheral blood stem cell transplantation in an adult with aplastic anemia.

    Science.gov (United States)

    Mun, Je-Ho; Park, Hyun-Je; Kim, Hoon-Soo; Kim, Su-Han; Ko, Hyun-Chang; Kim, Byung-Soo; Kim, Moon-Bum

    2012-02-01

    Lichens striatus (LS) is an acquired, self-limiting inflammatory dermatosis that follows the lines of Blaschko. The etiology of the eruption is unknown, but several theories have been proposed with focus on environmental factors, viral infection, cutaneous injury, hypersensitivity, and genetic predisposition. We describe a 19-year-old woman who developed a unilateral linear eruption 17 months after allogenic peripheral blood stem cell transplantation. Histopathology revealed features, which were consistent with LS. To the best of our knowledge, our patient is the first case describing the appearance of LS occurring after allogenic stem cell transplantation. We speculate that this condition represents an unusual form of localized, chronic graft-versus-host disease.

  11. Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review.

    Science.gov (United States)

    Pollack, Seth M; O'Connor, Thomas P; Hashash, Jana; Tabbara, Imad A

    2009-12-01

    Allogeneic hematopoietic stem cell transplantation provides many patients, with hematological and malignant diseases, hope of remission and in some cases cure. Because the toxicities of this approach are severe, its use has been limited to younger healthier patients. Nonmyeloablative and reduced intensity conditioning regimens depend more on donor cellular immune effects and less on the cytotoxic effects of the conditioning regimen to eradicate the underlying disease. This approach is based on the induction of host tolerance to donor cells followed by the administration of scheduled donor T-lymphocytes infusions. Accumulated clinical data have been encouraging, and prospective studies are underway to compare this approach to conventional myeloablative allogeneic stem cell transplantation with regard to outcome, durability of responses, effects on the immune system, and the consequences of late complications such as chronic graft-versus-host disease.

  12. Single-centre experience of allogeneic haemopoietic stem cell ...

    African Journals Online (AJOL)

    There were 31 sibling matched peripheral-blood stem cell (PBSC) transplants and 1 maternal haploidentical PBSC transplant. Stem cells were mobilised from bone marrow into peripheral blood by administering granulocyte-colony stimulating factor to donors. PBSCs were harvested by apheresis. Eight patients received ...

  13. Combination cell therapy with mesenchymal stem cells and neural stem cells for brain stroke in rats.

    Science.gov (United States)

    Hosseini, Seyed Mojtaba; Farahmandnia, Mohammad; Razi, Zahra; Delavari, Somayeh; Shakibajahromi, Benafsheh; Sarvestani, Fatemeh Sabet; Kazemi, Sepehr; Semsar, Maryam

    2015-05-01

    Brain stroke is the second most important events that lead to disability and morbidity these days. Although, stroke is important, there is no treatment for curing this problem. Nowadays, cell therapy has opened a new window for treating central nervous system disease. In some previous studies the Mesenchymal stem cells and neural stem cells. In this study, we have designed an experiment to assess the combination cell therapy (Mesenchymal and Neural stem cells) effects on brain stroke. The Mesenchymal stem cells were isolated from adult rat bone marrow and the neural stem cells were isolated from ganglion eminence of rat embryo 14 days. The Mesenchymal stem cells were injected 1 day after middle cerebral artery occlusion (MCAO) and the neural stem cells transplanted 7 day after MCAO. After 28 days, the neurological outcomes and brain lesion volumes were evaluated. Also, the activity of Caspase 3 was assessed in different groups. The group which received combination cell therapy had better neurological examination and less brain lesion. Also the combination cell therapy group had the least Caspase 3 activity among the groups. The combination cell therapy is more effective than Mesenchymal stem cell therapy and neural stem cell therapy separately in treating the brain stroke in rats.

  14. Lichen Striatus Occurring after Allogenic Peripheral Blood Stem Cell Transplantation in an Adult with Aplastic Anemia

    OpenAIRE

    Mun, Je-Ho; Park, Hyun-Je; Kim, Hoon-Soo; Kim, Su-Han; Ko, Hyun-Chang; Kim, Byung-Soo; Kim, Moon-Bum

    2012-01-01

    Lichens striatus (LS) is an acquired, self-limiting inflammatory dermatosis that follows the lines of Blaschko. The etiology of the eruption is unknown, but several theories have been proposed with focus on environmental factors, viral infection, cutaneous injury, hypersensitivity, and genetic predisposition. We describe a 19-year-old woman who developed a unilateral linear eruption 17 months after allogenic peripheral blood stem cell transplantation. Histopathology revealed features, which w...

  15. Gender-Dependent Survival of Allogeneic Trophoblast Stem Cells in Liver

    OpenAIRE

    Epple-Farmer, Jessica; Debeb, Bisrat G.; Smithies, Oliver; Binas, Bert

    2009-01-01

    In view of the well-known phenomenon of trophoblast immune privilege, trophoblast stem cells (TSCs) might be expected to be immune privileged, which could be of interest for cell or gene therapies. Yet in the ectopic sites tested so far, TSC transplants fail to show noticeable immune privilege and seem to lack physiological support. However, we show here that after portal venous injection, green fluorescent protein (GFP)-labeled TSCs survive for several months in the livers of allogeneic fema...

  16. Potential uses for cord blood mesenchymal stem cells.

    Science.gov (United States)

    Zarrabi, Morteza; Mousavi, Seyed Hadi; Abroun, Saeid; Sadeghi, Bahareh

    2014-01-01

    Stem cell therapy is a powerful technique for the treatment of a number of diseases. Stem cells are derived from different tissue sources, the most important of which are the bone marrow (BM), umbilical cord (UC) blood and liver. Human UC mesenchymal stem cells (hUC-MSCs) are multipotent, non-hematopoietic stem cells that have the ability to self-renew and differentiate into other cells and tissues such as osteoblasts, adipocytes and chondroblasts. In a number of reports, human and mouse models of disease have hUC-MSCs treatments. In this article, we review studies that pertain to the use of hUC-MSCs as treatment for diseases.

  17. Isolation of Mesenchymal Stem Cells from Adipose Tissue

    OpenAIRE

    Islam, Andi Asadul

    2015-01-01

    BACKGROUND: In searching for the best source of stem cells, researcher found adipose stem cells as one of the ideal source due to its easiness in harvesting and its potential for differentiating into other cell lineage. METHODS: We isolated stem cells from adipose tissue, cultured and confirmed its immunophenotype using polymerase chain reaction. RESULTS: Cluster of differentiation (CD)44, CD73, CD90, CD105 were expressed, which represent immunophenotype of mesenchymal stem cells.  CONCLUSION...

  18. Applications of Mesenchymal Stem Cells in Oral and Craniofacial Regeneration.

    Science.gov (United States)

    Shakoori, Pasha; Zhang, Quanzhou; Le, Anh D

    2017-02-01

    The field of tissue engineering and regenerative medicine has been rapidly expanded through multidisciplinary integration of research and clinical practice in response to unmet clinical needs for reconstruction of dental, oral, and craniofacial structures. The significance of the various types of stem cells, specifically mesenchymal stem cells derived from the orofacial tissues, ranging from dental pulp stem cells to periodontal ligament stem cells to mucosa/gingiva has been thoroughly investigated and their applications in tissue regeneration are outlined in this article. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    Science.gov (United States)

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL). Copyright © 2016. Published by Elsevier Inc.

  20. A Prospective, Randomized, Masked, and Placebo-Controlled Efficacy Study of Intraarticular Allogeneic Adipose Stem Cells for the Treatment of Osteoarthritis in Dogs.

    Science.gov (United States)

    Harman, Robert; Carlson, Kim; Gaynor, Jamie; Gustafson, Scott; Dhupa, Sarit; Clement, Keith; Hoelzler, Michael; McCarthy, Tim; Schwartz, Pamela; Adams, Cheryl

    2016-01-01

    Osteoarthritis (OA) is a degenerative joint disease with a high prevalence in dogs. Mesenchymal stem cells (MSCs) have been used to treat humans, dogs, and horses with OA. This report describes a prospective, randomized, blinded, and placebo-controlled clinical efficacy study of intraarticular allogeneic adipose stem cells for the treatment of dogs with OA. Health assessments and measurements of pain and activity impairment were performed at baseline and at selected time points through day 60. The primary outcome variable was the owner Client-Specific Outcome Measurement (CSOM) and secondary measures included veterinary pain on manipulation, veterinary global score, and owner global score. The dogs were treated with either a saline placebo or a single dose of allogeneic adipose-derived MSCs in either one or two joints. Seventy-four dogs were statistically analyzed for efficacy outcomes. Success in the primary outcome variable, CSOM, was statistically improved in the treated dogs compared to the placebo dogs (79.2 versus 55.4%, p  = 0.029). The veterinary pain on manipulation score (92.8 versus 50.2%, p  = 0.017) and the veterinary global score (86.9 versus 30.8%, p  = 0.009) were both statistically improved in treated dogs compared to placebo. There was no detected significant difference between treated and placebo dogs in the incidence of adverse events or negative health findings. Allogeneic adipose-derived stem cell treatment was shown to be efficacious compared to placebo. This large study of dogs also provides valuable animal clinical safety and efficacy outcome data to our colleagues developing human stem cell therapy.

  1. Isolation of mesenchymal stem cells from equine umbilical cord blood

    DEFF Research Database (Denmark)

    Koch, Thomas Gadegaard; Heerkens, Tammy; Thomsen, Preben Dybdahl

    2007-01-01

    . The hypothesis of this study was that equine MSCs could be isolated from fresh whole equine cord blood. Results: Cord blood was collected from 7 foals immediately after foaling. The mononuclear cell fraction was isolated by Ficoll density centrifugation and cultured in a DMEM low glucose based media at 38.5o......Background: There are no published studies on stem cells from equine cord blood although commercial storage of equine cord blood for future autologous stem cell transplantations is available. Mesenchymal stem cells (MSC) have been isolated from fresh umbilical cord blood of humans collected non......-invasively at the time of birth and from sheep cord blood collected invasively by a surgical intrauterine approach. Mesenchymal stem cells isolation percentage from frozen-thawed human cord blood is low and the future isolation percentage of MSCs from cryopreserved equine cord blood is therefore expectedly low...

  2. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

    NARCIS (Netherlands)

    Halter, Joerg P.; Schuepbach, W. Michael M.; Mandel, Hanna; Casali, Carlo; Orchard, Kim; Collin, Matthew; Valcarcel, David; Rovelli, Attilio; Filosto, Massimiliano; Dotti, Maria T.; Marotta, Giuseppe; Pintos, Guillem; Barba, Pere; Accarino, Anna; Ferra, Christelle; Illa, Isabel; Beguin, Yves; Bakker, Jaap A.; Boelens, Jaap J.; de Coo, Irenaeus F. M.; Fay, Keith; Sue, Carolyn M.; Nachbaur, David; Zoller, Heinz; Sobreira, Claudia; Simoes, Belinda Pinto; Hammans, Simon R.; Savage, David; Marti, Ramon; Chinnery, Patrick F.; Elhasid, Ronit; Gratwohl, Alois; Hirano, Michio

    2015-01-01

    Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known

  3. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

    NARCIS (Netherlands)

    J.P. Halter (Joerg P.); W. Michael; M. Schüpbach; H. Mandel (Hanna); C. Casali (carlo); K. Orchard (Kim); M. Collin (Matthew); D. Valcarcel (David); A. Rovelli (Attilio); M. Filosto (Massimiliano); M.T. Dotti (Maria Teresa); G. Marotta (Giuseppe); G. Pintos (Guillem); P. Barba (Pere); A. Accarino (Anna); C. Ferra (Christelle); I. Illa (Isabel); Y. Beguin (Yves); J.A. Bakker (Jaap A.); J.J. Boelens (Jaap Jan); I.F.M. de Coo (René); K. Fay (Keith); C.M. Sue (Carolyn M.); D. Nachbaur (David); H. Zoller (Heinz); C. Sobreira (Claudia); B. Pinto Simoes (Belinda); S.R. Hammans (Simon R.); D. Savage (David); R. Martí (Ramon); P.F. Chinnery (Patrick); R. Elhasid (Ronit); A. Gratwohl (Alois); M. Hirano (Michio); G. Barros Navarro; J.F. Benoist; J. Bierau (Jörgen); A. Bucalossi; M.A. Carluccio; J. Coll-Canti; M.S. Cotelli; T. Diesch; R. Di Fabio (Roberto); M.A. Donati (Maria); J.H. Garvin; K. Hill; L. Kappeler; T. Ku Hne; M.C. Lara; M. Lenoci; G. Lucchini (Giovanna); W. Marques; H. Mattle; A. Meyer; R. Parini; J. Passweg (Jakob Robert); F. Pieroni; A. Rodriguez-Palmero; F. Santus; M. Scarpelli; P. Schlesser; F. Sicurelli; M. Stern; A.B. Stracieri; P. Tonin; J. Torres-Torronteras; J.C. Voltarelli; I. Zaidman

    2015-01-01

    textabstractHaematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of

  4. Mesenchymal Stem Cells, Nanofiber Scaffolds and Ocular Surface Reconstruction

    Czech Academy of Sciences Publication Activity Database

    Holáň, Vladimír; Javorková, Eliška

    2013-01-01

    Roč. 9, č. 5 (2013), s. 609-619 ISSN 1550-8943 R&D Projects: GA ČR GAP304/11/0653; GA ČR(CZ) GAP301/11/1568 Grant - others:GA MŠk(CZ) UK668012; GA MŠk(CZ) SVV 265211 Institutional support: RVO:68378041 Keywords : mesenchymal stem cell s * limbal stem cell s * ocular surface injuries Subject RIV: EC - Immunology Impact factor: 3.214, year: 2013

  5. Mesenchymal Stem Cells: Emerging Therapy for Duchenne Muscular Dystrophy

    OpenAIRE

    Markert, Chad; Atala, Anthony; Cann, Jennifer K.; Christ, George; Furth, Mark; Ambrosio, Fabrisia; Childers, Martin K.

    2009-01-01

    Multipotent cells that can give rise to bone, cartilage, fat, connective tissue, skeletal and cardiac muscle are termed mesenchymal stem cells (MSCs). These cells were first identified in the bone marrow, distinct from blood-forming stem cells. Based on the embryologic derivation, availability, and various pro-regenerative characteristics, research exploring their use in cell therapy shows great promise for patients with degenerative muscle diseases and a number of other conditions. In this r...

  6. Mandibular Reconstruction in Ameloblastoma Using Allogeneic Cord Stem Cells and Alloplastic Graft Material - Case Report.

    Science.gov (United States)

    Manimaran, K; Chandramohan, M; Kannan, R; Sankaranarayanan, S; Ravi, V R; Sharma, Rohini

    Ameloblastoma is a histologically benign odontogenic tumour and has a tendency of locally aggressive behaviour. This is second most prevalent odontogenic tumour and most common in the molar-ramus-angle region and surgical resection is only treatment option. In this article, we propose an innovative approach to deal with these cases by using alloplastic graft with cord stem cells. Over 2.5 years follow-up, we could demonstrate bone regeneration using this technique with no recurrence. To the best of our knowledge, this is the first report of successful regeneration of part of ramus and body of mandible using allogeneic cord stem cells in cases of Ameloblastoma.

  7. Adult Stromal (Skeletal, Mesenchymal) Stem Cells: Advances Towards Clinical Applications

    DEFF Research Database (Denmark)

    Kermani, Abbas Jafari; Harkness, Linda; Zaher, Walid

    2014-01-01

    Mesenchymal Stem Cells (MSC) are non-hematopoietic adult stromal cells that reside in a perivascular niche in close association with pericytes and endothelial cells and possess self-renewal and multi-lineage differentiation capacity. The origin, unique properties, and therapeutic benefits of MSC ...

  8. Biomaterials Influence Macrophage-Mesenchymal Stem Cell Interaction In Vitro

    NARCIS (Netherlands)

    N. Grotenhuis (Nienke); S.F. De Witte (Samantha Fh); G.J.V.M. van Osch (Gerjo); Y. Bayon (Yves); J.F. Lange (Johan); Y.M. Bastiaansen-Jenniskens (Yvonne)

    2016-01-01

    textabstractBackground: Macrophages and mesenchymal stem cells (MSCs) are important cells in wound healing. We hypothesized that the cross-talk between macrophages and adipose tissue-derived MSCs (ASCs) is biomaterial dependent, thereby influencing processes involved in wound healing. Materials and

  9. Mesenchymal stem cell ingrowth and differentiation on coralline hydroxyapatite scaffolds

    DEFF Research Database (Denmark)

    Mygind, Tina; Stiehler, Maik; Baatrup, Anette

    2007-01-01

    Culture of osteogenic cells on a porous scaffold could offer a new solution to bone grafting using autologous human mesenchymal stem cells (hMSC) from the patient. We compared coralline hydroxyapatite scaffolds with pore sizes of 200 and 500 microm for expansion and differentiation of hMSCs. We...

  10. Tumourigenicity and radiation resistance of mesenchymal stem cells

    DEFF Research Database (Denmark)

    D'Andrea, Filippo P; Horsman, Michael Robert; Kassem, Moustapha

    2011-01-01

    . Nontumourigenic (TERT4) and tumourigenic (TRET20) cell lines, from an immortalised mesenchymal stem cell line, were grown in culture prior to irradiation and gene expression analysis. Radiation resistance was measured using a clonogenic assay. Differences in gene expression between the two cell lines, both under...

  11. Mesenchymal stem cells for the treatment of tendon disorders

    Czech Academy of Sciences Publication Activity Database

    Machová-Urdzíková, Lucia; Lesný, Petr; Syková, Eva; Jendelová, Pavla

    2013-01-01

    Roč. 6, 8A (2013), s. 14-23 ISSN 1937-6871 R&D Projects: GA ČR GAP304/10/0326 Institutional support: RVO:68378041 Keywords : Tendinophaty * Mesenchymal Stem Cells * Tendon Rupture Subject RIV: FP - Other Medical Disciplines

  12. The role of bone marrow derived mesenchymal stem cells in ...

    African Journals Online (AJOL)

    Stroke is the third most common cause of death, and a leading cause of physical disability in adults. Recovery after a major stroke is usually limited, but cell therapy, especially by application of mesenchymal stem cells (MSCs) is emerging with fixed neurologic deficits. The aim of the current study was directed to isolation ...

  13. white leghorn chimeras based on bone marrow mesenchymal stem

    African Journals Online (AJOL)

    white leghorn chimeras based on bone marrow mesenchymal stem cells. Xinxin Qin, Lei Rui, Wenting Zhang, Zhuyu Qiu and Zandong Li*. State Key Laboratory of Agrobiotechnology, Department of Biochemistry and Molecular Biology, College of Biological Science,. China Agricultural University, Beijing 100193, China.

  14. Proteomic techniques for characterisation of mesenchymal stem cell secretome.

    Czech Academy of Sciences Publication Activity Database

    Kupcová Skalníková, Helena

    2013-01-01

    Roč. 95, č. 12 (2013), s. 2196-2211 ISSN 0300-9084 R&D Projects: GA MŠk ED2.1.00/03.0124; GA TA ČR TA01011466 Institutional support: RVO:67985904 Keywords : mesenchymal stem cells * secretome * exosome * conditioned medium * proteomics Subject RIV: CE - Biochemistry Impact factor: 3.123, year: 2013

  15. Research on human placenta-derived mesenchymal stem cells ...

    African Journals Online (AJOL)

    PCR) technology, amplified hVEGF165 gene fragments from human leukemia cells HL-60. hVEGF165 gene was reconstructed in pIRES2-EGFP and transferred into the human placenta-derived mesenchymal stem cells (HPMSCs) by ...

  16. Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, J.C. [Department of Vascular Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China); Zheng, G.F. [Department of Vascular Surgery, The People' s Hospital of Ganzhou, Ganzhou (China); Wu, L.; Ou Yang, L.Y.; Li, W.X. [Department of Vascular Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China)

    2014-08-08

    Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs) expressing human basic fibroblast growth factor (hbFGF). After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC), MSCs expressing hbFGF (hbFGF-MSC), MSC controls, and phosphate-buffered saline (PBS) controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF) expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001); however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008) and microvessel density (P<0.001). Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease.

  17. Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats

    Directory of Open Access Journals (Sweden)

    J.C. Zhang

    2014-10-01

    Full Text Available Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs expressing human basic fibroblast growth factor (hbFGF. After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC, MSCs expressing hbFGF (hbFGF-MSC, MSC controls, and phosphate-buffered saline (PBS controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001; however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008 and microvessel density (P<0.001. Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease.

  18. Impact of stem cell source on allogeneic stem cell transplantation outcome in hematological malignancies

    Directory of Open Access Journals (Sweden)

    Stamatović Dragana

    2011-01-01

    Full Text Available Background/Aim. Peripheral blood (PB is used more frequently as a source of stem cells (SCs for allogeneic transplantation. However, the influence of cell source on the clinical outcome of SC transplantation is not yet well established. The aim of this study was to compare the results of PBSC transplantation (PBSCT with bone marrow transplantation (BMT on the basis of engraftment, frequency and severity of immediate (mucositis, acute Graft versus Host Disease - aGvHD and delayed (chronic GvHD - cGvHD complications, as well as transplant-related mortality (TRM, transfusion needs, relapses and overall survival (OS. Methods. We analyzed 158 patients, women/men ratio 64/94 median age 29 (range 9-57, who underwent allogeneic SC transplantation between 1989 and 2009. All included patients had diseases as follows: acute myeloid leukemia (AML - 39, acute lymphoblastic leukemia (ALL - 47, chronic myeloid leukemia (CML - 32, myelodysplastic syndrome (MDS - 10, Hodgkin’s lymphoma (HL - 2, multiple myeloma (MM - 3, granulocytic sarcoma (GrSa - 3, severe aplastic anemia (sAA - 22. The patients underwent transplantations were divided into two groups: BMT group (74 patients and PBSCT group (84 patients. Each recipient had HLA identical sibling donor. SCs from bone marrow were collected by multiple aspirations of iliac bone and from PB by one “Large Volume Leukapheresis” (after recombinant human granulocyte colony stimulating factor, rHuG-CSF application (5-12 μg/kgbm, 5 days. Conditioning regimens were applied according to primary disease, GvHD prophylaxis consisted of combination of a cyclosporine A and methotrexate. Results. Engraftment, according to the count of polymorphonuclear and platelets, were significantly (p < 0.001 faster in the PBSCT vs BMT group. The needs for transfusion support were significantly (p < 0.01 higher in the BMT group. Those patients had more frequently oropharingeal mucositis grade 3/4 (33.3% vs 10.0%, p < 0.05. There were

  19. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    Directory of Open Access Journals (Sweden)

    Kosuke Fujita

    Full Text Available Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be

  20. Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: a concise review

    NARCIS (Netherlands)

    Vonk, L.A.; de Windt, T.S.; Slaper-Cortenbach, Ineke C.M.; Saris, Daniël B.F.

    2015-01-01

    The evolution of articular cartilage repair procedures has resulted in a variety of cell-based therapies that use both autologous and allogeneic mesenchymal stromal cells (MSCs). As these cells are increasingly available and show promising results both in vitro and in vivo, cell-based strategies,

  1. Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why : A concise review

    NARCIS (Netherlands)

    Vonk, Lucienne A.; De Windt, Tommy S.; Slaper-Cortenbach, Ineke C M; Saris, Daniël B F

    2015-01-01

    The evolution of articular cartilage repair procedures has resulted in a variety of cell-based therapies that use both autologous and allogeneic mesenchymal stromal cells (MSCs). As these cells are increasingly available and show promising results both in vitro and in vivo, cell-based strategies,

  2. Anti-leukemic therapies induce cytogenetic changes of human bone marrow-derived mesenchymal stem cells.

    Science.gov (United States)

    Yeh, Su-Peng; Lo, Wen-Jyi; Lin, Chiao-Lin; Liao, Yu-Min; Lin, Chen-Yuan; Bai, Li-Yuan; Liang, Ji-An; Chiu, Chang-Fang

    2012-02-01

    Both bone marrow hematopoietic cells (BM-HCs) and mesenchymal stem cells (BM-MSCs) may have cytogenetic aberrations in leukemic patients, and anti-leukemic therapy may induce cytogenetic remission of BM-HCs. The impact of anti-leukemic therapy on BM-MSCs remains unknown. Cytogenetic studies of BM-MSCs from 15 leukemic patients with documented cytogenetic abnormalities of BM-HCs were investigated. To see the influence of anti-leukemic therapy on BM-MSCs, cytogenetic studies were carried out in seven of them after the completion of anti-leukemic therapy, including anthracycline/Ara-C-based chemotherapy in two patients, high-dose busulfan/cyclophosphamide-based allogeneic transplantation in two patients, and total body irradiation (TBI)-based allogeneic transplantation in three patients. To simulate the effect of TBI in vitro, three BM-MSCs from one leukemic patient and two normal adults were irradiated using the same dosage and dosing schedule of TBI and cytogenetics were re-examined after irradiation. At the diagnosis of leukemia, two BM-MSCs had cytogenetic aberration, which were completely different to their BM-HCs counterpart. After the completion of anti-leukemic therapy, cytogenetic aberration was no longer detectable in one patient. Unexpectedly, BM-MSCs from three patients receiving TBI-based allogeneic transplantation acquired new, clonal cytogenetic abnormalities after transplantation. Similarly, complex cytogenetic abnormalities were found in all the three BM-MSCs exposed to in vitro irradiation. In conclusion, anti-leukemic treatments induce not only "cytogenetic remission" but also new cytogenetic abnormalities of BM-MSCs. TBI especially exerts detrimental effect on the chromosomal integrity of BM-MSCs and highlights the equal importance of investigating long-term adverse effect of anti-leukemic therapy on BM-MSCs as opposed to beneficial effect on BM-HCs.

  3. Glial origin of mesenchymal stem cells in a tooth model system

    NARCIS (Netherlands)

    Kaukua, Nina; Shahidi, Maryam Khatibi; Konstantinidou, Chrysoula; Dyachuk, Vyacheslav; Kaucka, Marketa; Furlan, Alessandro; An, Zhengwen; Wang, Longlong; Hultman, Isabell; Ahrlund-Richter, Lars; Blom, Hans; Brismar, Hjalmar; Lopes, Natalia Assaife; Pachnis, Vassilis; Suter, Ueli; Clevers, Hans; Thesleff, Irma; Sharpe, Paul; Ernfors, Patrik; Fried, Kaj; Adameyko, Igor

    2014-01-01

    Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair. The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells

  4. Mesenchymal stem cells as therapeutic delivery vehicles targeting tumor stroma

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Christensen, Rikke; Sørensen, Flemming Brandt

    2011-01-01

    better understanding and in vivo supporting data. The homing ability of hMSCs was investigated by creating a human xenograft model by transplanting an ovarian cancer cell line into immunocompromised mice. Then, genetically engineered hMSC-telo1 cells were injected through the tail vein......The field of stem cell biology continues to evolve by characterization of further types of stem cells and by exploring their therapeutic potential for experimental and clinical applications. Human mesenchymal stem cells (hMSCs) are one of the most promising candidates simply because...

  5. Allogeneic hematopoietic stem cell transplantation in patients with advanced indolent lymphoproliferative disorders

    Directory of Open Access Journals (Sweden)

    Ana Marcela Rojas Fonseca-Hial

    2016-06-01

    Full Text Available ABSTRACT BACKGROUND: The role of allogeneic hematopoietic stem cell transplantation for advanced indolent lymphoproliferative disorders remains to be established. OBJECTIVE: This paper aims to describe the results of allogeneic hematopoietic stem cell transplantation in patients with advanced indolent lymphoproliferative disorders. METHODS: This article reports on 29 adult patients submitted to allogeneic transplantations from 1997 to 2010. RESULTS: Most had follicular non-Hodgkin lymphoma (n = 14 or chronic lymphocytic leukemia (n = 12. The median age was 44 years (range: 24-53 years and 65% of patients were male. Only 21% had had access to rituximab and 45% to fludarabine. All had advanced disease (stage IV with partial response or stable disease. Most underwent myeloablative conditioning n = 17 - 59%. In this scenario, refractory disease was observed in seven (24% patients, the 100-day mortality rate was 17% (n = 5 and relapse occurred in four patients (18%. The main cause of death throughout the follow up was refractory disease in six of the 12 patients who died. Moderate and severe chronic graft-versus-host disease was frequent; about 41% of 24 patients analyzed. The overall survival rates and disease free survival at 42 months were 56.7% and 45.4%, respectively. According to Kaplan-Meyer analysis, the median time from diagnosis to transplant predicted the overall survival; however age, gender and conditioning regimen did not predict the prognosis. It was impossible to reach other conclusions because of the small sample size in this study. CONCLUSIONS: The role of allogeneic transplantations should be re-evaluated in the era of targeted therapy.

  6. Factors influencing platelet transfusion refractoriness in patients undergoing allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Solves, Pilar; Sanz, Jaime; Freiria, Carmen; Santiago, Marta; Villalba, Ana; Gómez, Inés; Montesinos, Pau; Montoro, Juan; Piñana, Jose Luis; Lorenzo, José Ignacio; Puig, Nieves; Sanz, Guillermo F; Sanz, Miguel Ángel; Carpio, Nelly

    2018-01-01

    Hematopoietic stem cell transplantation has been considered a risk factor for development of platelet transfusion refractoriness. The objective of this study was to assess the platelet transfusion refractoriness rate in patients undergoing allogeneic hematopoietic stem cell transplantation from different sources. We retrospectively reviewed the charts and transfusion records of patients who underwent allogeneic stem cell transplantation at our institution between 2013 and 2015. The evaluation of post-transfusion platelet count was assessed for each transfusion given, from day of progenitor infusion to day 30 after transplantation. Of 167 patients included in this study, 101 received peripheral blood stem cell transplantation (PBSCT) and 66 received umbilical cord blood transplantation (UCBT). Overall, the percentage of platelet transfusions with a 14-h CCI lower than 5000 was 59.3%, being these data significantly higher for UCBT (67.6%) than for PBSCT (31.0%). Seventy-eight percent of patients underwent UCBT become refractory, while 38.6% of patients who received PBSCT were refractory. Factors associated to platelet refractoriness were lower CD34+ cell dose infused, higher number of antibiotics used, presence of anti-HLA I antibodies, and reduced-intensity conditioning regimen. Platelet refractoriness is a frequent and complex adverse event and remains a therapeutic challenge in the management of patients undergoing HSCT. There is a higher rate of platelet refractoriness in patients who received UCBT as compared to patients who received PBSCT.

  7. Induced Pluripotent Stem Cell Derived Mesenchymal Stem Cells for Attenuating Age-Related Bone Loss

    Science.gov (United States)

    2012-07-01

    Mesenchymal stem cell (MSC) differentiation towards the bone forming osteoblastic lineage decreases as a function of age and may contribute to age-related...problem of age-related reduced availability of MSC we propose to examine the bone anabolic potential of induced pluripotent stem cell (iPS) derived MSC

  8. Lung function after allogeneic hematopoietic stem cell transplantation in children

    DEFF Research Database (Denmark)

    Uhlving, Hilde Hylland; Larsen Bang, Cæcilie; Christensen, Ib Jarle

    2013-01-01

    Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF......-versus-host disease (GvHD). Other factors associated with PF decline were malignant diagnosis, busulfan-based conditioning, patient and donor age, female donor to male recipient, as well as chronic GvHD. Mild to moderate decline in PF is frequent and appears associated with acute GvHD and other parameters...

  9. Comparison of Alternative Mesenchymal Stem Cell Sources for Cell Banking and Musculoskeletal Advanced Therapies

    NARCIS (Netherlands)

    Cavallo, Carola; Cuomo, Carmela; Fantini, Sara; Ricci, Francesca; Tazzari, Pier Luigi; Lucarelli, Enrico; Donati, Davide; Facchini, Andrea; Lisignoli, Gina; Fornasari, Pier Maria; Grigolo, Brunella; Moroni, Lorenzo

    2011-01-01

    With the continuous discovery of new alternative sources containing mesenchymal stem cells (MSCs), regenerative medicine therapies may find tailored applications in the clinics. Although these cells have been demonstrated to express specific mesenchymal markers and are able to differentiate into

  10. Mesenchymal Stem Cells and Their Clinical Applications in Osteoarthritis.

    Science.gov (United States)

    Chang, Yu-Hsun; Liu, Hwan-Wun; Wu, Kun-Chi; Ding, Dah-Ching

    2016-01-01

    Osteoarthritis is a chronic degenerative joint disorder characterized by articular cartilage destruction and osteophyte formation. Chondrocytes in the matrix have a relatively slow turnover rate, and the tissue itself lacks a blood supply to support repair and remodeling. Researchers have evaluated the effectiveness of stem cell therapy and tissue engineering for treating osteoarthritis. All sources of stem cells, including embryonic, induced pluripotent, fetal, and adult stem cells, have potential use in stem cell therapy, which provides a permanent biological solution. Mesenchymal stem cells (MSCs) isolated from bone marrow, adipose tissue, and umbilical cord show considerable promise for use in cartilage repair. MSCs can be sourced from any or all joint tissues and can modulate the immune response. Additionally, MSCs can directly differentiate into chondrocytes under appropriate signal transduction. They also have immunosuppressive and anti-inflammatory paracrine effects. This article reviews the current clinical applications of MSCs and future directions of research in osteoarthritis.

  11. Potential Spermatogenesis Recovery with Bone Marrow Mesenchymal Stem Cells in an Azoospermic Rat Model

    Directory of Open Access Journals (Sweden)

    Deying Zhang

    2014-07-01

    Full Text Available Non-obstructive azoospermia is the most challenging type of male infertility. Stem cell based therapy provides the potential to enhance the recovery of spermatogenesis following cancer therapy. Bone marrow-derived mesenchymal stem cells (BMSCs possess the potential to differentiate or trans-differentiate into multi-lineage cells, secrete paracrine factors to recruit the resident stem cells to participate in tissue regeneration, or fuse with the local cells in the affected region. In this study, we tested whether spermatogenically-induced BMSCs can restore spermatogenesis after administration of an anticancer drug. Allogeneic BMSCs were co-cultured in conditioned media derived from cultured testicular Sertoli cells in vitro, and then induced stem cells were transplanted into the seminiferous tubules of a busulfan-induced azoospermatic rat model for 8 weeks. The in vitro induced BMSCs exhibited specific spermatogonic gene and protein markers, and after implantation the donor cells survived and located at the basement membranes of the recipient seminiferous tubules, in accordance with what are considered the unique biological characteristics of spermatogenic stem cells. Molecular markers of spermatogonial stem cells and spermatogonia (Vasa, Stella, SMAD1, Dazl, GCNF, HSP90α, integrinβ1, and c-kit were expressed in the recipient testis tissue. No tumor mass, immune response, or inflammatory reaction developed. In conclusion, BMSCs might provide the potential to trans-differentiate into spermatogenic-like-cells, enhancing endogenous fertility recovery. The present study indicates that BMSCs might offer alternative treatment for the patients with azoospermatic infertility after cancer chemotherapy.

  12. Peripheral blood stem cell collection for allogeneic hematopoietic stem cell transplantation: Practical implications after 200 consequent transplants.

    Science.gov (United States)

    Goren Sahin, Deniz; Arat, Mutlu

    2017-12-01

    Proper stem cell mobilization is one of the most important steps in hematopoietic stem cell transplantation (HSCT). The aim of this paper is to share our 6 years' experience and provide practical clinical approaches particularly for stem cell mobilization and collection within the series of more than 200 successive allogeneic HSCT at our transplant center. Two hundred and seven consecutive patients who underwent allogeneic peripheral blood stem cell transplantation were included in this study. Age, sex, weight, complete blood counts, CD34 + cell counts, total collected amount of CD34 + cells, CD34 + cells per 10l processed, mobilization failure and adverse events were reviewed. Median age was 40.2±12.9 (21-68) years and 46.4±13.4 (17-67) years for donors and patients, respectively. The number of donors who had undergone adequate CD34 + cell harvesting and completed the procedure on the fourth day was 67 (32.8% of all patients). Only 12 patients required cell apheresis both on day 5 and 6. Apheresis was completed on day 4 and/or day 5 in 94.2% of all our donors. There was no significant association between CD34 + stem cell volume and age, gender and weight values of donors. Mobilization failure was not seen in our series. G-CSF is highly effective in 1/3 of the donors on the 4th day in order to collect enough number of stem cells. We propose that peripheral stem cell collection might start on day 4th of G-CSF treatment for avoiding G-CSF related side effects and complications. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Acute colonic pseudo-obstruction following allogeneic stem cell transplantation successfully treated by neostigmine.

    Science.gov (United States)

    Yahng, Seung-Ah; Yoon, Jae-Ho; Shin, Seung-Hwan; Lee, Sung-Eun; Eom, Ki-Seong; Kim, Yoo-Jin

    2013-06-01

    Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie's syndrome, is a rare clinical syndrome of massive large bowel dilatation without mechanical obstruction, which may cause significant morbidity and mortality. Treatment focuses on decompressing a severely dilated colon. The proposed theory that this severe ileus results from an imbalance in the autonomous regulation of colonic movement supports the rationale for using neostigmine, a reversible acetylcholinesterase inhibitor, in patients who failed conservative care. Although gastrointestinal complications are frequent following allogeneic stem cell transplantation (SCT), the incidence of ACPO in a transplant setting is unknown and, if not vigilant, this adynamic ileus can be underestimated. We describe the case of a patient with myelodysplastic syndrome undergoing non-myeloablative allogeneic SCT from a partially human leukocyte antigen-mismatched sibling donor, and whose clinical course was complicated by ACPO in the early post-engraftment period. The ileus was not associated with gut graft-versus-host disease or infectious colitis. After 3 days of conservative care, intravenous neostigmine (2 mg/day) was administered for 3 consecutive days. Symptoms and radiologic findings began to improve 72 hours after the initial injection of neostigmine, and complete response without any associated complications was achieved within a week. Thus, neostigmine can be a safe medical therapy with successful outcome for patients who develop ACPO following allogeneic SCT.

  14. Culture-expanded allogenic adipose tissue-derived stem cells attenuate cartilage degeneration in an experimental rat osteoarthritis model.

    Directory of Open Access Journals (Sweden)

    Li Mei

    Full Text Available Mesenchymal stem cell (MSC-based cell therapy is a promising avenue for osteoarthritis (OA treatment. In the present study, we evaluated the efficacy of intra-articular injections of culture-expanded allogenic adipose tissue-derived stem cells (ADSCs for the treatment of anterior cruciate ligament transection (ACLT induced rat OA model. The paracrine effects of major histocompatibility complex (MHC-unmatched ADSCs on chondrocytes were investigated in vitro. Rats were divided into an OA group that underwent ACLT surgery and a sham-operated group that did not undergo ACLT surgery. Four weeks after surgery mild OA was induced in the OA group. Subsequently, the OA rats were randomly divided into ADSC and control groups. A single dose of 1 × 106 ADSCs suspended in 60 μL phosphate-buffered saline (PBS was intra-articularly injected into the rats of the ADSC group. The control group received only 60 μL PBS. OA progression was evaluated macroscopically and histologically at 8 and 12 weeks after surgery. ADSC treatment did not cause any adverse local or systemic reactions. The degeneration of articular cartilage was significantly weaker in the ADSC group compared to that in the control group at both 8 and 12 weeks. Chondrocytes were co-cultured with MHC-unmatched ADSCs in trans-wells to assess the paracrine effects of ADSCs on chondrocytes. Co-culture with ADSCs counteracted the IL-1β-induced mRNA upregulation of the extracellular matrix-degrading enzymes MMP-3 and MMP-13 and the pro-inflammatory cytokines TNF-α and IL-6 in chondrocytes. Importantly, ADSCs increased the expression of the anti-inflammatory cytokine IL-10 in chondrocytes. The results of this study indicated that the intra-articular injection of culture-expanded allogenic ADSCs attenuated cartilage degeneration in an experimental rat OA model without inducing any adverse reactions. MHC-unmatched ADSCs protected chondrocytes from inflammatory factor-induced damage. The paracrine effects

  15. Culture-expanded allogenic adipose tissue-derived stem cells attenuate cartilage degeneration in an experimental rat osteoarthritis model.

    Science.gov (United States)

    Mei, Li; Shen, Bojiang; Ling, Peixue; Liu, Shaoying; Xue, Jiajun; Liu, Fuyan; Shao, Huarong; Chen, Jianying; Ma, Aibin; Liu, Xia

    2017-01-01

    Mesenchymal stem cell (MSC)-based cell therapy is a promising avenue for osteoarthritis (OA) treatment. In the present study, we evaluated the efficacy of intra-articular injections of culture-expanded allogenic adipose tissue-derived stem cells (ADSCs) for the treatment of anterior cruciate ligament transection (ACLT) induced rat OA model. The paracrine effects of major histocompatibility complex (MHC)-unmatched ADSCs on chondrocytes were investigated in vitro. Rats were divided into an OA group that underwent ACLT surgery and a sham-operated group that did not undergo ACLT surgery. Four weeks after surgery mild OA was induced in the OA group. Subsequently, the OA rats were randomly divided into ADSC and control groups. A single dose of 1 × 106 ADSCs suspended in 60 μL phosphate-buffered saline (PBS) was intra-articularly injected into the rats of the ADSC group. The control group received only 60 μL PBS. OA progression was evaluated macroscopically and histologically at 8 and 12 weeks after surgery. ADSC treatment did not cause any adverse local or systemic reactions. The degeneration of articular cartilage was significantly weaker in the ADSC group compared to that in the control group at both 8 and 12 weeks. Chondrocytes were co-cultured with MHC-unmatched ADSCs in trans-wells to assess the paracrine effects of ADSCs on chondrocytes. Co-culture with ADSCs counteracted the IL-1β-induced mRNA upregulation of the extracellular matrix-degrading enzymes MMP-3 and MMP-13 and the pro-inflammatory cytokines TNF-α and IL-6 in chondrocytes. Importantly, ADSCs increased the expression of the anti-inflammatory cytokine IL-10 in chondrocytes. The results of this study indicated that the intra-articular injection of culture-expanded allogenic ADSCs attenuated cartilage degeneration in an experimental rat OA model without inducing any adverse reactions. MHC-unmatched ADSCs protected chondrocytes from inflammatory factor-induced damage. The paracrine effects of ADSCs on

  16. Voriconazole-Induced Periostitis Mimicking Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Karen Sweiss

    2016-01-01

    Full Text Available Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT. It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy.

  17. Suspected Pulmonary Infection with Trichoderma longibrachiatum after Allogeneic Stem Cell Transplantation.

    Science.gov (United States)

    Akagi, Tomoaki; Kawamura, Chizuko; Terasawa, Norio; Yamaguchi, Kohei; Kubo, Kohmei

    2017-01-01

    Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B.

  18. How Does Influenza A (H1N1 Infection Proceed in Allogeneic Stem Cell Transplantation Recipients?

    Directory of Open Access Journals (Sweden)

    Sinem Civriz Bozdağ

    2012-03-01

    Full Text Available Clinical course of H1N1 infection in Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT patients is contraversial. We report three AHSCT patients who were infected with Influenza A/H1N1 infection. All of the patients were diagnosed with different hematological diagnosis and were at different stages of transplantation.All of them were treated with oseltamivir,zanamivir was switched with oseltamivir in one patient. All of the three patients were survived without any complication. Swine flu, can display with different courses and progress with bacterial or other viral infections in immunsupressed patients.

  19. Post-influenzal triazole-resistant aspergillosis following allogeneic stem cell transplantation.

    Science.gov (United States)

    Talento, Alida Fe; Dunne, Katie; Murphy, Niamh; O'Connell, Brian; Chan, Grace; Joyce, Eimear Ann; Hagen, Ferry; Meis, Jacques F; Fahy, Ruauri; Bacon, Larry; Vandenberge, Elisabeth; Rogers, Thomas R

    2018-03-23

    Influenza virus infection is now recognised as a risk factor for invasive pulmonary aspergillosis (IPA). Delays in diagnosis contribute to delayed commencement of antifungal therapy. Additionally, the emergence of resistance to first-line triazole antifungal agents puts emphasis on early detection to prevent adverse outcomes. We present 2 allogeneic stem cell transplant patients who developed IPA due to triazole-resistant Aspergillus fumigatus following influenza infection. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole-resistance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  20. In vitro and in vivo neurogenic potential of mesenchymal stem cells ...

    Indian Academy of Sciences (India)

    Keywords. Clinical trials; mesenchymal stem cells (MSCs); neuronal differentiation; self-renewal. Abstract. Regenerative medicine is an evolving interdisciplinary topic of research involving numerous technological methods that utilize stem cells to repair damaged tissues. Particularly, mesenchymal stem cells (MSCs) are a ...

  1. Mesenchymal Stem Cell-Based Therapy for Prostate Cancer

    Science.gov (United States)

    2014-09-01

    Mesenchymal Stem Cell-Based Therapy for Prostate Cancer PRINCIPAL INVESTIGATOR: John Isaacs; Jeffrey Karp ...clinical trials for CRPC. The team is composed of Drs. Jeffrey Karp Co-Director of Regenerative Therapeutics at the Brigham & Women’s Hospital...encapsulating a PSA-activated thapsigargin-based prodrug (G115, Fig. 5) were generated by the Karp lab with the properties outlined in Table 7. These

  2. Induction of mesenchymal stem cell chondrogenesis by polyacrylate substrates

    OpenAIRE

    Glennon-Alty, Laurence; Williams, Rachel; Dixon, Simon; Murray, Patricia

    2013-01-01

    Mesenchymal stem cells (MSCs) can generate chondrocytes in vitro, but typically need to be cultured as aggregates in the presence of transforming growth factor beta (TGF-?), which makes scale-up difficult. Here we investigated if polyacrylate substrates modelled on the functional group composition and distribution of the Arg-Gly-Asp (RGD) integrin-binding site could induce MSCs to undergo chondrogenesis in the absence of exogenous TGF-?. Within a few days of culture on the biomimetic polyacry...

  3. The Alliance of Mesenchymal Stem Cells, Bone, and Diabetes

    Directory of Open Access Journals (Sweden)

    Nicola Napoli

    2014-01-01

    Full Text Available Bone fragility has emerged as a new complication of diabetes. Several mechanisms in diabetes may influence bone homeostasis by impairing the action between osteoblasts, osteoclasts, and osteocytes and/or changing the structural properties of the bone tissue. Some of these mechanisms can potentially alter the fate of mesenchymal stem cells, the initial precursor of the osteoblast. In this review, we describe the main factors that impair bone health in diabetic patients and their clinical impact.

  4. Mesenchymal stem cells in diabetes treatment: progress and perspectives

    Directory of Open Access Journals (Sweden)

    Yu CHENG

    2016-08-01

    Full Text Available Diabetes is a chronic metabolic disorder caused by relative or absolute insulin deficient or reduced sensitivity of target cells to insulin. Mesenchymal stem cells (MSCs are adult stem cells with multiple differentiation potential, self-renewable and immunoregulatory properties. Accumulating evidences from clinic or animal experiments recent years showed that MSCs infusion could ameliorate hyperglycemia in diabetes. The research progress of MSCs in diabetes treatment is summarized and a corresponding perspective is herewith proposed in present paper. DOI: 10.11855/j.issn.0577-7402.2016.07.16

  5. The mechanosensor of mesenchymal stem cells: mechanosensitive channel or cytoskeleton?

    Science.gov (United States)

    Xiao, E; Chen, Chider; Zhang, Yi

    2016-09-20

    Mesenchymal stem cells (MSCs) are multipotent adult stem cells. MSCs and their potential for use in regenerative medicine have been investigated extensively. Recently, the mechanisms by which MSCs detect mechanical stimuli have been described in detail. As in other cell types, both mechanosensitive channels, such as transient receptor potential melastatin 7 (TRPM7), and the cytoskeleton, including actin and actomyosin, have been implicated in mechanosensation in MSCs. This review will focus on discussing the precise role of TRPM7 and the cytoskeleton in mechanosensation in MSCs.

  6. Improvement of renal function after human umbilical cord mesenchymal stem cell treatment on chronic renal failure and thoracic spinal cord entrapment: a case report.

    Science.gov (United States)

    Rahyussalim, Ahmad Jabir; Saleh, Ifran; Kurniawati, Tri; Lutfi, Andi Praja Wira Yudha

    2017-11-30

    Chronic renal failure is an important clinical problem with significant socioeconomic impact worldwide. Thoracic spinal cord entrapment induced by a metabolic yield deposit in patients with renal failure results in intrusion of nervous tissue and consequently loss of motor and sensory function. Human umbilical cord mesenchymal stem cells are immune naïve and they are able to differentiate into other phenotypes, including the neural lineage. Over the past decade, advances in the field of regenerative medicine allowed development of cell therapies suitable for kidney repair. Mesenchymal stem cell studies in animal models of chronic renal failure have uncovered a unique potential of these cells for improving function and regenerating the damaged kidney. We report a case of a 62-year-old ethnic Indonesian woman previously diagnosed as having thoracic spinal cord entrapment with paraplegic condition and chronic renal failure on hemodialysis. She had diabetes mellitus that affected her kidneys and had chronic renal failure for 2 years, with creatinine level of 11 mg/dl, and no urinating since then. She was treated with human umbilical cord mesenchymal stem cell implantation protocol. This protocol consists of implantation of 16 million human umbilical cord mesenchymal stem cells intrathecally and 16 million human umbilical cord mesenchymal stem cells intravenously. Three weeks after first intrathecal and intravenous implantation she could move her toes and her kidney improved. Her creatinine level decreased to 9 mg/dl. Now after 8 months she can raise her legs and her creatinine level is 2 mg/dl with normal urinating. Human umbilical cord mesenchymal stem cell implantations led to significant improvement for spinal cord entrapment and kidney failure. The major histocompatibility in allogeneic implantation is an important issue to be addressed in the future.

  7. Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti-tumor Treatment

    Directory of Open Access Journals (Sweden)

    Daria S. Chulpanova

    2018-03-01

    Full Text Available Mesenchymal stem cells (MSCs are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs, which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment.

  8. Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies

    Directory of Open Access Journals (Sweden)

    Guihong Li

    2016-01-01

    Full Text Available Animal and clinical studies have confirmed the therapeutic effect of bone marrow mesenchymal stem cells on cerebral ischemia, but their mechanisms of action remain poorly understood. Here, we summarize the transplantation approaches, directional migration, differentiation, replacement, neural circuit reconstruction, angiogenesis, neurotrophic factor secretion, apoptosis, immunomodulation, multiple mechanisms of action, and optimization strategies for bone marrow mesenchymal stem cells in the treatment of ischemic stroke. We also explore the safety of bone marrow mesenchymal stem cell transplantation and conclude that bone marrow mesenchymal stem cell transplantation is an important direction for future treatment of cerebral ischemia. Determining the optimal timing and dose for the transplantation are important directions for future research.

  9. Gender-Dependent Survival of Allogeneic Trophoblast Stem Cells in Liver

    Science.gov (United States)

    Epple-Farmer, Jessica; Debeb, Bisrat G.; Smithies, Oliver; Binas, Bert

    2012-01-01

    In view of the well-known phenomenon of trophoblast immune privilege, trophoblast stem cells (TSCs) might be expected to be immune privileged, which could be of interest for cell or gene therapies. Yet in the ectopic sites tested so far, TSC transplants fail to show noticeable immune privilege and seem to lack physiological support. However, we show here that after portal venous injection, green fluorescent protein (GFP)-labeled TSCs survive for several months in the livers of allogeneic female but not male mice. Gonadectomy experiments revealed that this survival does not require the presence of ovarian hormones but does require the absence of testicular factors. By contrast, GFP-labeled allogeneic embryonic stem cells (ESCs) are reliably rejected; however, these same ESCs survive when mixed with unlabeled TSCs. The protective effect does not require immunological compatibility between ESCs and TSCs. Tumors were not observed in animals with either successfully engrafted TSCs or coinjected ESCs. We conclude that in a suitable hormonal context and location, ectopic TSCs can exhibit and confer immune privilege. These findings suggest applications in cell and gene therapy as well as a new model for studying trophoblast immunology and physiology. PMID:19523327

  10. Acute Fibrinous and Organizing Pneumonia Associated With Allogenic Hematopoietic Stem Cell Transplant Successfully Treated With Corticosteroids

    Directory of Open Access Journals (Sweden)

    Lam-Phuong Nguyen DO

    2016-04-01

    Full Text Available Acute fibrinous and organizing pneumonia (AFOP is an extremely rare, relatively new, and distinct histological pattern of acute lung injury characterized predominately by the presence of intra-alveolar fibrin and associated organizing pneumonia. AFOP may be idiopathic or associated with a wide spectrum of clinical conditions. It has a variable clinical presentation from mild respiratory symptoms to that similar to the acute respiratory distress syndrome. Currently there is no consensus on treatment, and corticosteroids previously were of unclear benefit. To date, there are less than 40 cases of AFOP reported in the literature and only one has been linked to hematopoietic stem cell transplantation. Here we report the first case series of 2 patients who developed AFOP following allogenic stem cell transplant that were successfully treated with high-dose corticosteroids.

  11. Plerixafor (a CXCR4 antagonist following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery

    Directory of Open Access Journals (Sweden)

    Michael M. B. Green

    2016-08-01

    Full Text Available Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1 maintains hematopoietic stem/progenitor cells (HSPCs in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28 (PBSC or bone marrow (n = 2 transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04 and platelet recovery >20 K (p = 0.04 compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

  12. Role of Mesenchymal Stem Cells In Tumorigenesis

    Science.gov (United States)

    2009-08-01

    growth and metastasis. 1 Body. Methods: Isolation of mASC. Perirenal , pelvine and subcutaneous fat tissue were dissected from EGFP...tumor invasion in the inter- play of tissue resident stem cells from the fat tissue and breast cancer cells. 2009 Elsevier Ireland Ltd. All rights...Herfarth, Secretion of RANTES (CCL5) and interleukin-10 from mesenteric adipose tissue and from creeping fat in Crohn’s disease: regulation by steroid

  13. Mesenchymal Stem Cells and Induced Pluripotent Stem Cells as Therapies for Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Juan Xiao

    2015-04-01

    Full Text Available Multiple sclerosis (MS is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC and induced pluripotent stem cell (iPSCs derived precursor cells can modulate the autoimmune response in the central nervous system (CNS and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS.

  14. Autologous Transplantation of Amniotic Fluid-Derived Mesenchymal Stem Cells into Sheep Fetuses.

    Science.gov (United States)

    Shaw, S W Steven; Bollini, Sveva; Nader, Khalil Abi; Gastaldello, Annalisa; Mehta, Vedanta; Filppi, Elisa; Cananzi, Mara; Gaspar, H Bobby; Qasim, Waseem; De Coppi, Paolo; David, Anna L

    2016-03-01

    Long-term engraftment and phenotype correction has been difficult to achieve in humans after in utero stem cell transplantation mainly because of allogeneic rejection. Autologous cells could be obtained during gestation from the amniotic fluid with minimal risk for the fetus and the mother. Using a sheep model, we explored the possibility of using amniotic fluid mesenchymal stem cells (AFMSCs) for autologous in utero stem cell/gene therapy. We collected amniotic fluid (AF) under ultrasound-guided amniocentesis in early gestation pregnant sheep ( n = 9, 58 days of gestation, term = 145 days). AFMSCs were isolated and expanded in all sampled fetal sheep. Those cells were transduced using an HIV vector encoding enhanced green fluorescent protein (GFP) with 63.2% (range 38.3-96.2%) transduction efficiency rate. After expansion, transduced AFMSCs were injected into the peritoneal cavity of each donor fetal sheep at 76 days under ultrasound guidance. One ewe miscarried twin fetuses after amniocentesis. Intraperitoneal injection was successful in the remaining 7 fetal sheep giving a 78% survival for the full procedure. Tissues were sampled at postmortem examination 2 weeks later. PCR analysis detected GFP-positive cells in fetal tissues including liver, heart, placenta, membrane, umbilical cord, adrenal gland, and muscle. GFP protein was detected in these tissues by Western blotting and further confirmed by cytofluorimetric and immunofluorescence analyses. This is the first demonstration of autologous stem cell transplantation in the fetus using AFMSCs. Autologous cells derived from AF showed widespread organ migration and could offer an alternative way to ameliorate prenatal congenital disease.

  15. Strategies to improve homing of mesenchymal stem cells for greater efficacy in stem cell therapy.

    Science.gov (United States)

    Naderi-Meshkin, Hojjat; Bahrami, Ahmad Reza; Bidkhori, Hamid Reza; Mirahmadi, Mahdi; Ahmadiankia, Naghmeh

    2015-01-01

    Stem/progenitor cell-based therapeutic approach in clinical practice has been an elusive dream in medical sciences, and improvement of stem cell homing is one of major challenges in cell therapy programs. Stem/progenitor cells have a homing response to injured tissues/organs, mediated by interactions of chemokine receptors expressed on the cells and chemokines secreted by the injured tissue. For improvement of directed homing of the cells, many techniques have been developed either to engineer stem/progenitor cells with higher amount of chemokine receptors (stem cell-based strategies) or to modulate the target tissues to release higher level of the corresponding chemokines (target tissue-based strategies). This review discusses both of these strategies involved in the improvement of stem cell homing focusing on mesenchymal stem cells as most frequent studied model in cellular therapies. © 2014 International Federation for Cell Biology.

  16. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis.

    Science.gov (United States)

    Koh, Yong-Gon; Jo, Seung-Bae; Kwon, Oh-Ryong; Suh, Dong-Suk; Lee, Seung-Woo; Park, Sung-Ho; Choi, Yun-Jin

    2013-04-01

    The purpose of this study was to evaluate the clinical and imaging results of patients who received intra-articular injections of autologous mesenchymal stem cells for the treatment of knee osteoarthritis. The study group comprised 18 patients (6 men and 12 women), among whom the mean age was 54.6 years (range, 41 to 69 years). In each patient the adipose synovium was harvested from the inner side of the infrapatellar fat pad by skin incision extension at the arthroscopic lateral portal site after the patient underwent arthroscopic debridement. After stem cells were isolated, a mean of 1.18 × 10(6) stem cells (range, 0.3 × 10(6) to 2.7 × 10(6) stem cells) were prepared with approximately 3.0 mL of platelet-rich plasma (with a mean of 1.28 × 10(6) platelets per microliter) and injected into the selected knees of patients. Clinical outcome was evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index, the Lysholm score, and the visual analog scale (VAS) for grading knee pain. We also compared magnetic resonance imaging (MRI) data collected both preoperatively and at the final follow-up. Western Ontario and McMaster Universities Osteoarthritis Index scores decreased significantly (P stem cells injected. The results of our study are encouraging and show that intra-articular injection of infrapatellar fat pad-derived mesenchymal stem cells is effective for reducing pain and improving knee function in patients being treated for knee osteoarthritis. Level IV, therapeutic case series. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  17. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

    NARCIS (Netherlands)

    C. Schmid (Christoph); M. Labopin (Myriam); A. Nagler (Arnon); D. Niederwieser (Dietger); L. Castagna (Luca); R. Tabrizi (Reza); M. Stadler (Michael); J. Kuball (Jürgen); J.J. Cornelissen (Jan); J. Vorlicek (Jiri); G. Socié (Gerard); M. Falda (M.); L. Vindelov (Lars); P. Ljungman (Per); G. Jackson (Graham); N. Kröger (Nicolaus); A. Rank (Andreas); E. Polge (Emmanuelle); V. Rocha (Vanderson); M. Mohty (Mohamad)

    2012-01-01

    textabstractBecause information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute LeukemiaWorking Party of EBMT. Among 2815 RIC

  18. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Schmid, Christoph; Labopin, Myriam; Nagler, Arnon

    2012-01-01

    Since information on management and outcome of adults with AML relapsing after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC HSCT) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC tran...

  19. Associations between gastrointestinal toxicity, micro RNA and cytokine production in patients undergoing myeloablative allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Pontoppidan, Peter Erik Lotko; Jordan, Karina Kwi Im; Carlsen, Anting Liu

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure with a high risk of treatment related mortality. The primary aim of the present study was to examine associations between markers of gastrointestinal toxicity, markers of systemic inflammation, and plasma levels of micro...... that these miRNAs may play a role in the regulation of the inflammatory environment during immune reconstitution after HSCT....

  20. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible : results of the HOVON 76 Trial

    NARCIS (Netherlands)

    Kneppers, Evelien; van der Holt, Bronno; Kersten, Marie-Jose; Zweegman, Sonja; Meijer, Ellen; Huls, Gerwin; Cornelissen, Jan J.; Janssen, Jeroen J.; Huisman, Cynthia; Cornelisse, Petra B.; Bruijnen, Cheryl P.; Emmelot, Maarten; Sonneveld, Pieter; Lokhorst, Henk M.; Mutis, Tuna; Minnema, Monique C.

    2011-01-01

    To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT.

  1. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial

    NARCIS (Netherlands)

    Kneppers, Evelien; van der Holt, Bronno; Kersten, Marie-Jose; Zweegman, Sonja; Meijer, Ellen; Huls, Gerwin; Cornelissen, Jan J.; Janssen, Jeroen J.; Huisman, Cynthia; Cornelisse, Petra B.; Bruijnen, Cheryl P.; Emmelot, Maarten; Sonneveld, Pieter; Lokhorst, Henk M.; Mutis, Tuna; Minnema, Monique C.

    2011-01-01

    To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT.

  2. A Characterization of the Oral Microbiome in Allogeneic Stem Cell Transplant Patients

    Science.gov (United States)

    Ames, Nancy J.; Sulima, Pawel; Ngo, Thoi; Barb, Jennifer; Munson, Peter J.; Paster, Bruce J.; Hart, Thomas C.

    2012-01-01

    Background The mouth is a complex biological structure inhabited by diverse bacterial communities. The purpose of this study is to describe the effects of allogeneic stem cell transplantation on the oral microbiota and to examine differences among those patients who acquired respiratory complications after transplantation. Methodology/Principal Findings All patients were consented at the National Institutes of Health, Clinical Center. Bacterial DNA was analyzed from patients' oral specimens using the Human Oral Microbe Identification Microarray. The specimens were collected from four oral sites in 45 allogeneic transplantation patients. Specimens were collected at baseline prior to transplantation, after transplantation at the nadir of the neutrophil count and after myeloid engraftment. If respiratory signs and symptoms developed, additional specimens were obtained. Patients were followed for 100 days post transplantation. Eleven patients' specimens were subjected to further statistical analysis. Many common bacterial genera, such as Streptococcus, Veillonella, Gemella, Granulicatella and Camplyobacter were identified as being present before and after transplantation. Five of 11 patients developed respiratory complications following transplantation and there was preliminary evidence that the oral microbiome changed in their oral specimens. Cluster analysis and principal component analysis revealed this change in the oral microbiota. Conclusions/Significance After allogeneic transplantation, the oral bacterial community's response to a new immune system was not apparent and many of the most common core oral taxa remained unaffected. However, the oral microbiome was affected in patients who developed respiratory signs and symptoms after transplantation. The association related to the change in the oral microbiota and respiratory complications after transplantation will be validated by future studies using high throughput molecular methods. PMID:23144704

  3. Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience.

    Science.gov (United States)

    Fernandes, Juliana Folloni; Kerbauy, Fabio Rodrigues; Ribeiro, Andreza Alice Feitosa; Kutner, Jose Mauro; Camargo, Luis Fernando Aranha; Stape, Adalberto; Troster, Eduardo Juan; Zamperlini-Netto, Gabriele; Azambuja, Alessandra Milani Prandini de; Carvalho, Bruna; Dorna, Mayra de Barros; Vilela, Marluce Dos Santos; Jacob, Cristina Miuki Abe; Costa-Carvalho, Beatriz Tavares; Cunha, Jose Marcos; Carneiro-Sampaio, Magda Maria; Hamerschlak, Nelson

    2011-06-01

    To report the experience of a tertiary care hospital with allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies. Seven pediatric patients with primary immunodeficiencies (severe combined immunodeficiency: n = 2; combined immunodeficiency: n = 1; chronic granulomatous disease: n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1) who underwent eight hematopoietic stem cell transplants in a single center, from 2007 to 2010, were studied. Two patients received transplants from HLA-identical siblings; the other six transplants were done with unrelated donors (bone marrow: n = 1; cord blood: n = 5). All patients had pre-existing infections before hematopoietic stem cell transplants. One patient received only anti-thymocyte globulin prior to transplant, three transplants were done with reduced intensity conditioning regimens and four transplants were done after myeloablative therapy. Two patients were not evaluated for engraftment due to early death. Three patients engrafted, two had primary graft failure and one received a second transplant with posterior engraftment. Two patients died of regimen related toxicity (hepatic sinusoidal obstruction syndrome); one patient died of progressive respiratory failure due to Parainfluenza infection present prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Patients' status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

  4. Multilineage Potential Research of Bovine Amniotic Fluid Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Yuhua Gao

    2014-02-01

    Full Text Available The use of amnion and amniotic fluid (AF are abundant sources of mesenchymal stem cells (MSCs that can be harvested at low cost and do not pose ethical conflicts. In human and veterinary research, stem cells derived from these tissues are promising candidates for disease treatment, specifically for their plasticity, their reduced immunogenicity, and high anti-inflammatory potential. This work aimed to obtain and characterize bovine amniotic fluid mesenchymal stem cells (AFMSC. The bovine AF from the amniotic cavity of pregnant gilts in the early stages of gestation (3- and 4-m-old bovine embryos was collected. AFMSCs exhibit a fibroblastic-like morphology only starting from the fourth passage, being heterogeneous during the primary culture. Immunofluorescence results showed that AFMSCs were positive for β-integrin, CD44, CD73 and CD166, but negative for CD34, CD45. Meanwhile, AFMSCs expressed ES cell markers, such as Oct4, and when appropriately induced, are capable of differentiating into ectodermal and mesodermal lineages. This study reinforces the emerging importance of these cells as ideal tools in veterinary medicine; future studies aimed at a deeper evaluation of their immunological properties will allow a better understanding of their role in cellular therapy.

  5. Isolation of mesenchymal stem cells from human vermiform appendix.

    Science.gov (United States)

    De Coppi, Paolo; Pozzobon, Michela; Piccoli, Martina; Gazzola, Maria Vittoria; Boldrin, Luisa; Slanzi, Elisa; Destro, Roberta; Zanesco, Luigi; Zanon, Giovanni Franco; Gamba, Piergiorgio

    2006-09-01

    Recent findings have shown that pluripotent stem cells exist in areas outside the bone marrow (BM). Moreover, it has been demonstrated that the appendix is important for the development of mucosal gut immunity, and hematopoietic progenitors have been isolated from animal and human appendices. Non-inflamed appendices removed during laparotomy were processed and cultured until the appearance of adherent cells. Differentiations (performed under osteogenic, adipogenic, and myogenic conditions) were confirmed by immunohistochemistry and cytochemistry. Polymerase chain reaction and cytofluorimetric analyses were performed to evidence the presence of genes and protein specific lineages in appendix-derived mesenchymal stem cells (ADMCs). ADMCs were present in non-inflamed appendices. ADMCs under osteogenic conditions differentiated in osteoblasts and showed increased alkaline phosphatase expression; at the gene level, we observed the expression of Core binding factor alpha 1 (Cbfa1) and osteocalcin in osteogenic induced ADMCs. Under adipogenic conditions, lipidic drops in the cytoplasm, expression of lipoprotein lipase (LpL), and peroxisome proliferator-activated receptor gamma were observed; under myogenic conditions, myotubes expressing muscle specific proteins like desmin were formed. Myogenic regulatory factor 4 and MyoD were selectively induced in the ADMCs under myogenic conditions. This study shows for the first time that mesenchymal stem cells can be isolated from normal appendices obtained from a pediatric and adult age group (0-18 years of age). This finding not only may further knowledge of the maturation of the intestinal immunesystem but also could indicate a new physiological role of the human vermiform appendix.

  6. Molecular and environmental cues in cardiac differentiation of mesenchymal stem cells

    NARCIS (Netherlands)

    Ramkisoensing, Arti Anushka

    2014-01-01

    In this thesis molecular and environmental cues in cardiac differentiation of mesenchymal stem cells were investigated. The main conclusions were that the cardiac differentiation potential of human mesenchymal stem cells negatively correlates with donor age. This in its own shows a negative

  7. Design and development of a magnetic device for mesenchymal stem cell retaining in deep targets

    Science.gov (United States)

    Banis, G. C.

    2017-12-01

    This paper focuses on the retaining of mesenchymal stem cells in blood flow conditions using the appropriate magnetic field. Mesenchymal stem cells can be tagged with magnetic nanoparticles and thus, they can be manipulated from distance, through the application of an external magnetic field. In this paper the case of kidney as target of the therapy is being studied.

  8. Venous Thromboembolism after Allogeneic Pediatric Hematopoietic Stem Cell Transplantation: A Single-Center Study

    Directory of Open Access Journals (Sweden)

    Fatih Azık

    2015-09-01

    Full Text Available Objective: Venous thromboembolism (VTE in children who undergo hematopoietic stem cell transplantation (HSCT has high morbidity. The aim of this study is to assess the incidence of VTE in allogeneic pediatric HSCT recipients and the contribution of pretransplant prothrombotic risk factors to thrombosis. Materials and Methods: We retrospectively evaluated 92 patients between April 2010 and November 2012 undergoing allogeneic HSCT who had completed 100 days post-HSCT. Before HSCT, coagulation profiles; acquired and inherited prothrombotic risk factors including FV G1691A (factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR C677T, and MTHFR A1298C mutations; and serum homocysteine and lipoprotein (a, plasma antithrombin III, protein C, and protein S levels were obtained from all patients. Results: In the screening of thrombophilia, 8 patients (9% were heterozygous for factor V Leiden, 5 (6% were homozygous for MTHFR 677TT, 12 (14% were homozygous for MTHFR 1298CC, and 2 (2% were heterozygous for prothrombin G20210A mutation. We observed VTE in 5 patients (5.4%; a prothrombotic risk factor was found in 3 out of these 5 patients, while 4 out of 5 patients had central venous catheters. It was determined there was no significant relationship between VTE and inherited prothrombotic risk factors. Conclusion: VTE after HSCT seems to be a low-frequency event that may be due to low-dose, low-molecular-weight heparin prophylaxis, and the role of inherited prothrombotic risk factors cannot be entirely excluded without a prospective study.

  9. Chloroma of the Testis After Allogeneic Peripheral Blood Stem Cell Transplantation: A Case Report

    Directory of Open Access Journals (Sweden)

    Shih-Wen Hu

    2004-10-01

    Full Text Available Chloroma, or granulocytic sarcoma, is a rare extramedullary solid hematologic cancer that affects many sites, usually in concert with acute myeloid leukemia. It is infrequently associated with other myeloproliferative disorders or chronic myelogenous leukemia. Chloroma of the testis after allogeneic bone marrow transplantation is particularly sparsely represented in the literature. It is often incorrectly diagnosed as malignant lymphoma, especially large-cell lymphoma, owing to the similarity of the histologic morphology, scanty eosinophilic myelocytes, and no or overlooked history of leukemia. Although erroneous diagnosis is decreasing with the advent of ancillary studies, the diagnosis of chloroma continues to be a nightmare for pathologists. It is thus suggested that an appropriate panel of marker studies be performed in conjunction with clinical correlation and circumspection to avoid reaching a misleading conclusion and improper treatment of patients. We report an interesting case of a 35-year-old male with a clinical history of chronic myelogenous leukemia post allogeneic peripheral blood stem cell transplantation and complete molecular remission, who was found to have chloroma of the left testis.

  10. Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

    Science.gov (United States)

    Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

    2005-03-01

    Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure.

  11. Monitoring of pathogen-specific T-cell immune reconstitution after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Fuji, Shigeo; Kapp, Markus; Einsele, Hermann

    2013-09-17

    The clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) has been significantly improved during the last decades with regard to the reduction in organ failure, infection, and severe acute graft-versus-host disease. However, severe complications due to infectious diseases are still one of the major causes of morbidity and mortality after allogeneic HSCT, in particular in patients receiving haploidentical HSCT or cord blood transplant due to a slow and often incomplete immune reconstitution. In order to improve the immune control of pathogens without an increased risk of alloreactivity, adoptive immunotherapy using highly enriched pathogen-specific T cells offers a promising approach. In order to identify patients who are at high risk for infectious diseases, several monitoring assays have been developed with potential for the guidance of immunosuppressive drugs and adoptive immunotherapy in clinical practice. In this article, we aim to give a comprehensive overview regarding current developments of T-cell monitoring techniques focusing on T cells against viruses and fungi. In particular, we will focus on rather simple, fast, non-labor-intensive, cellular assays which could be integrated in routine clinical screening approaches.

  12. Importance of mesenchymal stem cells in autologous fat grafting

    DEFF Research Database (Denmark)

    Trojahn Kølle, Stig-Frederik; Oliveri, Roberto S; Glovinski, Peter Viktor

    2012-01-01

    the fat graft with adipose tissue-derived mesenchymal stem cells (ASC) before transplantation. We have reviewed original studies published on fat transplantation enriched with ASC. We found four murine and three human studies that investigated the subject after a sensitive search of publications....... In the human studies, so-called cell assisted lipotransfer (CAL) increased the ASC concentration 2-5 times compared with non-manipulated fat grafts, which caused a questionable improvement in survival of fat grafts, compared with that of traditional lipofilling. In contrast, in two of the murine studies ASC...

  13. Human bone-marrow-derived mesenchymal stem cells

    DEFF Research Database (Denmark)

    Kassem, Moustapha; Abdallah, Basem M

    2008-01-01

    Mesenchymal stem cells (MSC) are a group of cells present in bone-marrow stroma and the stroma of various organs with the capacity for mesoderm-like cell differentiation into, for example, osteoblasts, adipocytes, and chondrocytes. MSC are being introduced in the clinic for the treatment...... of a variety of clinical conditions. The aim of this review is to provide an update regarding the biology of MSC, their identification and culture, and mechanisms controlling their proliferation and differentiation. We also review the current status of their clinical use. Areas in which research is needed...

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    Lifescience Database Archive (English)

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  13. File list: DNS.Adp.05.AllAg.Adipose-Derived_Mesenchymal_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.

    Directory of Open Access Journals (Sweden)

    Marilène Binsfeld

    Full Text Available Multiple myeloma (MM is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD.Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor or autologous (Balb/cJ donor transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses

  15. Systemic Delivery of Bone Marrow Mesenchymal Stem Cells for In Situ Intervertebral Disc Regeneration

    Science.gov (United States)

    Almeida, Catarina R.; Almeida, Maria Inês; Silva, Andreia M.; Molinos, Maria; Lamas, Sofia; Pereira, Catarina L.; Teixeira, Graciosa Q.; Monteiro, António T.; Santos, Susana G.; Gonçalves, Raquel M.; Barbosa, Mário A.

    2016-01-01

    Abstract Cell therapies for intervertebral disc (IVD) regeneration presently rely on transplantation of IVD cells or stem cells directly to the lesion site. Still, the harsh IVD environment, with low irrigation and high mechanical stress, challenges cell administration and survival. In this study, we addressed systemic transplantation of allogeneic bone marrow mesenchymal stem cells (MSCs) intravenously into a rat IVD lesion model, exploring tissue regeneration via cell signaling to the lesion site. MSC transplantation was performed 24 hours after injury, in parallel with dermal fibroblasts as a control; 2 weeks after transplantation, animals were killed. Disc height index and histological grading score indicated less degeneration for the MSC‐transplanted group, with no significant changes in extracellular matrix composition. Remarkably, MSC transplantation resulted in local downregulation of the hypoxia responsive GLUT‐1 and in significantly less herniation, with higher amounts of Pax5+ B lymphocytes and no alterations in CD68+ macrophages within the hernia. The systemic immune response was analyzed in the blood, draining lymph nodes, and spleen by flow cytometry and in the plasma by cytokine array. Results suggest an immunoregulatory effect in the MSC‐transplanted animals compared with control groups, with an increase in MHC class II+ and CD4+ cells, and also upregulation of the cytokines IL‐2, IL‐4, IL‐6, and IL‐10, and downregulation of the cytokines IL‐13 and TNF‐α. Overall, our results indicate a beneficial effect of systemically transplanted MSCs on in situ IVD regeneration and highlight the complex interplay between stromal cells and cells of the immune system in achieving successful tissue regeneration. Stem Cells Translational Medicine 2017;6:1029–1039 PMID:28297581

  16. Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Marks, David I; Liu, Qifa; Slavin, Monica

    2017-05-01

    Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden. Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients. Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT.

  17. Socially disadvantaged parents of children treated with allogeneic haematopoietic stem cell transplantation (HSCT)

    DEFF Research Database (Denmark)

    Larsen, Hanne Bækgaard; Heilmann, Carsten; Johansen, Christoffer

    2013-01-01

    PURPOSE: This study was undertaken to test a daily Family Navigator Nurse (FNN) conducted intervention program, to support parents during the distressful experience of their child's Allogeneic Haematopoietic Stem Cell Transplantation (HSCT). METHODS: A qualitative analysis of the supportive...... intervention program for parents whose child is under HSCT treatment while hospitalized. Parents to 25 children were included in the intervention group. Twenty-five parents were included in a participant observational study and 21 of these completed a semi-structured interview 100 days following HSCT. RESULTS......: Three main problems faced by all parents included 1) the emotional strain of the child's HSCT; 2) re-organizing of the family's daily life to include hospitalization with the child; and 3) the financial strain of manoeuvring within the Danish welfare system. The FNN performed daily intervention rounds...

  18. Prognosis of Allogeneic Haematopoietic Stem Cell Recipients Admitted to the Intensive Care Unit

    DEFF Research Database (Denmark)

    Lindgaard, Sidsel Christy; Nielsen, Jonas; Lindmark, Anders

    2016-01-01

    BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is a procedure with inherent complications and intensive care may be necessary. We evaluated the short- and long-term outcomes of the HSCT recipients requiring admission to the intensive care unit (ICU). METHODS: We...... ventilation had a statistically significant effect on in-ICU (p = 0.02), 6-month (p = 0.049) and 1-year (p = 0.014) mortality. Renal replacement therapy also had a statistically significant effect on in-hospital (p = 0.038) and 6-month (p = 0.026) mortality. Short ICU admissions, i.e. ... to the ICU was confirmed in our study. Mechanical ventilation, renal replacement therapy and an ICU admission of ≥10 days were each risk factors for mortality in the first year after ICU admission....

  19. Solid organ transplantation after allogeneic hematopoietic stem cell transplantation: a retrospective, multicenter study of the EBMT

    DEFF Research Database (Denmark)

    Koenecke, C; Hertenstein, B; Schetelig, J

    2010-01-01

    To analyze the outcome of solid organ transplantation (SOT) in patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT), a questionnaire survey was carried out within 107 European Group of Blood and Marrow Transplantation centers. This study covered HSCT between 1984...... and 2007 in Europe. Forty-five SOT in 40 patients were reported. Fifteen liver, 15 renal, 13 lung, 1 heart and 1 skin transplantations were performed in 28 centers. Overall survival (OS) of patients after SOT was 78% at 5 years (95% confidence interval [CI], 64% to 92%). OS at 5 years was 100% for renal......, 71% (95% CI, 46% to 96%) for liver and 63% (95% CI, 23% to 100%) for lung transplant recipients. The 2-year-incidence of SOT failure was 20% (95% CI, 4% to 36%) in patients with graft-versus-host disease (GvHD) and 7% (95% CI, 0% to 21%) in patients without GvHD before SOT. The relapse incidence...

  20. Outcome of match related allogeneic stem cell transplantation procedures performed from 2004 till 2011

    Directory of Open Access Journals (Sweden)

    Ali Natasha

    2012-05-01

    Full Text Available Abstract We present our initial experience of allogeneic stem cell transplant procedure performed between April 2004 and August 2011 for various haematological disorders. All patients with non-malignant and malignant haematological disorders with HLA matched donors were selected after pre-transplant workup. Ninety seven patients underwent the procedure. Most common indications for transplant were aplastic anaemia in n = 34 (35%, followed by β-Thalassemia major in n = 21 (21.6% and chronic myeloid leukemia in n = 11 patients (11.3%. Primary graft failure present was present in 2.06%. Incidence of graft versus host disease (GvHD in our patients was 34%. After median follow-up of five years the overall survival was 71.3% with a mean survival time of 51.2 ± 3.3 months.

  1. Successful allogeneic stem cells transplantation in severe aplastic anaemia complicated by dengue fever

    International Nuclear Information System (INIS)

    Ullah, K.; Satti, T.M.; Ahmed, P.; Raza, A.; Akhtar, F.M.; Tariq, W.U.Z.

    2007-01-01

    Aplastic anaemia is characterized by severe compromise of haematopoiesis and hypocellular bone marrow. Haemorrhagic episodes in patients with aplastic anemia occur usually secondary to thrombocytopenia and require frequent support with platelet concentrates and other blood products. Infection with dengue virus (particularly dengue sero type-2 of South Asian genotype) is associated with dengue haemorrhagic fever. Dengue infection further worsens the disease process in patients with aplastic anaemia due to uncontrolled haemorrhagic diathesis and major organ failure, which may prove fatal in these already immunocompromised patients, if not treated in time. Recent epidemics of dengue haemorrhagic fever has not only affected the southern region of our country but also spread to other areas of the country. With this background, we report a case of aplastic anaemia complicated by dengue haemorrhagic fever who achieved successful engraftment after allogeneic stem cell transplantation from sibling brother and is having normal healthy post transplant life. (author)

  2. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    DEFF Research Database (Denmark)

    Nicolini, Franck Emmanuel; Basak, Grzegorz W; Soverini, Simona

    2011-01-01

    T315I(+) Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL(T315I) mutations. Median follow......-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie......, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic...

  3. [Immune regulatory effect of human bone marrow mesenchymal stem cells on T lymphocyte].

    Science.gov (United States)

    Lu, Xiao-Xi; Liu, Ting; Meng, Wen-Tong; Zhu, Huan-Ling; Xi, Ya-Ming; Liu, Yong-Mei

    2005-08-01

    To investigate the immune regulatory effects of human bone marrow mesenchymal stem cells on alloantigen T lymphocyte in vitro, human MSCs were isolated and expanded from bone marrow cells, and identified with cell morphology, and the phenotypes were assessed by immunohistochemistry and flow cytometry. As the stimulation factor of T lymphocytes proliferation, either PHA or dendritic cells isolated from cord blood were cocultured with CD2(+) T lymphocytes from peripheral blood mononuclear cells by magnetic beads with or without MSC in 96-well plats for seven days. T cell proliferation was assessed by [(3)H]-thymidine incorporation using a liquid scintillation counter. T cell subsets, Th1, Th2, Tc1 and Tc2 were analyzed by flow cytometry after co-culture of CD2(+) T cells with MSCs for 10 days. The results showed that a significant decrease of CD2(+) T cell proliferation was evident when MSC were added back to T cells stimulated by DC or PHA, and an increase of Th2 and Tc2 subsets were observed after co-culture of MSC with T lymphocytes. It is suggested that allogeneic MSC can suppress T cell proliferation in vitro and the cause of that was partly depend on interaction of cells and the alteration of T cell subsets.

  4. Differentiation-dependent secretion of proangiogenic factors by mesenchymal stem cells.

    Directory of Open Access Journals (Sweden)

    Allison I Hoch

    Full Text Available Mesenchymal stem cells (MSCs are a promising cell population for cell-based bone repair due to their proliferative potential, ability to differentiate into bone-forming osteoblasts, and their secretion of potent trophic factors that stimulate angiogenesis and neovascularization. To promote bone healing, autogenous or allogeneic MSCs are transplanted into bone defects after differentiation to varying degrees down the osteogenic lineage. However, the contribution of the stage of osteogenic differentiation upon angiogenic factor secretion is unclear. We hypothesized that the proangiogenic potential of MSCs was dependent upon their stage of osteogenic differentiation. After 7 days of culture, we observed the greatest osteogenic differentiation of MSCs when cells were cultured with dexamethasone (OM+. Conversely, VEGF protein secretion and upregulation of angiogenic genes were greatest in MSCs cultured in growth media (GM. Using conditioned media from MSCs in each culture condition, GM-conditioned media maximized proliferation and enhanced chemotactic migration and tubule formation of endothelial colony forming cells (ECFCs. The addition of a neutralizing VEGF(165/121 antibody to conditioned media attenuated ECFC proliferation and chemotactic migration. ECFCs seeded on microcarrier beads and co-cultured with MSCs previously cultured in GM in a fibrin gel exhibited superior sprouting compared to MSCs previously cultured in OM+. These results confirm that MSCs induced farther down the osteogenic lineage possess reduced proangiogenic potential, thereby providing important findings for consideration when using MSCs for bone repair.

  5. Experimental observation of human bone marrow mesenchymal stem cell transplantation into rabbit intervertebral discs.

    Science.gov (United States)

    Tao, Hao; Lin, Yazhou; Zhang, Guoqing; Gu, Rui; Chen, Bohua

    2016-09-01

    Allogeneic bone marrow mesenchymal stem cell (BMSC) transplantation has been investigated worldwide. However, few reports have addressed the survival status of human BMSCs in the intervertebral discs (IVDs) in vivo following transplantation. The current study aimed to observe the survival status of human BMSCs in rabbit IVDs. The IVDs of 15 New Zealand white rabbits were divided into three groups: Punctured blank control group (L1-2); punctured physiological saline control group (L2-3); and punctured human BMSCs transfected with green fluorescent protein (GFP) group (L3-4, L4-5 and L5-6). One, 2, 4, 6 and 8 weeks after transplantation the IVDs were removed and a fluorescence microscope was used to observe the density of GFP-positive human BMSCs. The results indicated that in the sections of specimens removed at 1, 2, 4, 6 and 8 weeks post-transplantation, no GFP-positive cells were observed in the control groups, whereas GFP-positive cells were apparent in the nucleus pulposus at all periods in the GFP-labeled human BMSCs group, and the cell density at 6 and 8 weeks was significantly less than that at 1, 2 and 4 weeks post-transplantation (P<0.001). Thus, it was identified that human BMSCs were able to survive in the rabbit IVDs for 8 weeks.

  6. Bone marrow mesenchymal stem cells ameliorate colitis-associated tumorigenesis in mice.

    Science.gov (United States)

    Chen, Zexian; He, Xiaowen; He, Xiaosheng; Chen, Xiuting; Lin, Xutao; Zou, Yifeng; Wu, Xiaojian; Lan, Ping

    2014-08-08

    Bone marrow-derived mesenchymal stem cell (MSC) is widely studied in inflammatory bowel disease (IBD) in basic and clinical research. However, patients with IBD have higher risk of developing colorectal cancer and MSC has dual effect on tumorigenesis. This study aims to evaluate the role of MSC on tumorigenesis of IBD. MSCs were isolated from the bone marrow of allogenic mice and identified by flow cytometry. Mice in the model of colitis-associated tumorigenesis induced by azoxymethane and dextran sulfate sodium were injected with MSCs. Colon length, spleen size and tumors formation were assessed macroscopically. Pro-inflammatory cytokines and STAT3 phosphorylation in colon tissues were analyzed. MSCs ameliorated the severity of colitis associated tumorigenesis compared with PBS control, with attenuated weight loss, longer colons and smaller spleens. Tumor number and tumor load were significantly less in the MSC group while tumor size remained comparable. Histological assessment indicated MSCs could reduce histological damage of the colon tissue. Decreased expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), and down-regulation of STAT3 phosphorylation in colon tissue were found after MSC treatment. MSCs might ameliorate the tumorigenesis of inflammatory bowel disease by suppression of expression of pro-inflammatory cytokines and STAT3 activation. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Composition of Mineral Produced by Dental Mesenchymal Stem Cells.

    Science.gov (United States)

    Volponi, A A; Gentleman, E; Fatscher, R; Pang, Y W Y; Gentleman, M M; Sharpe, P T

    2015-11-01

    Mesenchymal stem cells isolated from different dental tissues have been described to have osteogenic/odontogenic-like differentiation capacity, but little attention has been paid to the biochemical composition of the material that each produces. Here, we used Raman spectroscopy to analyze the mineralized materials produced in vitro by different dental cell populations, and we compared them with the biochemical composition of native dental tissues. We show that different dental stem cell populations produce materials that differ in their mineral and matrix composition and that these differ from those of native dental tissues. In vitro, BCMP (bone chip mass population), SCAP (stem cells from apical papilla), and SHED (stem cells from human-exfoliated deciduous teeth) cells produce a more highly mineralized matrix when compared with that produced by PDL (periodontal ligament), DPA (dental pulp adult), and GF (gingival fibroblast) cells. Principal component analyses of Raman spectra further demonstrated that the crystallinity and carbonate substitution environments in the material produced by each cell type varied, with DPA cells, for example, producing a more carbonate-substituted mineral and with SCAP, SHED, and GF cells creating a less crystalline material when compared with other dental stem cells and native tissues. These variations in mineral composition reveal intrinsic differences in the various cell populations, which may in turn affect their specific clinical applications. © International & American Associations for Dental Research 2015.

  8. Intra-arterial delivery of mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Mitsuyoshi Watanabe

    2016-01-01

    Full Text Available While treatments have been developed to combat stroke, such as intravenous recombinant tissue plasminogen activator and endovascular recanalization therapies, their ability to decrease the long-term disability that accompanies stroke is limited. Currently, stem cell research focused on mesenchymal stem cells (MSCs. MSCs are multipotent, nonhematopoietic stem cells found in the stromal fraction of the bone marrow, along with the connective tissue of most organs. MSCs are an increasingly appealing cell source due to the relative ease in which they can be retrieved, developed, and handled in vitro. Despite the fact that numerous paths of stem cell transport to the brain in acute ischemic stroke (AIS exist, the intra-arterial (IA route of stem cell transport is most attractive. This is due to its great potential for clinical translation, especially considering the growing clinical application of endovascular treatment for AIS. Here, we evaluate research examining IA delivery of MSCs to the stroke region. The results of the study revealed the maximum tolerated dose and that the optimal time for administration was 24 h, following cerebral ischemia. It is important that future translational studies are performed to establish IA administration of MSCs as a widely used treatment for AIS.

  9. Mesenchymal Stem Cell Therapy in Diabetes Mellitus: Progress and Challenges

    Directory of Open Access Journals (Sweden)

    Nagwa El-Badri

    2013-01-01

    Full Text Available Advanced type 2 diabetes mellitus is associated with significant morbidity and mortality due to cardiovascular, nervous, and renal complications. Attempts to cure diabetes mellitus using islet transplantation have been successful in providing a source for insulin secreting cells. However, limited donors, graft rejection, the need for continued immune suppression, and exhaustion of the donor cell pool prompted the search for a more sustained source of insulin secreting cells. Stem cell therapy is a promising alternative for islet transplantation in type 2 diabetic patients who fail to control hyperglycemia even with insulin injection. Autologous stem cell transplantation may provide the best outcome for those patients, since autologous cells are readily available and do not entail prolonged hospital stays or sustained immunotoxic therapy. Among autologous adult stem cells, mesenchymal stem cells (MSCs therapy has been applied with varying degrees of success in both animal models and in clinical trials. This review will focus on the advantages of MSCs over other types of stem cells and the possible mechanisms by which MSCs transplant restores normoglycemia in type 2 diabetic patients. Sources of MSCs including autologous cells from diabetic patients and the use of various differentiation protocols in relation to best transplant outcome will be discussed.

  10. Immunosuppressive and remodelling properties of mesenchymal stem cells in a model of chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Patricia Semedo

    2009-12-01

    Full Text Available Objective: To investigate the role of mesenchymal stem cells in fibrogenesis using a model of chronic renal insufficiency. Methods: Mesenchymal stem cells  were obtained from tibias and femurs of Wistar-EPM rats. After three to five passages, the cells were submitted to phenotypic analyses and differentiation. Wistar rats were submitted to the 5/6 nephrectomy model, and 2.105 mesenchymal stem cells  were administered intravenously to each rat every two weeks until the eighth week. Rresults: Sex-determining region Y was observed in female rats treated with stem cells. Serum and urine analyses showed improvement of functional parameters in mesenchymal stem cells treated animals, such as creatinine, serum urea, and proteinuria. Moreover, hemocrit analysis showed improvement of anemia in mesenchymal stem cells treated animals. Masson’s Trichromium and Picrosirius Red staining demonstrated reduced levels of fibrosis in mesenchymal stem cells treated in animals. These results were corroborated by reduced vimentin, collagen I, TGFβ, FSP-1, MCP-1 and Smad3 mRNA expression. Renal IL-6 and TNFα mRNA expression levels were significantly decreased after mesenchymal stem cells treatment, while IL-4 and IL-10 expression were increased. Serum expression of IL-1α, IL-1β, IL-6, IFN-γ, TNF-α, and IL-10 was decreased in mesenchymal cell-treated animals. Cconclusions: Altogether, these results suggest that mesenchymal stem cells therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal lesion. The immunosuppresive and remodeling properties of the mesenchymal stem cells  may be involved in the improved fibrotic outcome.

  11. Tackling mantle cell lymphoma (MCL: Potential benefit of allogeneic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Satish Shanbhag

    2010-07-01

    Full Text Available Satish Shanbhag1,2, Mitchell R Smith1, Robert VB Emmons21Department of Medical Oncology, Fox Chase Cancer Center, 2Division of Bone Marrow Transplantation, Temple University, Philadelphia, PA, USAAbstract: Mantle cell lymphoma (MCL is a type of non-Hodgkins lymphoma (NHL associated with poor progression-free and overall survival. There is a high relapse rate with conventional cytotoxic chemotherapy. Intensive combination chemotherapy including rituximab, dose intense CHOP- (cyclophosphamide-doxorubicin-vincristine-prednisone like regimens, high dose cytarabine, and/or consolidation with autologous stem cell transplant (autoSCT have shown promise in significantly prolonging remissions. Data from phase II studies show that even in patients with chemotherapy refractory MCL, allogeneic stem cell transplant (alloSCT can lead to long term disease control. Most patients with MCL are not candidates for myeloablative alloSCT due to their age, comorbidities, and performance status. The advent of less toxic reduced intensity conditioning (RIC regimens, which rely more on the graft-versus-lymphoma (GVL effect, have expanded the population of patients who would be eligible for alloSCT. RIC regimens alter the balance of toxicity and efficacy favoring its use. Treatment decisions are complicated by introduction of novel agents which are attractive options for older, frail patients. Further studies are needed to determine the role and timing of alloSCT in MCL. Currently, for selected fit patients with chemotherapy resistant MCL or those who progress after autoSCT, alloSCT may provide long term survival.Keywords: mantle cell lymphoma, allogeneic SCT, nonmyeloablative, GVL

  12. Impact of Molecular Genetics on Outcome in Myelofibrosis Patients after Allogeneic Stem Cell Transplantation.

    Science.gov (United States)

    Kröger, Nicolaus; Panagiota, Victoria; Badbaran, Anita; Zabelina, Tatjana; Triviai, Ioanna; Araujo Cruz, Michelle Maria; Shahswar, Rabia; Ayuk, Francis; Gehlhaar, Marten; Wolschke, Christine; Bollin, Robin; Walter, Carolin; Dugas, Martin; Wiehlmann, Lutz; Lehmann, Ulrich; Koenecke, Christian; Chaturvedi, Anuhar; Alchalby, Haefaa; Stadler, Michael; Eder, Matthias; Christopeit, Max; Göhring, Gudrun; Koenigsmann, Michael; Schlegelberger, Brigitte; Kreipe, Hans-Heinrich; Ganser, Arnold; Stocking, Carol; Fehse, Boris; Thol, Felicitas; Heuser, Michael

    2017-07-01

    Molecular genetics may influence outcome for patients with myelofibrosis. To determine the impact of molecular genetics on outcome after allogeneic stem cell transplantation, we screened 169 patients with primary myelofibrosis (n = 110), post-essential thrombocythemia/polycythemia vera myelofibrosis (n = 46), and myelofibrosis in transformation (n = 13) for mutations in 16 frequently mutated genes. The most frequent mutation was JAK2V617F (n = 101), followed by ASXL1 (n = 49), calreticulin (n = 34), SRSF2 (n = 16), TET2 (n = 10), U2AF1 (n = 11), EZH2 (n = 7), MPL (n = 6), IDH2 (n = 5), IDH1 (n = 4), and CBL (n = 1). The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 21% and of relapse at 5 years 25%. The 5-year rates progression-free (PFS) and overall survival (OS) were and 56%, respectively. In a multivariate analysis CALR mutation was an independent factor for lower NRM (HR, .415; P = .05), improved PFS (HR, .393; P = .01), and OS (HR, .448; P = .03). ASXL1 and IDH2 mutations were independent risk factors for lower PFS (HR, 1.53 [P = .008], and HR, 5.451 [P = .002], respectively), whereas no impact was observed for "triple negative" patients. Molecular genetics, especially CALR, IDH2, and ASXL1 mutations, may thus be useful to predict outcome independently from known clinical risk factors after allogeneic stem cell transplantation for myelofibrosis. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  13. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

    Directory of Open Access Journals (Sweden)

    Maria Ausiliatrice Puglisi

    2011-01-01

    Full Text Available Mesenchymal stem cells (MSCs, represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases.

  14. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

    Science.gov (United States)

    Puglisi, Maria Ausiliatrice; Tesori, Valentina; Lattanzi, Wanda; Piscaglia, Anna Chiara; Gasbarrini, Giovanni Battista; D'Ugo, Domenico M.; Gasbarrini, Antonio

    2011-01-01

    Mesenchymal stem cells (MSCs), represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases. PMID:22228987

  15. Mesenchymal stem cells homing to improve bone healing

    Directory of Open Access Journals (Sweden)

    Weiping Lin

    2017-04-01

    Full Text Available Cell therapy continues to attract growing interest as a promising approach to treat a variety of diseases. Mesenchymal stem cells (MSCs have been one of the most intensely studied candidates for cell therapy. Since the homing capacity of MSCs is an important determinant of effective MSC-based therapy, the enhancement of homing efficiency is essential for optimizing the therapeutic outcome. Furthermore, trafficking of endogenous MSCs to damaged tissues, also referred to as endogenic stem cell homing, and the subsequent participation of MSCs in tissue regeneration are considered to be a natural self-healing response. Therefore, strategies to stimulate and reinforce the mobilisation and homing of MSCs have become a key point in regenerative medicine. The current review focuses on advances in the mechanisms and factors governing trafficking of MSCs, and the relationship between MSC mobilisation and skeletal diseases, providing insights into strategies for their potential translational implications.

  16. Genetically engineered mesenchymal stem cells: applications in spine therapy.

    Science.gov (United States)

    Aslan, Hadi; Sheyn, Dima; Gazit, Dan

    2009-01-01

    Spine disorders and intervertebral disc degeneration are considered the main causes for the clinical condition commonly known as back pain. Spinal fusion by implanting autologous bone to produce bony bridging between the two vertebrae flanking the degenerated-intervertebral disc is currently the most efficient treatment for relieving the symptoms of back pain. However, donor-site morbidity, complications and the long healing time limit the success of this approach. Novel developments undertaken by regenerative medicine might bring more efficient and available treatments. Here we discuss the pros and cons of utilizing genetically engineered mesenchymal stem cells for inducing spinal fusion. The combination of the stem cells, gene and carrier are crucial elements for achieving optimal spinal fusion in both small and large animal models, which hopefully will lead to the development of clinical applications.

  17. Major non-ABO incompatibility caused by anti-Jk(a) in a patient before allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Kim, M Y; Chaudhary, P; Shulman, I A; Pullarkat, V

    2013-01-01

    A 49-year-old white man with blood group AB, D+ was found to have alloanti-Jk(a) and -K when he developed a delayed hemolytic transfusion reaction before allogeneic hematopoietic stem cell transplant (HSCT). Given that his stem cell donor was blood group O, D+, Jk(a+), K-, rituximab was added to his conditioning regimen of fludarabine and melphalan to prevent hemolysis of engrafting Jk(a+) donor red blood cells. The patient proceeded to receive a peripheral blood stem cell transplant from a matched unrelated donor with no adverse events. To our knowledge, this is the first case of successful management of major non-ABO incompatibility caused by anti-Jk(a) in a patient receiving an allogeneic HSCT reported in the literature.

  18. Induction of mesenchymal stem cell chondrogenesis by polyacrylate substrates.

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    Glennon-Alty, Laurence; Williams, Rachel; Dixon, Simon; Murray, Patricia

    2013-04-01

    Mesenchymal stem cells (MSCs) can generate chondrocytes in vitro, but typically need to be cultured as aggregates in the presence of transforming growth factor beta (TGF-β), which makes scale-up difficult. Here we investigated if polyacrylate substrates modelled on the functional group composition and distribution of the Arg-Gly-Asp (RGD) integrin-binding site could induce MSCs to undergo chondrogenesis in the absence of exogenous TGF-β. Within a few days of culture on the biomimetic polyacrylates, both mouse and human MSCs, and a mesenchymal-like mouse-kidney-derived stem cell line, began to form multi-layered aggregates and started to express the chondrocyte-specific markers, Sox9, collagen II and aggrecan. Moreover, collagen II tended to be expressed in the centre of the aggregates, similarly to developing limb buds in vivo. Surface analysis of the substrates indicated that those with the highest surface amine content were most effective at promoting MSC chondrogenesis. These results highlight the importance of surface group functionality and the distribution of those groups in the design of substrates to induce MSC chondrogenesis. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  19. Mesenchymal stem cell and osteoarthritis: a literature review

    Directory of Open Access Journals (Sweden)

    Zhaleh Shariati Sarabi

    2016-04-01

    Full Text Available The most common disease in the aged population is osteoarthritis (OA that is resulting in progressive dysfunction following isolated cartilage injuries, subchondral bone remodeling, tissue loss, marginal osteophytes, and loss of joint space. Mesenchymal stem cells (MSCs are multipotent stem cells; they are able to produce many or all joint tissues. Bone marrow and adipose tissue are rich sources of mesenchymal cells that are useful for the reconstruction of injured tissues such as bone, cartilage, or cardiac muscle. Recently, some studies have been performed on the use of the direct intra-articular injection of mononuclear cells (MNCs and MSCs as potential therapeutic targets in OA. In this review, the history of MSCs in the treatment of OA are explained. Injection of Bone Marrow Aspirates Concentrate (BMAC has significantly improved both joint pain and function in radiologic findings; some studies suggested that the injection would be even more effective in early to moderate phases of OA. Injection of MSCs in combination with growth factors may be better solution for the treatment.

  20. Implications of mesenchymal stem cells in regenerative medicine.

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    Kariminekoo, Saber; Movassaghpour, Aliakbar; Rahimzadeh, Amirbahman; Talebi, Mehdi; Shamsasenjan, Karim; Akbarzadeh, Abolfazl

    2016-05-01

    Mesenchymal stem cells (MSCs) are a population of multipotent progenitors which reside in bone marrow, fat, and some other tissues and can be isolated from various adult and fetal tissues. Self-renewal potential and multipotency are MSC's hallmarks. They have the capacity of proliferation and differentiation into a variety of cell lineages like osteoblasts, condrocytes, adipocytes, fibroblasts, cardiomyocytes. MSCs can be identified by expression of some surface molecules like CD73, CD90, CD105, and lack of hematopoietic specific markers including CD34, CD45, and HLA-DR. They are hopeful tools for regenerative medicine for repairing injured tissues. Many studies have focused on two significant features of MSC therapy: (I) systemically administered MSCs home to sites of ischemia or injury, and (II) MSCs can modulate T-cell-mediated immunological responses. MSCs express chemokine receptors and ligands involved in cells migration and homing process. MSCs induce immunomedulatory effects on the innate (dendritic cells, monocyte, natural killer cells, and neutrophils) and the adaptive immune system cells (T helper-1, cytotoxic T lymphocyte, and B lymphocyte) by secreting soluble factors like TGF-β, IL-10, IDO, PGE-2, sHLA-G5, or by cell-cell interaction. In this review, we discuss the main applications of mesenchymal stem in Regenerative Medicine and known mechanisms of homing and Immunomodulation of MSCs.

  1. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells

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    Ra Jeong Chan

    2011-10-01

    Full Text Available Abstract Prolonged life expectancy, life style and environmental changes have caused a changing disease pattern in developed countries towards an increase of degenerative and autoimmune diseases. Stem cells have become a promising tool for their treatment by promoting tissue repair and protection from immune-attack associated damage. Patient-derived autologous stem cells present a safe option for this treatment since these will not induce immune rejection and thus multiple treatments are possible without any risk for allogenic sensitization, which may arise from allogenic stem cell transplantations. Here we report the outcome of treatments with culture expanded human adipose-derived mesenchymal stem cells (hAdMSCs of 10 patients with autoimmune associated tissue damage and exhausted therapeutic options, including autoimmune hearing loss, multiple sclerosis, polymyotitis, atopic dermatitis and rheumatoid arthritis. For treatment, we developed a standardized culture-expansion protocol for hAdMSCs from minimal amounts of fat tissue, providing sufficient number of cells for repetitive injections. High expansion efficiencies were routinely achieved from autoimmune patients and from elderly donors without measurable loss in safety profile, genetic stability, vitality and differentiation potency, migration and homing characteristics. Although the conclusions that can be drawn from the compassionate use treatments in terms of therapeutic efficacy are only preliminary, the data provide convincing evidence for safety and therapeutic properties of systemically administered AdMSC in human patients with no other treatment options. The authors believe that ex-vivo-expanded autologous AdMSCs provide a promising alternative for treating autoimmune diseases. Further clinical studies are needed that take into account the results obtained from case studies as those presented here.

  2. Comparison of autologous versus allogeneic epithelial-like stem cell treatment in an in vivo equine skin wound model.

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    Broeckx, Sarah Y; Borena, Bizunesh M; Van Hecke, Lore; Chiers, Koen; Maes, Sofie; Guest, Deborah J; Meyer, Evelyne; Duchateau, Luc; Martens, Ann; Spaas, Jan H

    2015-10-01

    Several studies report beneficial effects of autologous and allogeneic stem cells on wound healing. However, no comparison between autologous versus allogeneic epithelial-like stem cells (EpSCs) has been made so far. For this reason, we first hypothesize that both EpSC types enhance wound healing in comparison to vehicle treatment and untreated controls. Second, on the basis of other studies, we hypothesized that there would be no difference between autologous and allogeneic EpSCs. Twelve full-thickness skin wounds were created in six horses. Each horse was subjected to (i) autologous EpSCs, (ii) allogeneic EpSCs, (iii) vehicle treatment or (iv) untreated control. Wound evaluation was performed at day 3, 7 and 14 through wound exudates and at week 1, 2 and 5 through biopsies. Wound circumference and surface were significantly smaller in autologous EpSC-treated wounds. A significantly lower amount of total granulation tissue (overall) and higher vascularization (week 1) was observed after both EpSC treatments. Significantly more major histocompatibility complex II-positive and CD20-positive cells were noticed in EpSC-treated wounds at week 2. In autologous and allogeneic groups, the number of EpSCs in center biopsies was low after 1 week (11.7% and 6.1%), decreased to 7.6% and 1.7%, respectively (week 2), and became undetectable at week 5. These results confirm the first hypothesis and partially support the second hypothesis. Besides macroscopic improvements, both autologous and allogeneic EpSCs had similar effects on granulation tissue formation, vascularization and early cellular immune response. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  3. Cell therapy of congenital corneal diseases with umbilical mesenchymal stem cells: lumican null mice.

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    Hongshan Liu

    Full Text Available BACKGROUND: Keratoplasty is the most effective treatment for corneal blindness, but suboptimal medical conditions and lack of qualified medical personnel and donated cornea often prevent the performance of corneal transplantation in developing countries. Our study aims to develop alternative treatment regimens for congenital corneal diseases of genetic mutation. METHODOLOGY/PRINCIPAL FINDINGS: Human mesenchymal stem cells isolated from neonatal umbilical cords were transplanted to treat thin and cloudy corneas of lumican null mice. Transplantation of umbilical mesenchymal stem cells significantly improved corneal transparency and increased stromal thickness of lumican null mice, but human umbilical hematopoietic stem cells failed to do the same. Further studies revealed that collagen lamellae were re-organized in corneal stroma of lumican null mice after mesenchymal stem cell transplantation. Transplanted umbilical mesenchymal stem cells survived in the mouse corneal stroma for more than 3 months with little or no graft rejection. In addition, these cells assumed a keratocyte phenotype, e.g., dendritic morphology, quiescence, expression of keratocyte unique keratan sulfated keratocan and lumican, and CD34. Moreover, umbilical mesenchymal stem cell transplantation improved host keratocyte functions, which was verified by enhanced expression of keratocan and aldehyde dehydrogenase class 3A1 in lumican null mice. CONCLUSIONS/SIGNIFICANCE: Umbilical mesenchymal stem cell transplantation is a promising treatment for congenital corneal diseases involving keratocyte dysfunction. Unlike donated corneas, umbilical mesenchymal stem cells are easily isolated, expanded, stored, and can be quickly recovered from liquid nitrogen when a patient is in urgent need.

  4. Wnt/β-Catenin Signaling Determines the Vasculogenic Fate of Postnatal Mesenchymal Stem Cells.

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    Zhang, Zhaocheng; Nör, Felipe; Oh, Min; Cucco, Carolina; Shi, Songtao; Nör, Jacques E

    2016-06-01

    Vasculogenesis is the process of de novo blood vessel formation observed primarily during embryonic development. Emerging evidence suggest that postnatal mesenchymal stem cells are capable of recapitulating vasculogenesis when these cells are engaged in tissue regeneration. However, the mechanisms underlining the vasculogenic differentiation of mesenchymal stem cells remain unclear. Here, we used stem cells from human permanent teeth (dental pulp stem cells [DPSC]) or deciduous teeth (stem cells from human exfoliated deciduous teeth [SHED]) as models of postnatal primary human mesenchymal stem cells to understand mechanisms regulating their vasculogenic fate. GFP-tagged mesenchymal stem cells seeded in human tooth slice/scaffolds and transplanted into immunodeficient mice differentiate into human blood vessels that anastomize with the mouse vasculature. In vitro, vascular endothelial growth factor (VEGF) induced the vasculogenic differentiation of DPSC and SHED via potent activation of Wnt/β-catenin signaling. Further, activation of Wnt signaling is sufficient to induce the vasculogenic differentiation of postnatal mesenchymal stem cells, while Wnt inhibition blocked this process. Notably, β-catenin-silenced DPSC no longer differentiate into endothelial cells in vitro, and showed impaired vasculogenesis in vivo. Collectively, these data demonstrate that VEGF signaling through the canonical Wnt/β-catenin pathway defines the vasculogenic fate of postnatal mesenchymal stem cells. Stem Cells 2016;34:1576-1587. © 2016 AlphaMed Press.

  5. Tumorigenic hybrids between mesenchymal stem cells and gastric cancer cells enhanced cancer proliferation, migration and stemness.

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    Xue, Jianguo; Zhu, Yuan; Sun, Zixuan; Ji, Runbi; Zhang, Xu; Xu, Wenrong; Yuan, Xiao; Zhang, Bin; Yan, Yongmin; Yin, Lei; Xu, Huijuan; Zhang, Leilei; Zhu, Wei; Qian, Hui

    2015-10-24

    Emerging evidence indicates that inappropriate cell-cell fusion might contribute to cancer progression. Similarly, mesenchymal stem cells (MSCs) can also fuse with other cells spontaneously and capable of adopting the phenotype of other cells. The aim of our study was to investigate the role of MSCs participated cell fusion in the tumorigenesis of gastric cancer. We fused human umbilical cord mesenchymal stem cells (hucMSCs) with gastric cancer cells in vitro by polyethylene glycol (PEG), the hybrid cells were sorted by flow cytometer. The growth and migration of hybrids were assessed by cell counting, cell colony formation and transwell assays. The proteins and genes related to epithelial- mesenchymal transition and stemness were tested by western blot, immunocytochemistry and real-time RT-PCR. The expression of CD44 and CD133 was examined by immunocytochemistry and flow cytometry. The xenograft assay was used to evaluation the tumorigenesis of the hybrids. The obtained hybrids exhibited epithelial- mesenchymal transition (EMT) change with down-regulation of E-cadherin and up-regulation of Vimentin, N-cadherin, α-smooth muscle actin (α-SMA), and fibroblast activation protein (FAP). The hybrids also increased expression of stemness factors Oct4, Nanog, Sox2 and Lin28. The expression of CD44 and CD133 on hybrid cells was stronger than parental gastric cancer cells. Moreover, the migration and proliferation of heterotypic hybrids were enhanced. In addition, the heterotypic hybrids promoted the growth abilities of gastric xenograft tumor in vivo. Taken together, our results suggest that cell fusion between hucMSCs and gastric cancer cells could contribute to tumorigenic hybrids with EMT and stem cell-like properties, which may provide a flexible tool for investigating the roles of MSCs in gastric cancer.

  6. Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation.

    Science.gov (United States)

    Zhou, Ya-Jing; Liu, Jian-Min; Wei, Shu-Ming; Zhang, Yun-Hao; Qu, Zhen-Hua; Chen, Shu-Bo

    2015-08-01

    Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats.

  7. Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

    Science.gov (United States)

    Zhou, Ya-jing; Liu, Jian-min; Wei, Shu-ming; Zhang, Yun-hao; Qu, Zhen-hua; Chen, Shu-bo

    2015-01-01

    Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-labeled bone marrow mesenchymal stem cells and fluorogold-labeled nerve fibers were increased and hindlimb motor function of spinal cord-injured rats was markedly improved. These improvements were more prominent in rats subjected to bone marrow mesenchymal cell transplantation combined with propofol administration than in rats receiving monotherapy. These results indicate that propofol can enhance the therapeutic effects of bone marrow mesenchymal stem cell transplantation on spinal cord injury in rats. PMID:26487860

  8. Therapeutic Effect of Human Adipose Tissue-Derived Mesenchymal Stem Cells in Experimental Corneal Failure Due to Limbal Stem Cell Niche Damage.

    Science.gov (United States)

    Galindo, Sara; Herreras, José M; López-Paniagua, Marina; Rey, Esther; de la Mata, Ana; Plata-Cordero, María; Calonge, Margarita; Nieto-Miguel, Teresa

    2017-10-01

    Limbal stem cells are responsible for the continuous renewal of the corneal epithelium. The destruction or dysfunction of these stem cells or their niche induces limbal stem cell deficiency (LSCD) leading to visual loss, chronic pain, and inflammation of the ocular surface. To restore the ocular surface in cases of bilateral LSCD, an extraocular source of stem cells is needed to avoid dependence on allogeneic limbal stem cells that are difficult to obtain, isolate, and culture. The aim of this work was to test the tolerance and the efficacy of human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) to regenerate the ocular surface in two experimental models of LSCD that closely resemble different severity grades of the human pathology. hAT-MSCs transplanted to the ocular surface of the partial and total LSCD models developed in rabbits were well tolerated, migrated to inflamed tissues, reduced inflammation, and restrained the evolution of corneal neovascularization and corneal opacity. The expression profile of the corneal epithelial cell markers CK3 and E-cadherin, and the limbal epithelial cell markers CK15 and p63 was lost in the LSCD models, but was partially recovered after hAT-MSC transplantation. For the first time, we demonstrated that hAT-MSCs improve corneal and limbal epithelial phenotypes in animal LSCD models. These results support the potential use of hAT-MSCs as a novel treatment of ocular surface failure due to LSCD. hAT-MSCs represent an available, non-immunogenic source of stem cells that may provide therapeutic benefits in addition to reduce health care expenses. Stem Cells 2017;35:2160-2174. © 2017 AlphaMed Press.

  9. Mesenchymal stem cell therapy for osteoarthritis: current perspectives

    Directory of Open Access Journals (Sweden)

    Wyles CC

    2015-08-01

    Full Text Available Cody C Wyles,1 Matthew T Houdek,2 Atta Behfar,3 Rafael J Sierra,21Mayo Medical School, 2Department of Orthopedic Surgery, 3Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USAAbstract: Osteoarthritis (OA is a painful chronic condition with a significant impact on quality of life. The societal burden imposed by OA is increasing in parallel with the aging population; however, no therapies have demonstrated efficacy in preventing the progression of this degenerative joint disease. Current mainstays of therapy include activity modification, conservative pain management strategies, weight loss, and if necessary, replacement of the affected joint. Mesenchymal stem cells (MSCs are a multipotent endogenous population of progenitors capable of differentiation to musculoskeletal tissues. MSCs have a well-documented immunomodulatory role, managing the inflammatory response primarily through paracrine signaling. Given these properties, MSCs have been proposed as a potential regenerative cell therapy source for patients with OA. Research efforts are focused on determining the ideal source for derivation, as MSCs are native to several tissues. Furthermore, optimizing the mode of delivery remains a challenge both for appropriate localization of MSCs and for directed guidance toward stemming the local inflammatory process and initiating a regenerative response. Scaffolds and matrices with growth factor adjuvants may prove critical in this effort. The purpose of this review is to summarize the current state of MSC-based therapeutics for OA and discuss potential barriers that must be overcome for successful implementation of cell-based therapy as a routine treatment strategy in orthopedics.Keywords: mesenchymal stem cell, osteoarthritis, treatment, regenerative medicine, cell therapy

  10. Myogenic differentiation of mesenchymal stem cells for muscle regeneration in urinary tract.

    Science.gov (United States)

    Yang, Bin; Zheng, Jun-hua; Zhang, Yuan-yuan

    2013-01-01

    This article was to review the current status of adult mesenchymal stem cells transplantation for muscle regeneration in urinary tract and propose the future prospect in this field. The data used in this review were mainly obtained from articles listed in Medline and PubMed (2000-2013). The search terms were "mesenchymal stem cells", "bladder", "stress urinary incontinence" and "tissue engineering". Articles regarding the adult mesenchymal stem cells for tissue engineering of bladder and stress urinary incontinence were selected and reviewed. Adult mesenchymal stem cells had been identified and well characterized in human bone marrow, adipose tissue, skeletal muscle and urine, and demonstrated the capability of differentiating into smooth muscle cells and skeletal muscle cells under myogenic differentiation conditions in vitro. Multiple preclinical and clinical studies indicated that adult mesenchymal stem cells could restore and maintain the structure and function of urinary muscle tissues after transplanted, and potentially improve the quality of life in patients. Smooth or skeletal myogenic differentiation of mesenchymal stem cells with regenerative medicine technology may provide a novel approach for muscle regeneration and tissue repair in urinary tract. The long-term effect and safety of mesenchymal stem cell transplantation should be further evaluated before this approach becomes widely used in patients.

  11. Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

    Science.gov (United States)

    Planchon, Sarah M; Lingas, Karen T; Reese Koç, Jane; Hooper, Brittney M; Maitra, Basabi; Fox, Robert M; Imrey, Peter B; Drake, Kylie M; Aldred, Micheala A; Lazarus, Hillard M; Cohen, Jeffrey A

    2018-01-01

    Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 10 6 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

  12. Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole.

    Science.gov (United States)

    Barajas, Megan R; McCullough, Kristen B; Merten, Julianna A; Dierkhising, Ross A; Bartoo, Gabriel T; Hashmi, Shahrukh K; Hogan, William J; Litzow, Mark R; Patnaik, Mrinal M; Wilson, John W; Wolf, Robert C; Wermers, Robert A

    2016-03-01

    Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase

  13. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma.

    Science.gov (United States)

    Khouri, Issa F; Lee, Ming-S; Saliba, Rima M; Jun, Gu; Fayad, Luis; Younes, Anas; Pro, Barbara; Acholonu, Sandra; McLaughlin, Peter; Katz, Ruth L; Champlin, Richard E

    2003-12-01

    Patients with relapsed mantle-cell lymphoma have poor prognosis and short survival. Our aim was to determine the efficacy of nonablative allogeneic stem-cell transplantation in patients with relapsed mantle-cell lymphoma. Eighteen patients were treated in one of two consecutive trials. Thirteen patients underwent a conditioning regimen of fludarabine (30 mg/m2 daily for 3 days), cyclophosphamide (750 mg/m2 daily for 3 days), and high-dose rituximab. For the remaining five patients, the conditioning regimen consisted of cisplatin (25 mg/m2 daily for 4 days), fludarabine (30 mg/m2 daily for 2 days), and cytarabine (1,000 mg/m2 daily for 2 days). Tacrolimus and methotrexate were used for graft-versus-host disease prophylaxis. The median age was 56.5 years. Patients underwent a median of three prior chemotherapy regimens. Prior autologous transplantation failed in five (28%) patients and 16 (89%) had chemosensitive disease. Donor cell engraftment occurred in all patients. Eight patients (44%) required no platelet or RBC transfusion, and acute graft-versus-host disease of greater than grade 2 did not develop in any patient. The day-100 mortality was 0%. Complete remission (CR) occurred in 17 patients. Three patients progressed, and one was reinduced into continuous CR with donor lymphocyte infusion. With a median follow-up period of 26 months, the actuarial probability of current-event-free-survival at 3 years was 82% (95% CI, 65% to 99%). Our data suggest that nonablative allogeneic transplantation is a safe and potentially effective strategy for patients with relapsed and chemosensitive mantle-cell lymphoma.

  14. Donor Selection for Allogenic Hemopoietic Stem Cell Transplantation: Clinical and Ethical Considerations

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    Irene Riezzo

    2017-01-01

    Full Text Available Allogenic hematopoietic progenitor cell transplantation (allo-HSCT is an established treatment for many diseases. Stem cells may be obtained from different sources: mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The progress in transplantation procedures, the establishment of experienced transplant centres, and the creation of unrelated adult donor registries and cord blood banks gave those without an human leucocyte antigen- (HLA- identical sibling donor the opportunity to find a donor and cord blood units worldwide. HSCT imposes operative cautions so that the entire donation/transplantation procedure is safe for both donors and recipients; it carries with it significant clinical, moral, and ethical concerns, mostly when donors are minors. The following points have been stressed: the donation should be excluded when excessive risks for the donor are reasonable, donors must receive an accurate information regarding eventual adverse events and health burden for the donors themselves, a valid consent is required, and the recipient’s risks must be outweighed by the expected benefits. The issue of conflict of interest, when the same physician has the responsibility for both donor selection and recipient care, is highlighted as well as the need of an adequate insurance protection for all the parties involved.

  15. Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Mendorf, Alexander; Klyuchnikov, Evgeny; Langebrake, Claudia; Rohde, Holger; Ayuk, Francis; Regier, Marc; Christopeit, Maximilian; Zabelina, Tatjana; Bacher, Adelbert; Stübig, Thomas; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus

    2015-01-01

    Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials. © 2015 S. Karger AG, Basel.

  16. A novel method to isolate mesenchymal stem cells from mouse umbilical cord.

    Science.gov (United States)

    Zhang, Bin; Zhang, Jie; Shi, Hui; Mao, Fei; Wang, Juanjuan; Yan, Yongmin; Zhang, Xu; Qian, Hui; Xu, Wenrong

    2018-01-01

    Mesenchymal stem cells (MSCs), derived from various tissues, are considered an ideal cell source for clinical use, among which MSCs from the umbilical cord exhibit advantages over those from adult tissues. In preclinical studies, mouse models and xenogeneic MSC treatment are most commonly used to imitate diseases and clinical practice, respectively. However, the efficiency of cross‑species therapy remains controversial, making it difficult to elucidate the underlying mechanisms. Thus, allogeneic therapy may be more instructive and meaningful in clinical use. To confirm this hypothesis, the present study established a novel method for the isolation and expansion of MSCs from mouse umbilical cords (mUC‑MSCs) to support in vivo experiments in mice. MSCs were isolated from mUCs and mouse bone marrow (mBM), and then identified by flow cytometry. The differences in mUC‑MSCs and mBM‑MSCs were analyzed using a growth curve and their differentiation ability. The results showed that the harvested cells exhibited general characteristics of MSCs and possessed the capacity for long‑term culture. Despite having similar morphology and surface antigens to MSCs derived from mouse bone marrow, the mUC‑MSCs showed differences in purification, proliferation, stem cell markers and differentiation. In addition to detailed characterization, the present study verified the presence of Toll‑like receptor 3 (TLR3), an important component of immune responses, in mUC‑MSCs. It was found that the activation of TLR3 upregulated the levels of stemness‑related proteins, and enhanced the secretion and mRNA levels of inflammatory cytokines in the pre‑treated mUC‑MSCs. Collectively, the results of the present study provide further insight into the features of newly established mUC‑MSCs, providing novel evidence for the selection of murine MSCs and their responses to TLR3 priming.

  17. Role of Mesenchymal Derived Stem Cells in Stimulating Dormant Tumor Cells to Proliferate and Form Clinical Metastases

    Science.gov (United States)

    2017-07-01

    stroma; cytokines; chemokines; mesenchymal stem cells; hematologic stem cells; metastasis; quiescence; animal models; fibrosis; basement membrane extract...chemokines; mesenchymal stem cells; hematologic stem cells; metastasis; quiescence; animal models; fibrosis; basement membrane extract; 3D culture...will publish our findings once these studies have been completed. The Kaplan and Green labs meet regularly to share data and discuss experimental

  18. Advances of mesenchymal stem cells derived from bone marrow and dental tissue in craniofacial tissue engineering.

    Science.gov (United States)

    Yang, Maobin; Zhang, Hongming; Gangolli, Riddhi

    2014-05-01

    Bone and dental tissues in craniofacial region work as an important aesthetic and functional unit. Reconstruction of craniofacial tissue defects is highly expected to ensure patients to maintain good quality of life. Tissue engineering and regenerative medicine have been developed in the last two decades, and been advanced with the stem cell technology. Bone marrow derived mesenchymal stem cells are one of the most extensively studied post-natal stem cell population, and are widely utilized in cell-based therapy. Dental tissue derived mesenchymal stem cells are a relatively new stem cell population that isolated from various dental tissues. These cells can undergo multilineage differentiation including osteogenic and odontogenic differentiation, thus provide an alternative source of mesenchymal stem cells for tissue engineering. In this review, we discuss the important issues in mesenchymal stem cell biology including the origin and functions of mesenchymal stem cells, compare the properties of these two types of mesenchymal cells, update recent basic research and clinic applications in this field, and address important future challenges.

  19. Guidance of mesenchymal stem cells on fibronectin structured hydrogel films.

    Directory of Open Access Journals (Sweden)

    Annika Kasten

    Full Text Available Designing of implant surfaces using a suitable ligand for cell adhesion to stimulate specific biological responses of stem cells will boost the application of regenerative implants. For example, materials that facilitate rapid and guided migration of stem cells would promote tissue regeneration. When seeded on fibronectin (FN that was homogeneously immmobilized to NCO-sP(EO-stat-PO, which otherwise prevents protein binding and cell adhesion, human mesenchymal stem cells (MSC revealed a faster migration, increased spreading and a more rapid organization of different cellular components for cell adhesion on fibronectin than on a glass surface. To further explore, how a structural organization of FN controls the behavior of MSC, adhesive lines of FN with varying width between 10 µm and 80 µm and spacings between 5 µm and 20 µm that did not allow cell adhesion were generated. In dependance on both line width and gaps, cells formed adjacent cell contacts, were individually organized in lines, or bridged the lines. With decreasing sizes of FN lines, speed and directionality of cell migration increased, which correlated with organization of the actin cytoskeleton, size and shape of the nuclei as well as of focal adhesions. Together, defined FN lines and gaps enabled a fine tuning of the structural organization of cellular components and migration. Microstructured adhesive substrates can mimic the extracellular matrix in vivo and stimulate cellular mechanisms which play a role in tissue regeneration.

  20. Characterization of mesenchymal stem cells derived from equine adipose tissue

    Directory of Open Access Journals (Sweden)

    A.M. Carvalho

    2013-08-01

    Full Text Available Stem cell therapy has shown promising results in tendinitis and osteoarthritis in equine medicine. The purpose of this work was to characterize the adipose-derived mesenchymal stem cells (AdMSCs in horses through (1 the assessment of the capacity of progenitor cells to perform adipogenic, osteogenic and chondrogenic differentiation; and (2 flow cytometry analysis using the stemness related markers: CD44, CD90, CD105 and MHC Class II. Five mixed-breed horses, aged 2-4 years-old were used to collect adipose tissue from the base of the tail. After isolation and culture of AdMSCs, immunophenotypic characterization was performed through flow cytometry. There was a high expression of CD44, CD90 and CD105, and no expression of MHC Class II markers. The tri-lineage differentiation was confirmed by specific staining: adipogenic (Oil Red O, osteogenic (Alizarin Red, and chondrogenic (Alcian Blue. The equine AdMSCs are a promising type of adult progenitor cell for tissue engineering in veterinary medicine.

  1. Cytokines and soluble tumour necrosis factor I receptor levels during pretransplant conditioning in allogeneic stem-cell transplantation

    DEFF Research Database (Denmark)

    Andersen, Johnny; Heilmann, Carsten; Jacobsen, Niels

    2005-01-01

    The inflammatory response induced by the conditioning regime may be related to the outcome in allogeneic stem-cell transplantation (SCT). However, previous statements concerning the prognostic significance of cytokine measurements during conditioning have not been conclusive. We investigated...... a broad range of cytokines in plasma samples drawn daily immediately before start of pretransplant conditioning and during the conditioning. The presented data indicate that single-day measurements of inflammatory cytokines during conditioning may lead to unreliable conclusions concerning their prognostic...

  2. Impact of oral gut decontamination on Staphylococcus aureus colonisation in patients undergoing allogeneic haematopoietic stem cell transplantation.

    Science.gov (United States)

    Wilk, C Matthias; Weber, Isabel; Seidl, Kati; Rachmühl, Carole; Holzmann-Bürgel, Anne; Müller, Antonia M S; Kuster, Stefan P; Schanz, Urs; Zinkernagel, Annelies S

    2017-12-01

    Recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) are severely immunocompromised and are at increased risk of infection. In this prospective, observational, single-centre study including 110 allo-HSCT recipients, the rate of Staphylococcus aureus colonisation was reduced from 11.8% to 0% (P <0.001) following peritransplant oral gut decontamination. No invasive S. aureus infections were observed. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  3. Mesenchymal stem cell in venous leg ulcer: An intoxicating therapy.

    Science.gov (United States)

    Athanerey, Anjali; Patra, Pradeep Kumar; Kumar, Awanish

    2017-08-01

    Venous leg ulcers (VLU) are a prevalent and reoccurring type of complicated wound, turning as a considerable public healthcare issue, with critical social and economic concern. There are both medical and surgical therapies to treat venous leg ulcers; however, a cure does not yet exist. Mesenchymal stem cells (MSC) are capable and proved of accelerating wound healing in vivo and their study with human chronic wounds is currently awaited. MSCs are a promising source of adult progenitor cells for cellular therapy and have been demonstrated to differentiate into various mesenchymal cell lineages. They have a crucial and integral role in native wound healing by regulating immune response and inflammation. Improved understanding of the cellular and molecular mechanisms at work in delayed wound healing compels to the development of cellular therapy in VLU. This review focuses on the current treatment option of VLU and further emphasizing the role of MSCs in accelerating the healing process. With further understanding of the mechanism of action of these cells in wound improvement and, the involvement of cytokines can also be revealed that could be used for the therapeutic purpose for VLU healing. Clinical uses of MSCs have been started already, and induced MSCs are surely a promising tool or compelling therapy for VLU. Copyright © 2017 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

  4. IL-17 inhibits chondrogenic differentiation of human mesenchymal stem cells.

    Directory of Open Access Journals (Sweden)

    Masahiro Kondo

    Full Text Available OBJECTIVE: Mesenchymal stem cells (MSCs can differentiate into cells of mesenchymal lineages, such as osteoblasts and chondrocytes. Here we investigated the effects of IL-17, a key cytokine in chronic inflammation, on chondrogenic differentiation of human MSCs. METHODS: Human bone marrow MSCs were pellet cultured in chondrogenic induction medium containing TGF-β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression. RESULTS: Over-expression of cartilage matrix and chondrogenic marker genes was noted in chondrogenic cultures, but was inhibited by IL-17 in a dose-dependent manner. Expression and phosphorylation of SOX9, the master transcription factor for chondrogenesis, were induced within 2 days and phosphorylated SOX9 was stably maintained until day 21. IL-17 did not alter total SOX9 expression, but significantly suppressed SOX9 phosphorylation in a dose-dependent manner. At day 7, IL-17 also suppressed the activity of cAMP-dependent protein kinase A (PKA, which is known to phosphorylate SOX9. H89, a selective PKA inhibitor, also suppressed SOX9 phosphorylation, expression of chondrogenic markers and cartilage matrix, and also decreased chondrogenesis. CONCLUSIONS: IL-17 inhibited chondrogenesis of human MSCs through the suppression of PKA activity and SOX9 phosphorylation. These results suggest that chondrogenic differentiation of MSCs can be inhibited by a mechanism triggered by IL-17 under chronic inflammation.

  5. Mesenchymal stem cell therapy: Two steps forward, one step back

    Science.gov (United States)

    Ankrum, James; Karp, Jeffrey M.

    2010-01-01

    Mesenchymal stem cell (MSC) therapy is poised to establish a new clinical paradigm; however, recent trials have produced mixed results. Although MSC were originally considered to treat connective tissue defects, preclinical studies revealed potent immunomodulatory properties that prompted the use of MSC to treat numerous inflammatory conditions. Unfortunately, although clinical trials have met safety endpoints, efficacy has not been demonstrated. We believe the challenge to demonstrate efficacy can be attributed in part to an incomplete understanding of the fate of MSC following infusion. Here, we highlight the clinical status of MSC therapy and discuss the importance of cell-tracking techniques, which have advanced our understanding of the fate and function of systemically infused MSC and might improve clinical application. PMID:20335067

  6. The Modulatory Effects of Mesenchymal Stem Cells on Osteoclastogenesis

    Science.gov (United States)

    Sharaf-Eldin, Wessam E.; Abu-Shahba, Nourhan; Mahmoud, Marwa; El-Badri, Nagwa

    2016-01-01

    The effect of mesenchymal stem cells (MSCs) on bone formation has been extensively demonstrated through several in vitro and in vivo studies. However, few studies addressed the effect of MSCs on osteoclastogenesis and bone resorption. Under physiological conditions, MSCs support osteoclastogenesis through producing the main osteoclastogenic cytokines, RANKL and M-CSF. However, during inflammation, MSCs suppress osteoclast formation and activity, partly via secretion of the key anti-osteoclastogenic factor, osteoprotegerin (OPG). In vitro, co-culture of MSCs with osteoclasts in the presence of high concentrations of osteoclast-inducing factors might reflect the in vivo inflammatory pathology and prompt MSCs to exert an osteoclastogenic suppressive effect. MSCs thus seem to have a dual effect, by stimulating or inhibiting osteoclastogenesis, depending on the inflammatory milieu. This effect of MSCs on osteoclast formation seems to mirror the effect of MSCs on other immune cells, and may be exploited for the therapeutic potential of MSCs in bone loss associated inflammatory diseases. PMID:26823668

  7. Osteoarthritis and Mesenchymal Stem Cell Therapy: An Overview

    Directory of Open Access Journals (Sweden)

    I Gusti Ayu Putri Purwanthi

    2017-08-01

    Full Text Available Osteoarthritis (OA is the most common form of arthritis that affects cartilage joints and leads to disability. OA becomes the major public health problem, as it is the most leading cause of disability and morbidity worldwide. Treatment choices for OA can be classified into several categories such as non-pharmacologic, pharmacologic, surgical therapy, and cell-based therapy. There is no curative treatment for OA, while conventional treatments that are commonly used focus on alleviating the pain as the main symptom of the disease. Mesenchymal stem cells (MSCs that can be found in several tissues of human body offer a new strategy for OA treatment owing to their ability to differentiate into chondrocytes. This article provides an overview about the basic concept of osteoarthritis as well as an insight about the MSCs therapy, including their basic characteristics, source, and transplantation strategies in the OA area.

  8. Mesenchymal Stem Cells after Polytrauma: Actor and Target

    Directory of Open Access Journals (Sweden)

    Markus Huber-Lang

    2016-01-01

    Full Text Available Mesenchymal stem cells (MSCs are multipotent cells that are considered indispensable in regeneration processes after tissue trauma. MSCs are recruited to damaged areas via several chemoattractant pathways where they function as “actors” in the healing process by the secretion of manifold pro- and anti-inflammatory, antimicrobial, pro- and anticoagulatory, and trophic/angiogenic factors, but also by proliferation and differentiation into the required cells. On the other hand, MSCs represent “targets” during the pathophysiological conditions after severe trauma, when excessively generated inflammatory mediators, complement activation factors, and damage- and pathogen-associated molecular patterns challenge MSCs and alter their functionality. This in turn leads to complement opsonization, lysis, clearance by macrophages, and reduced migratory and regenerative abilities which culminate in impaired tissue repair. We summarize relevant cellular and signaling mechanisms and provide an up-to-date overview about promising future therapeutic MSC strategies in the context of severe tissue trauma.

  9. Restoration of Corneal Transparency by Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Sharad K. Mittal

    2016-10-01

    Full Text Available Transparency of the cornea is indispensable for optimal vision. Ocular trauma is a leading cause of corneal opacity, leading to 25 million cases of blindness annually. Recently, mesenchymal stem cells (MSCs have gained prominence due to their inflammation-suppressing and tissue repair functions. Here, we investigate the potential of MSCs to restore corneal transparency following ocular injury. Using an in vivo mouse model of ocular injury, we report that MSCs have the capacity to restore corneal transparency by secreting high levels of hepatocyte growth factor (HGF. Interestingly, our data also show that HGF alone can restore corneal transparency, an observation that has translational implications for the development of HGF-based therapy.

  10. [Immunomodulatory properties of stem mesenchymal cells in autoimmune diseases].

    Science.gov (United States)

    Sánchez-Berná, Isabel; Santiago-Díaz, Carlos; Jiménez-Alonso, Juan

    2015-01-20

    Autoimmune diseases are a cluster of disorders characterized by a failure of the immune tolerance and a hyperactivation of the immune system that leads to a chronic inflammation state and the damage of several organs. The medications currently used to treat these diseases usually consist of immunosuppressive drugs that have significant systemic toxic effects and are associated with an increased risk of opportunistic infections. Recently, several studies have demonstrated that mesenchymal stem cells have immunomodulatory properties, a feature that make them candidates to be used in the treatment of autoimmune diseases. In the present study, we reviewed the role of this therapy in the treatment of systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, Crohn's disease and multiple sclerosis, as well as the potential risks associated with its use. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  11. Separation of Mesenchymal Stem Cells Through a Strategic Centrifugation Protocol.

    Science.gov (United States)

    Ferlin, Kimberly M; Kaplan, David S; Fisher, John P

    2016-04-01

    Despite great promise surrounding mesenchymal stem cells (MSCs), their implementation for tissue engineering strategies remains in the development phases. Many of the concerns regarding the clinical use of MSCs originate from population heterogeneity, during both isolation and differentiation. In this study, we utilize our previously developed centrifugation cell adhesion protocol for the separation of MSCs. Our findings reveal that MSCs can be isolated from whole bone marrow using a 200 g (700 pN) centrifugal force after 24 h of culture on polystyrene with cell surface marker expression equivalent to positive controls. During differentiation, a centrifugation protocol with identical force parameters could be applied 14 days into chondrogenic differentiation to isolate differentiated chondrocytes, which exhibited increased expression of chondrogenic markers compared to controls. In summary, the use of our developed centrifugation cell adhesion protocol has proven to be an effective means to separate MSC populations, decreasing the heterogeneity of subsequent cell therapy products.

  12. Mesenchymal Stem Cells Obtained from Synovial Fluid Mesenchymal Stem Cell-Derived Induced Pluripotent Stem Cells on a Matrigel Coating Exhibited Enhanced Proliferation and Differentiation Potential

    OpenAIRE

    Zheng, Yu-Liang; Sun, Yang-Peng; Zhang, Hong; Liu, Wen-Jing; Jiang, Rui; Li, Wen-Yu; Zheng, You-Hua; Zhang, Zhi-Guang

    2015-01-01

    Induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) serve as a promising source for cell-based therapies in regenerative medicine. However, optimal methods for transforming iPSCs into MSCs and the characteristics of iPSC-MSCs obtained from different methods remain poorly understood. In this study, we developed a one-step method for obtaining iPSC-MSCs (CD146+STRO-1+ MSCs) from human synovial fluid MSC-derived induced iPSCs (SFMSC-iPSCs). CD146-STRO-1-SFMSCs were reprogram...

  13. Mesenchymal stem cells are highly resistant to sulfur mustard.

    Science.gov (United States)

    Schmidt, Annette; Scherer, Michael; Thiermann, Horst; Steinritz, Dirk

    2013-12-05

    The effect of sulfur mustard (SM) to the direct injured tissues of the skin, eyes and airways is well investigated. Little is known about the effect of SM to mesenchymal stem cells (MSC). However, this is an interesting aspect. Comparing the clinical picture of SM it is known today that MSC play an important role e.g. in chronic impaired wound healing. Therefore we wanted to get an understanding about how SM affects MSC and if these findings might become useful to get a better understanding of the effect of sulfur mustard gas with respect to skin wounds. We used mesenchymal stem cells, isolated from femoral heads from healthy donors and treated them with a wide range of SM to ascertain the dose-response-curve. With the determined inhibitory concentrations IC1 (1μM), IC5 (10μM), IC10 (20μM) and IC25 (40μM) we did further investigations. We analyzed the migratory ability and the differentiation capacity under influence of SM. Already very low concentrations of SM demonstrated a strong effect to the migratory activity whereas the differentiation capacity seemed not to be affected. Putting these findings together it seems to be likely that a link between MSC and the impaired wound healing after SM exposure might exist. Same as in patients with chronic impaired wound healing MSC had shown a reduced migratory activity. The fact that MSC are able to tolerate very high concentrations of SM and still do not lose their differentiation capacity may reveal new ways of treating wounds caused by sulfur mustard. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  14. Effect of Azithromycin on Airflow Decline–Free Survival After Allogeneic Hematopoietic Stem Cell Transplant

    Science.gov (United States)

    Chevret, Sylvie; Granata, Angela; Chevallier, Patrice; Vincent, Laure; Huynh, Anne; Tabrizi, Reza; Labussiere-Wallet, Hélène; Bernard, Marc; Chantepie, Sylvain; Bay, Jacques-Olivier; Thiebaut-Bertrand, Anne; Thepot, Sylvain; Contentin, Nathalie; Fornecker, Luc-Matthieu; Maillard, Natacha; Risso, Karine; Berceanu, Ana; Blaise, Didier; Peffault de La Tour, Regis; Chien, Jason W.; Coiteux, Valérie; Socié, Gérard

    2017-01-01

    Importance Bronchiolitis obliterans syndrome has been associated with increased morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). Previous studies have suggested that azithromycin may reduce the incidence of post–lung transplant bronchiolitis obliterans syndrome. Objective To evaluate if the early administration of azithromycin can improve airflow decline–free survival after allogeneic HSCT. Design, Setting, and Participants The ALLOZITHRO parallel-group trial conducted in 19 French academic transplant centers and involving participants who were at least 16 years old, had undergone allogeneic HSCT for a hematological malignancy, and had available pretransplant pulmonary function test results. Enrollment was from February 2014 to August 2015 with follow-up through April 26, 2017. Interventions Patients were randomly assigned to receive 3 times a week either 250 mg of azithromycin (n = 243) or placebo (n = 237) for 2 years, starting at the time of the conditioning regimen. Main Outcomes and Measures The primary efficacy end point was airflow decline–free survival at 2 years after randomization. Main secondary end points were overall survival and bronchiolitis obliterans syndrome at 2 years. Results Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline–free survival was 32.8% (95% CI, 25.9%-41.7%) with azithromycin and 41.3% (95% CI, 34.1%-50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1

  15. Photobiomodulation of Dental Derived Mesenchymal Stem Cells: A Systematic Review.

    Science.gov (United States)

    Marques, Márcia Martins; Diniz, Ivana Márcia Alves; de Cara, Sueli Patricia Harumi Miyagi; Pedroni, Ana Clara Fagundes; Abe, Gabriela Laranjeira; D'Almeida-Couto, Roberta Souza; Lima, Paula Loures Valle; Tedesco, Tamara Kerber; Moreira, Maria Stella

    2016-11-01

    This study aimed to conduct a systematic review of the literature published from 2000 to August 2015, to investigate the effect of photobiomodulation (PBM) therapy on dentoalveolar-derived mesenchymal stem cells (ddMSCs), assessing whether a clear conclusion can be reached from the data presented. Systematic reviews provide the best evidence on the effectiveness of a procedure and permit investigation of factors that may influence the performance of a method. To the best of our knowledge, no previous systematic review has evaluated the effects of PBM only on ddMSCs. The search was conducted in PubMed /MEDLINE ® , Scopus and Web of Science databases, and reported according to the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA Statement). Original research articles investigating the effects of PBM therapy on ddMSCs, published from 2000 to August 2015, were retrieved and used for this review according to the following eligibility criteria: evaluating PBM therapy, assessing stem cells of dentoalveolar origin, published in English, dealing with cells characterized as stem cells, and using light that did not need external chromophores. From the initial 3467 potentially relevant articles identified, 6 were excluded because they were duplicates, and 3453 were considered ineligible based on the inclusion criteria. Therefore, eight articles remained, and these were fully analyzed in order to closely check exclusion criteria items. Only one of them was excluded because the cultured cells studied were not characterized as stem cells. Finally, seven articles served as the basis for this systematic review. PBM therapy has no deleterious effects on ddMSCs. Although no other clear conclusion was obtained because of the scarce number of publications, the results of these studies are pointing to an important tendency of PBM therapy to improve ddMSCs' viability and proliferation.

  16. Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Shigeo eFuji

    2014-04-01

    Full Text Available Graft-versus-host disease (GVHD is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT. In the pathogenesis of acute GVHD, it has been established that donor-derived T cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT.

  17. Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Jaekel, N; Lieder, K; Albrecht, S; Leismann, O; Hubert, K; Bug, G; Kröger, N; Platzbecker, U; Stadler, M; de Haas, K; Altamura, S; Muckenthaler, M U; Niederwieser, D; Al-Ali, H K

    2016-01-01

    Elevated serum ferritin contributes to treatment-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The multicenter DE02 trial assessed the safety, efficacy and impact of deferasirox on iron homeostasis after allogeneic HSCT. Deferasirox was administered at a starting dose of 10 mg/kg per day to 76 recipients of allogeneic HSCT, with subsequent dose adjustments based on efficacy and safety. Deferasirox was initiated at a median of 168 days after HSCT, with 84% of patients still on immunosuppression. Baseline serum ferritin declined from 2045 to 957 ng/mL. Deferasirox induced a negative iron balance in 84% of patients. Hemoglobin increased in the first 3 months, and trough serum cyclosporine levels were stable. Median exposure was 330 days, with a median compliance rate of >80%. The most common investigator-reported drug-related adverse events (AEs) were increased blood creatinine (26.5%), nausea (9.0%) and abdominal discomfort (8.3%). Fifty-four (71.1%) patients experienced drug-related AEs, which occasionally resulted in discontinuation (gastrointestinal (n=6), skin (n=3), elevated transaminases (n=1) and creatinine (n=1)). The incidence of AEs appeared to be dose related, with 7.5 mg/kg per day being the best-tolerated dose. Low-dose deferasirox is an effective chelation therapy after allogeneic HSCT, with a manageable safety profile, even in patients receiving cyclosporine.

  18. Possible implication of bacterial infection in acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Fuji, Shigeo; Kapp, Markus; Einsele, Hermann

    2014-01-01

    Graft-versus-host disease (GVHD) is still one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). In the pathogenesis of acute GVHD, it has been established that donor-derived T-cells activated in the recipient play a major role in GVHD in initiation and maintenance within an inflammatory cascade. To reduce the risk of GVHD, intensification of GVHD prophylaxis like T-cell depletion is effective, but it inevitably increases the risk of infectious diseases and abrogates beneficial graft-versus-leukemia effects. Although various cytokines are considered to play an important role in the pathogenesis of GVHD, GVHD initiation is such a complex process that cannot be prevented by means of single inflammatory cytokine inhibition. Thus, efficient methods to control the whole inflammatory milieu both on cellular and humoral view are needed. In this context, infectious diseases can theoretically contribute to an elevation of inflammatory cytokines after allogeneic HSCT and activation of various subtypes of immune effector cells, which might in summary lead to an aggravation of acute GVHD. The appropriate treatments or prophylaxis of bacterial infection during the early phase after allogeneic HSCT might be beneficial to reduce not only infectious-related but also GVHD-related mortality. Here, we aim to review the literature addressing the interactions of bacterial infections and GVHD after allogeneic HSCT.

  19. Imaging gene expression in human mesenchymal stem cells: from small to large animals

    DEFF Research Database (Denmark)

    Willmann, Jürgen K; Paulmurugan, Ramasamy; Rodriguez-Porcel, Martin

    2009-01-01

    To evaluate the feasibility of reporter gene imaging in implanted human mesenchymal stem cells (MSCs) in porcine myocardium by using clinical positron emission tomography (PET)-computed tomography (CT) scanning....

  20. Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology

    NARCIS (Netherlands)

    Scharstuhl, A.; Schewe, B.; Benz, K.; Gaissmaier, C.; Bühring, H.J.; Stoop, R.

    2007-01-01

    Osteoarthritis (OA) is a multifactorial disease strongly correlated with history of joint trauma, joint dysplasia, and advanced age. Mesenchymal stem cells (MSCs) are promising cells for biological cartilage regeneration. Conflicting data have been published concerning the availability of MSCs from

  1. Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology.

    NARCIS (Netherlands)

    Scharstuhl, A.; Schewe, B.; Benz, K.; Gaissmaier, C.; Buhring, H.J.; Stoop, R.

    2007-01-01

    Osteoarthritis (OA) is a multifactorial disease strongly correlated with history of joint trauma, joint dysplasia, and advanced age. Mesenchymal stem cells (MSCs) are promising cells for biological cartilage regeneration. Conflicting data have been published concerning the availability of MSCs from

  2. Molecular profile and cellular characterization of human bone marrow mesenchymal stem cells: donor influence on chondrogenesis.

    Science.gov (United States)

    Cicione, Claudia; Díaz-Prado, Silvia; Muiños-López, Emma; Hermida-Gómez, Tamara; Blanco, Francisco J

    2010-01-01

    The use of autologous or allogenic stem cells has recently been suggested as an alternative therapeutic approach for treatment of cartilage defects. Bone marrow mesenchymal stem cells (BM-MSCs) are well-characterized multipotent cells that can differentiate into different cell types. Understanding the potential of these cells and the molecular mechanisms underlying their differentiation should lead to innovative protocols for clinical applications. The aim of this study was to evaluate the usefulness of surface antigen selection of BM-MSCs and to understand the mechanisms underlying their differentiation. MSCs were isolated from BM stroma and expanded. CD105+ subpopulation was isolated using a magnetic separator. We compared culture-expanded selected cells with non-selected cells. We analyzed the phenotypic profiles, the expression of the stem cell marker genes Nanog, Oct3/4, and Sox2 and the multi-lineage differentiation potential (adipogenic, osteogenic, and chondrogenic). The multi-lineage differentiation was confirmed using histochemistry, immunohistochemistry and/or real-time polymerase chain reaction (qPCR) techniques. The selected and non-selected cells displayed similar phenotypes and multi-lineage differentiation potentials. Analyzing each cell source individually, we could divide the six donors into two groups: one with a high percentage of CD29 (β1-integrin) expression (HL); one with a low percentage of CD29 (LL). These two groups had different chondrogenic capacities and different expression levels of the stem cell marker genes. This study showed that phenotypic profiles of donors were related to the chondrogenic potential of human BM-MSCs. The chondrogenic potential of donors was related to CD29 expression levels. The high expression of CD29 antigen seemed necessary for chondrogenic differentiation. Further investigation into the mechanisms responsible for these differences in BM-MSCs chondrogenesis is therefore warranted. Understanding the mechanisms

  3. Mesenchymal stem cell therapy in osteoarthritis: advanced tissue repair or intervention with smouldering synovial activation?

    OpenAIRE

    van Lent, Peter LEM; van den Berg, Wim B

    2013-01-01

    Although it is generally accepted that osteoarthritis is a degenerative condition of the cartilage, other tissues such as synovium in which immunological and inflammatory reactions occur contribute to the development of joint pathology. This sheds new light on the potential mechanism of action of mesenchymal stem cell therapy in osteoarthritis. Rather than tissue repair due to local transformation of injected mesenchymal stem cells to chondrocytes and filling defects in cartilage, such treatm...

  4. Propofol promotes spinal cord injury repair by bone marrow mesenchymal stem cell transplantation

    OpenAIRE

    Zhou, Ya-jing; Liu, Jian-min; Wei, Shu-ming; Zhang, Yun-hao; Qu, Zhen-hua; Chen, Shu-bo

    2015-01-01

    Propofol is a neuroprotective anesthetic. Whether propofol can promote spinal cord injury repair by bone marrow mesenchymal stem cells remains poorly understood. We used rats to investigate spinal cord injury repair using bone marrow mesenchymal stem cell transplantation combined with propofol administration via the tail vein. Rat spinal cord injury was clearly alleviated; a large number of newborn non-myelinated and myelinated nerve fibers appeared in the spinal cord, the numbers of CM-Dil-l...

  5. Umbilical Cord as Prospective Source for Mesenchymal Stem Cell-Based Therapy

    Science.gov (United States)

    2016-01-01

    The paper presents current evidence on the properties of human umbilical cord-derived mesenchymal stem cells, including origin, proliferative potential, plasticity, stability of karyotype and phenotype, transcriptome, secretome, and immunomodulatory activity. A review of preclinical studies and clinical trials using this cell type is performed. Prospects for the use of mesenchymal stem cells, derived from the umbilical cord, in cell transplantation are associated with the need for specialized biobanking and transplant standardization criteria. PMID:27651799

  6. [Bone marrow mesenchymal stem cells in Sprague-Dawley rat model of osteoarthritis].

    Science.gov (United States)

    Cui, Y P; Cao, Y P; Liu, H; Yang, X; Meng, Z C; Wang, R

    2015-04-18

    To investigate the efficacy of single time intra-articular different concentration of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) injection in the treatment of Sprague-Dawley (SD) rat model of osteoarthritis (OA). In the study, 32 SD rats were equally randomized into 4 groups: control group, high concentration group (1×10(7)/mL BM-MSCs), low concentration group (5×10(6)/mL BM-MSCs) and high vs. low concentration group. The two knees of each rat were set up to a pair. The induction of OA was performed surgically randomly at one side in model group, and bilaterally in the other groups, which were through anterior cruciate ligament transaction (ACLT) and medial meniscus excising. After the operation, the SD rats were allowed free movement. Four weeks later, different concentrations of allogeneic BM-MSCs isolated from the SD rats, expanded in vitro and suspended in phosphate buffered solution (PBS) were delivered in the articular cavity of both knees; PBS was used as the control. After injection, we excised the femoral nerve and sciatic nerve to disuse the low limb. The cartilage histological sections of knees were scored by Mankin scoring system to assess the severity of the pathology. mRNA of collagen II was detected by real time polymerase chain reaction (RT-PCR). eGFP was detected by fluorescence microscope. Assessments were carried out 4 weeks after the operation in model group, and 3 weeks after injection in the other groups. Mankin scores of the BM-MSCs side and control side were 6.60±0.40 vs. 10.00±0.32 in low concentration group (P0.05). mRNA expression of collagen II of the BM-MSCs side in low concentration group was 106%±1% in contrast to the control side. As in high concentration group it was 108%±1%, and 102%±1% in high vs. low concentration group. Labeled BM-MSCs were detected unexpectedly in the synovial membrane but not in cartilage tissue three weeks from injection. BM-MSCs could promote cartilage repair and inhibit OA progression

  7. Safety of Voriconazole and Sirolimus Coadministration after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Ceberio, Izaskun; Dai, Kefei; Devlin, Sean M.; Barke, Juliet N.; Castro-Malaspina, Hugo; Goldberg, Jenna D.; Giralt, Sergio; Adel, Nelly G.; Perales, Miguel-Angel

    2015-01-01

    Antifungal prophylaxis with azoles is considered standard in allogeneic hematopoietic stem-cell transplant (allo-HCT). Although sirolimus is being used increasingly for prevention of graft-versus-host disease (GVHD), it is a substrate of CYP3A4, which is inhibited by voriconazole, and concurrent administration can lead to significantly increased exposure to sirolimus. We identified 67 patients with hematologic malignancies who underwent allo-HCT with sirolimus, tacrolimus, and low-dose methotrexate and received concomitant voriconazole prophylaxis from April-2008 to June-2011. All patients underwent a non-myeloablative or reduced-intensity conditioned allo-HCT. Patients received sirolimus and voriconazole concurrently for a median of 113 days. The median daily dose reduction of sirolimus at start of coadministration was 90%. The median serum sirolimus trough-level before and at steady-state of coadministration were 5.8ng/mL (range 0-47.6) and 6.1ng/mL (range 1-14.2) (p=0.45), respectively. One patient with an average sirolimus level of 6 ng/mL developed sirolimus-related thrombotic microangiopathy that resolved after sirolimus discontinuation. No sinusoidal-obstructive syndrome was reported. Seventeen patients (25%) prematurely discontinued voriconazole because of adverse events. Only 2 patients (3%) presented with possible IFI at day100. We demonstrate that sirolimus and voriconazole coadministration with an empiric 90% sirolimus dose-reduction and close monitoring of sirolimus trough levels is safe and well tolerated. PMID:25599164

  8. Balance function in patients who had undergone allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Morishita, Shinichiro; Kaida, Katsuji; Aoki, Osamu; Yamauchi, Shinya; Wakasugi, Tatsushi; Ikegame, Kazuhiro; Ogawa, Hiroyasu; Domen, Kazuhisa

    2015-09-01

    A previous study reported a 45% incidence of falling among allogeneic haematopoietic stem cell transplantation (allo-HSCT) patients during hospitalisation. We investigated balance and physical function in allo-HSCT patients. Thirty patients (18 men and 12 women) who underwent allo-HSCT between February 2013 and September 2014 were included in this study. Patients were evaluated for up to 3 weeks before and 7 weeks after transplantation. Balance was evaluated using the Timed Up and Go test (TUG) and length of centre of pressure (CoP). Physical function was assessed using hand-grip strength, knee-extensor strength tests, and the 6 min walk test (6MWT). TUG and length of CoP were significantly increased following HSCT (PCoP were negatively correlated with hand grip and knee-extensor strength (P≤0.05). The allo-HSCT patients in this study had worsened dynamic and static movements of the CoP after transplantation as well as decline of physical function. Rehabilitation staff, nurses, and physicians should recognize the decreased balance function of patients who have undergone allo-HSCT. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Aoki, Jun; Numata, Ayumi; Yamamoto, Eri; Fujii, Eriko; Tanaka, Masatsugu; Kanamori, Heiwa

    2015-11-01

    Human herpesvirus-6 (HHV-6) is known to reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with development of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the clinical significance of HHV-6 reactivation after allo-HSCT remains unclear. Therefore, we conducted a retrospective analysis to elucidate the impact of HHV-6 reactivation on transplantation outcomes. Of 236 patients who underwent allo-HSCT, 138 (58.5%) developed HHV-6 reactivation and 98 (41.5%) did not. Univariate analysis indicated that at 3 years, patients with HHV-6 reactivation had significantly higher NRM (27.7% versus 13.7%, P = .003) and worse overall survival (42.1% versus 59.0%, P = .008) than those without reactivation. In multivariate analysis, HHV-6 reactivation was associated with higher incidence of acute GVHD (hazard ratio [HR], 1.87; P = .01), cytomegalovirus reactivation (HR, 2.24; P impact of HHV-6 reactivation on acute GVHD was observed only in patients who received myeloablative conditioning (MAC). These results indicate that HHV-6 reactivation was associated with development of acute GVHD, cytomegalovirus reactivation, and NRM. Furthermore, adverse impact of HHV-6 reactivation on transplantation outcomes was prominent in the setting of MAC. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  10. Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Vantyghem, Marie-Christine; Cornillon, Jérôme; Decanter, Christine; Defrance, Frédérique; Karrouz, Wassila; Leroy, Clara; Le Mapihan, Kristell; Couturier, Marie-Anne; De Berranger, Eva; Hermet, Eric; Maillard, Natacha; Marcais, Ambroise; Francois, Sylvie; Tabrizi, Reza; Yakoub-Agha, Ibrahim

    2014-10-29

    Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

  11. Effects of T-Cell Depletion on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in AML Patients

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    Gabriela Soriano Hobbs

    2015-03-01

    Full Text Available Graft versus host disease (GVHD remains one of the leading causes of morbidity and mortality associated with conventional allogeneic hematopoietic stem cell transplantation (HCT. The use of T-cell depletion significantly reduces this complication. Recent prospective and retrospective data suggest that, in patients with AML in first complete remission, CD34+ selected grafts afford overall and relapse-free survival comparable to those observed in recipients of conventional grafts, while significantly decreasing GVHD. In addition, CD34+ selected grafts allow older patients, and those with medical comorbidities or with only HLA-mismatched donors to successfully undergo transplantation. Prospective data are needed to further define which groups of patients with AML are most likely to benefit from CD34+ selected grafts. Here we review the history of T-cell depletion in AML, and techniques used. We then summarize the contemporary literature using CD34+ selection in recipients of matched or partially mismatched donors (7/8 or 8/8 HLA-matched, and provide a summary of the risks and benefits of using T-cell depletion.

  12. Diagnosis and treatment of fungal infections in allogeneic stem cell and solid organ transplant recipients.

    Science.gov (United States)

    Vehreschild, Jörg J; Rüping, Maria J G T; Steinbach, Angela; Cornely, Oliver A

    2010-01-01

    Invasive fungal diseases (IFD) are severe complications in patients receiving immunosuppression after solid organ or allogeneic stem cell transplantation. Extensive study has been conducted on therapeutic strategies for IFD in neutropenic patients, mostly those with hematological malignancy. There is an ongoing discussion on whether these studies may be applied to transplant patients as well. We have reviewed relevant literature on transplantation and clinical mycology of the last 20 years and selected articles relevant for today's treatment decisions. This article reports on the epidemiology of IFD in transplant recipients and current antifungal drugs in the context of tansplantation medicine. For invasive aspergillosis and invasive candidiasis, we give a detailed report of current clinical evidence. This review is intended as a quick-start for clinicians and other care providers new to transplant care and as an update for experienced transplant physicians. In a field in which evidence is scarce and conflicting, we provide evidence-based strategies for diagnosing and treating the most relevant IFD in transplant recipients. Physicians treating transplant patients should maintain a high level of awareness towards IFD. They should know the local epidemiology of IFD to make the optimal decision between current diagnostic and therapeutic strategies. Prophylaxis or early treatment should be considered given the high mortality of IFD.

  13. Pharmacokinetic Interaction Between Tacrolimus and Fentanyl in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Kitazawa, Fumiaki; Fuchida, Shin-Ichi; Kado, Yoko; Ueda, Kumi; Kokufu, Takatoshi; Okano, Akira; Hatsuse, Mayumi; Murakami, Satoshi; Nakayama, Yuko; Takara, Kohji; Shimazaki, Chihiro

    2017-09-26

    BACKGROUND Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl. MATERIAL AND METHODS A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay. RESULTS The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn's drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4. CONCLUSIONS The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

  14. Non-myeloablative allogeneic stem cell transplantation: a new treatment option for acquired angioedema?

    Science.gov (United States)

    Zegers, I H A; Aaldering, K N A; Nieuwhof, C M G; Schouten, H C

    2015-10-01

    Acquired angioedema is a rare disorder causing recurrent life-threatening angioedema, due to decreased activity of C1 esterase inhibitor. A 57-year-old man presented to our hospital with recurrent swelling of the hands, lips, tongue, scrotum and throat. Lab examination showed the presence of an IgM kappa monoclonal antibody. Additional analysis showed that in the IgM fraction autoantibody activity against C1 esterase inhibitor was present. This confirmed the diagnosis of acquired angioedema in the presence of lymphoplasmacytic lymphoma. Despite standard therapy, there was an increase in the episodes of laryngeal oedema. Therefore it was decided to perform a non-myeloablative allogeneic haematopoietic stem cell transplantation, with his HLA-identical brother as donor. The post-transplantation course was without complications. Five years following alloSCT he is in complete remission without symptoms and with increased C1 esterase inhibitor activity. In this case all other known treatment options for severe acquired angioedema failed. This is the first case describing treatment of severe acquired angioedema, caused by lymphoplasmacytic lymphoma, with an alloSCT.

  15. Impact of the basal metabolic ratio in predicting early deaths after allogeneic stem cell transplantation.

    Science.gov (United States)

    Nishiwaki, Satoshi; Miyamura, Koichi; Seto, Aika; Watanabe, Keisuke; Yanagisawa, Mayumi; Imahashi, Nobuhiko; Shimba, Makoto; Yasuda, Takahiko; Kuwatsuka, Yachiyo; Oba, Taku; Terakura, Seitaro; Kodera, Yoshihisa

    2009-09-01

    Early deaths after allogeneic stem cell transplantation (allo-SCT) are of major concern. On the assumption that both decreased and increased basal metabolism might relate to early deaths, we analyzed the risk factors for overall survival to days 30 (OS30) and 60 (OS60). The Harris-Benedict equation was used to calculate basal metabolism. Comparing a patient's basal metabolism (PBM) calculated from pretransplant body weight with the standard basal metabolism (SBM) calculated from standard body weight (body mass index (BMI) = 22), we defined the basal metabolic ratio (BMR) as a parameter (BMR = PBM/SBM). We retrospectively analyzed 360 adult patients transplanted between 1997 and 2006 at a single center in Japan. A multivariate analysis of OS30 showed risk factors to be: BMR BMR; LBR) (P = 0.01), BMR > 1.05 (high BMR; HBR) (P = 0.005) and non-complete remission (non-CR) (P 5 0.001), whereas a multivariate analysis of OS60 showed those risk factors to be: LBR (P = 0.02), HBR (P = 0.04), non-CR (P = 0.002), and performance status BMR BMR; ABR) (96.8 and 90.3% for ABR, 87.1 and 76.2% for LBR, and 87.8 and 81.1% for HBR). In conclusion, BMR could prove to be a predictor of early death after allo-SCT.

  16. Evaluation of timing of first vaccination in children after hematopoietic allogeneic stem cell transplantation.

    Science.gov (United States)

    Bauters, Tiene; Bordon Cueto De Braem, Victoria; Schelstraete, Petra; Van Lancker, Sophie; Laureys, Geneviève; Benoit, Yves; Dhooge, Catharina

    2016-04-01

    Protective immunity to vaccine preventable infectious diseases might be lost over time following hematopoietic stem cell transplantation (HSCT). Limited data are available on the appropriate follow-up of vaccination schedules in pediatric HSCT patients. This study aims to ascertain whether the guidelines for vaccination recommended in our hospital are followed and to which extent of conformity they are used. A 5-year survey, including all pediatric allogeneic HSCT patients, transplanted at the Ghent University hospital, Belgium. Data were collected from the patient's electronic (nursing and medical) charts. Data on vaccination schedules of 28 patients (54.9%) eligible for the recommended vaccinations were collected. Eleven patients (11/28; 39.3%) were vaccinated timely. In 14 out of 17 patients (82.4%) vaccination was postponed for medical reasons, while vaccination was postponed without medical reason in 17.6% (3/17). Vaccination data could not be retrieved in 43.1 (22/51) of patients. Vaccination was declined by the parents in one patient (2.0%). There is high level of agreement between the hospital guideline and the vaccination of pediatric HSCT patients. Health-care providers play a crucial role in effectively appropriate follow-up of vaccination schedules. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. [Effect of ABO-Incompatibility on Outcome of Allogeneic Hematopoietic Stem Cell Transplantation].

    Science.gov (United States)

    Yang, Bing-Bing; Gan, Yi-Feng; Chen, Peng; Chen, Yi; Yu, Kang

    2017-04-01

    To investigate the effect of ABO-incompatibility on the efficacy and complications of allogeneic hematopoietic stem cell transplantation(HSCT). The clinical data of 54 recipients who received ABO-incompatible allo-HSCT were retrospectively analyzed and were compared with 54 ABO-identical recipients as controls. Hematopoietic reconstruction and the blood type conversion time were dynamically observed and compared between 2 groups. The time of erythrocyte reconstitution was prolonged to 24 d in ABO-incompatible group, compared with that of 19 d in ABO-compatible group (P0.05). Major mismatch group and bidirectional mismatch group required more erythrocyte transfusions than that of ABO-compatible group. The surface antigen of erythrocyte change in major mismatch group was earlier than that of minor mismatch group (Pdisease (aGVHD) and survival were not significantly different between 2 groups. ABO-incompatibility can not influence the effect of allo-HSCT, but ABO-incompatibility delayed erythrocyte recovery, and required more RBC and platelet transfusions.

  18. Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

    Science.gov (United States)

    Itzykson, Raphael; Robin, Marie; Moins-Teisserenc, Helene; Delord, Marc; Busson, Marc; Xhaard, Aliénor; de Fontebrune, Flore Sicre; de Latour, Régis Peffault; Toubert, Antoine; Socié, Gérard

    2015-01-01

    Immune reconstitution after allogeneic stem cell transplantation is a dynamic and complex process depending on the recipient and donor characteristics, on the modalities of transplantation, and on the occurrence of graft-versus-host disease. Multivariate methods widely used for gene expression profiling can simultaneously analyze the patterns of a great number of biological variables on a heterogeneous set of patients. Here we use these methods on flow cytometry assessment of up to 25 lymphocyte populations to analyze the global pattern of long-term immune reconstitution after transplantation. Immune patterns were most distinct from healthy controls at six months, and had not yet fully recovered as long as two years after transplant. The two principal determinants of variability were linked to the balance of B and CD8+ T cells and of natural killer and B cells, respectively. Recipient’s cytomegalovirus serostatus, cytomegalovirus replication, and chronic graft-versus-host disease were the main factors shaping the immune pattern one year after transplant. We identified a complex signature of under- and over-representation of immune populations dictated by recipient’s cytomegalovirus seropositivity. Finally, we identified dimensions of variance in immune patterns as significant predictors of long-term non-relapse mortality, independently of chronic graft-versus-host disease. PMID:25261095

  19. CXCR4-Related Increase of Circulating Human Lymphoid Progenitors after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Glauzy, Salomé; André-Schmutz, Isabelle; Larghero, Jérôme; Ezine, Sophie; de Latour, Régis Peffault; Moins-Teisserenc, Hélène; Servais, Sophie; Robin, Marie; Socié, Gérard

    2014-01-01

    Immune recovery after profound lymphopenia is a major challenge in many clinical situations, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recovery depends, in a first step, on hematopoietic lymphoid progenitors production in the bone marrow (BM). In this study, we characterized CD34+Lin−CD10+ lymphoid progenitors in the peripheral blood of allo-HSCT patients. Our data demonstrate a strong recovery of this population 3 months after transplantation. This rebound was abolished in patients who developed acute graft-versus-host disease (aGVHD). A similar recovery profile was found for both CD24+ and CD24− progenitor subpopulations. CD34+lin−CD10+CD24− lymphoid progenitors sorted from allo-HSCT patients preserved their T cell potentiel according to in vitro T-cell differentiation assay and the expression profile of 22 genes involved in T-cell differentiation and homing. CD34+lin−CD10+CD24− cells from patients without aGVHD had reduced CXCR4 gene expression, consistent with an enhanced egress from the BM. CCR7 gene expression was reduced in patients after allo-HSCT, as were its ligands CCL21 and CCL19. This reduction was particularly marked in patients with aGVHD, suggesting a possible impact on thymic homing. Thus, the data presented here identify this population as an important early step in T cell reconstitution in humans and so, an important target when seeking to enhance immune reconstitution. PMID:24621606

  20. DNA Damage and Repair in Epithelium after Allogeneic Hematopoietic Stem Cell Transplantation

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    Maria Themeli

    2012-11-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation (allo-HSCT in humans, following hematoablative treatment, results in biological chimeras. In this case, the transplanted hematopoietic, immune cells and their derivatives can be considered the donor genotype, while the other tissues are the recipient genotype. The first sequel, which has been recognized in the development of chimerical organisms after allo-HSCT, is the graft versus host (GvH reaction, in which the new developed immune cells from the graft recognize the host’s epithelial cells as foreign and mount an inflammatory response to kill them. There is now accumulating evidence that this chronic inflammatory tissue stress may contribute to clinical consequences in the transplant recipient. It has been recently reported that host epithelial tissue acquire genomic alterations and display a mutator phenotype that may be linked to the occurrence of a GvH reaction. The current review discusses existing data on this recently discovered phenomenon and focuses on the possible pathogenesis, clinical significance and therapeutic implications.

  1. Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic Myelogenous Leukemia.

    Science.gov (United States)

    Zhang, Gui-Fang; Zhou, Min; Bao, Xie-Bing; Qiu, Hui-Ying; Li, Zheng; Xue, Sheng-Li

    2016-01-01

    To compare the relative merits of imatinib and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML). This cohort study was designed to compare the outcomes of imatinib (n=292) versus allo-HSCT (n=141) for CML, the clinical data of these patients being retrospectively analyzed so as to compare the event free survival (EFS) and overall survival (OS) between these two groups with patients in the chronic phase (CP) and advanced phases, including accelerate (AP) and blast phases (BP). (1) Patients treated with imatinib (278 in the CP) demonstrated superior EFS, OS, 5-year EFS and 5-year OS rates of 88.5% versus 70.0% (P0.05), 42.9% versus 57.1% (P>0.05), respectively, for imatinib (14 patients in the AP and BP) and allo-HSCT (21 patients in the AP and BP). Imatinib confers signi cant survival advantage (EFS and OS) for CML patients with CP compared with allo-HSCT treatment. However, the outcomes are equally good with both treatments in AP and BP patients.

  2. Genetic polymorphisms in the cytokine and chemokine system: their possible importance in allogeneic stem cell transplantation.

    Science.gov (United States)

    Loeffler, Juergen; Ok, Michael; Morton, Oliver C; Mezger, Markus; Einsele, Hermann

    2010-01-01

    Chemokines represent central players of the innate and adaptive immunity and are involved in the regulation of inflammatory events occurring during infectious complications or during graft vs. host disease (GvHD). Patients after allogeneic stem cell transplantation (alloSCT) are at a high risk for the development of acute GvHD or to suffer from fungal infections. Susceptibility to fungal infections and the course of GvHD can be genetically influenced by single nucleotide polymorphisms (SNPs), which regulate expression or biological activity of chemokines, and therefore have an impact on the outcome of invasive aspergillosis and GvHD. High lightened studies of abetting factors for GvHD revealed SNPs in TNFA, IL-6, IL-10, INF-γ, CCL2, CCL5 (RANTES), IL-1Ra, IL-23R, IL-7Ralpha, IL-10RB, and CCR9 genes as prevalent considerable. Furthermore, additional SNPs were described to be significantly associated with fungal infections (Aspergillus fumigatus, Candida albicans), including markers in CCL3, CCL4, CCL20, CXCL2, CXCL8, CXCL10, CCR1, and CCR2. This review summarizes the current knowledge about the growing number of genetic markers in chemokine genes and their relevance for patients after alloSCT.

  3. MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation.

    Science.gov (United States)

    Tomuleasa, Ciprian; Fuji, Shigeo; Cucuianu, Andrei; Kapp, Markus; Pileczki, Valentina; Petrushev, Bobe; Selicean, Sonia; Tanase, Alina; Dima, Delia; Berindan-Neagoe, Ioana; Irimie, Alexandru; Einsele, Hermann

    2015-07-01

    Allogeneic hematopoietic stem cell transplantation (HCT) is a well-established treatment for many malignant and non-malignant hematological disorders. As frequent complication in up to 50 % of all patients, graft-versus-host disease (GVHD) is still the main cause for morbidity and non-relapse mortality. Diagnosis of GVHD is usually done clinically, even though confirmation by pathology is often used to support the clinical findings. Effective treatment requires intensified immunosuppression as early as possible. Although several promising biomarkers have been proposed for an early diagnosis, no internationally recognized consensus has yet been established. Here, microRNAs (miRs) represent an interesting tool since miRs have been recently reported to be an important regulator of various cells, including immune cells such as T cells. Therefore, we could assume that miRs play a key role in the pathogenesis of acute GVHD, and their detection might be an interesting possibility in the early diagnosis and monitoring of acute GVHD. Recent studies additionally demonstrated the implication of miRs in the pathogenesis of acute GVHD. In this review, we aim to summarize the previous reports of miRs, focusing on the pathogenesis of acute GVHD and possible implications in diagnostic approaches.

  4. Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine.

    Science.gov (United States)

    Nowakowski, Adam; Walczak, Piotr; Janowski, Miroslaw; Lukomska, Barbara

    2015-10-01

    Mesenchymal stem cells (MSCs), which can be obtained from various organs and easily propagated in vitro, are one of the most extensively used types of stem cells and have been shown to be efficacious in a broad set of diseases. The unique and highly desirable properties of MSCs include high migratory capacities toward injured areas, immunomodulatory features, and the natural ability to differentiate into connective tissue phenotypes. These phenotypes include bone and cartilage, and these properties predispose MSCs to be therapeutically useful. In addition, MSCs elicit their therapeutic effects by paracrine actions, in which the metabolism of target tissues is modulated. Genetic engineering methods can greatly amplify these properties and broaden the therapeutic capabilities of MSCs, including transdifferentiation toward diverse cell lineages. However, cell engineering can also affect safety and increase the cost of therapy based on MSCs; thus, the advantages and disadvantages of these procedures should be discussed. In this review, the latest applications of genetic engineering methods for MSCs with regenerative medicine purposes are presented.

  5. Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Dixin Cui

    2017-01-01

    Full Text Available Temporomandibular joint osteoarthritis (TMJ OA is a degenerative disease, characterized by progressive cartilage degradation, subchondral bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical treatments have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In recent years, stem cell-based therapy has raised much attention as an alternative approach towards tissue repair and regeneration. Mesenchymal stem cells (MSCs, derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ OA. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the trophic modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will briefly discuss the pathogenesis of cartilage degeneration in TMJ OA and emphasize the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ OA, particularly focusing on the MSC-based therapy and tissue engineering.

  6. Clinical Applications of Mesenchymal Stem Cells in Chronic Diseases

    Directory of Open Access Journals (Sweden)

    Andrea Farini

    2014-01-01

    Full Text Available Extraordinary progress in understanding several key features of stem cells has been made in the last ten years, including definition of the niche, and identification of signals regulating mobilization and homing as well as partial understanding of the mechanisms controlling self-renewal, commitment, and differentiation. This progress produced invaluable tools for the development of rational cell therapy protocols that have yielded positive results in preclinical models of genetic and acquired diseases and, in several cases, have entered clinical experimentation with positive outcome. Adult mesenchymal stem cells (MSCs are nonhematopoietic cells with multilineage potential to differentiate into various tissues of mesodermal origin. They can be isolated from bone marrow and other tissues and have the capacity to extensively proliferate in vitro. Moreover, MSCs have also been shown to produce anti-inflammatory molecules which can modulate humoral and cellular immune responses. Considering their regenerative potential and immunoregulatory effect, MSC therapy is a promising tool in the treatment of degenerative, inflammatory, and autoimmune diseases. It is obvious that much work remains to be done to increase our knowledge of the mechanisms regulating development, homeostasis, and tissue repair and thus to provide new tools to implement the efficacy of cell therapy trials.

  7. Ion Channels in Hematopoietic and Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Serena Pillozzi

    2012-01-01

    Full Text Available Hematopoietic stem cells (HSCs reside in bone marrow niches and give rise to hematopoietic precursor cells (HPCs. These have more restricted lineage potential and eventually differentiate into specific blood cell types. Bone marrow also contains mesenchymal stromal cells (MSCs, which present multilineage differentiation potential toward mesodermal cell types. In bone marrow niches, stem cell interaction with the extracellular matrix is mediated by integrin receptors. Ion channels regulate cell proliferation and differentiation by controlling intracellular Ca2+, cell volume, release of growth factors, and so forth. Although little evidence is available about the ion channel roles in true HSCs, increasing information is available about HPCs and MSCs, which present a complex pattern of K+ channel expression. K+ channels cooperate with Ca2+ and Cl− channels in regulating calcium entry and cell volume during mitosis. Other K+ channels modulate the integrin-dependent interaction between leukemic progenitor cells and the niche stroma. These channels can also regulate leukemia cell interaction with MSCs, which also involves integrin receptors and affects the MSC-mediated protection from chemotherapy. Ligand-gated channels are also implicated in these processes. Nicotinic acetylcholine receptors regulate cell proliferation and migration in HSCs and MSCs and may be implicated in the harmful effects of smoking.

  8. Mesenchymal Stem Cells Derived from Dental Pulp: A Review.

    Science.gov (United States)

    Ledesma-Martínez, Edgar; Mendoza-Núñez, Víctor Manuel; Santiago-Osorio, Edelmiro

    2016-01-01

    The mesenchymal stem cells of dental pulp (DPSCs) were isolated and characterized for the first time more than a decade ago as highly clonogenic cells that were able to generate densely calcified colonies. Now, DPSCs are considered to have potential as stem cell source for orthopedic and oral maxillofacial reconstruction, and it has been suggested that they may have applications beyond the scope of the stomatognathic system. To date, most studies have shown that, regardless of their origin in third molars, incisors, or exfoliated deciduous teeth, DPSCs can generate mineralized tissue, an extracellular matrix and structures type dentin, periodontal ligament, and dental pulp, as well as other structures. Different groups worldwide have designed and evaluated new efficient protocols for the isolation, expansion, and maintenance of clinically safe human DPSCs in sufficient numbers for various therapeutics protocols and have discussed the most appropriate route of administration, the possible contraindications to their clinical use, and the parameters to be considered for monitoring their clinical efficacy and proper biological source. At present, DPSC-based therapy is promising but because most of the available evidence was obtained using nonhuman xenotransplants, it is not a mature technology.

  9. Mesenchymal Stem Cells Derived from Dental Pulp: A Review

    Directory of Open Access Journals (Sweden)

    Edgar Ledesma-Martínez

    2016-01-01

    Full Text Available The mesenchymal stem cells of dental pulp (DPSCs were isolated and characterized for the first time more than a decade ago as highly clonogenic cells that were able to generate densely calcified colonies. Now, DPSCs are considered to have potential as stem cell source for orthopedic and oral maxillofacial reconstruction, and it has been suggested that they may have applications beyond the scope of the stomatognathic system. To date, most studies have shown that, regardless of their origin in third molars, incisors, or exfoliated deciduous teeth, DPSCs can generate mineralized tissue, an extracellular matrix and structures type dentin, periodontal ligament, and dental pulp, as well as other structures. Different groups worldwide have designed and evaluated new efficient protocols for the isolation, expansion, and maintenance of clinically safe human DPSCs in sufficient numbers for various therapeutics protocols and have discussed the most appropriate route of administration, the possible contraindications to their clinical use, and the parameters to be considered for monitoring their clinical efficacy and proper biological source. At present, DPSC-based therapy is promising but because most of the available evidence was obtained using nonhuman xenotransplants, it is not a mature technology.

  10. Impairment of mesenchymal stem cells derived from oral leukoplakia.

    Science.gov (United States)

    Zhang, Zhihui; Song, Jiangyuan; Han, Ying; Mu, Dongdong; Su, Sha; Ji, Xiaoli; Liu, Hongwei

    2015-01-01

    Oral leukoplakia is one of the common precancerous lesions in oral mucosa. To compare the biological characteristics and regenerative capacities of mesenchymal stem cells (MSCs) from oral leukoplakia (epithelial hyperplasia and dysplasia) and normal oral mucosa, MSCs were isolated by enzyme digestion. Then these cells were identified by the expression of MSC related markers, STRO-1, CD105 and CD90, with the absent for the hematopoietic stem cell marker CD34 by flow cytometric detection. The self-renewal ability of MSCs from oral leukoplakia was enhanced, while the multipotent differentiation was descended, compared with MSCs from normal oral mucosa. Fibrin gel was used as a carrier for MSCs transplanted into immunocompromised mice to detect their regenerative capacity. The regenerative capacities of MSCs from oral leukoplakia became impaired partly. Collagen IV (Col IV) and matrix metalloproteinases-9 (MMP-9) were selected to analyze the potential mechanism for the functional changes of MSCs from oral leukoplakia by immunochemical and western blot analysis. The expression of Col IV was decreased and that of MMP-9 was increased by MSCs with the progression of oral leukoplakia, especially in MSCs from epithelial dysplasia. The imbalance between regenerative and metabolic self-regulatory functions of MSCs from oral leukoplakia may be related to the progression of this premalignant disorder.

  11. Adhesion of mesenchymal stem cells to biomimetic polymers: A review

    International Nuclear Information System (INIS)

    Shotorbani, Behnaz Banimohamad; Alizadeh, Effat; Salehi, Roya; Barzegar, Abolfazl

    2017-01-01

    The mesenchymal stem cells (MSCs) are promising candidates for cell therapy due to the self-renewal, multi-potency, ethically approved state and suitability for autologous transplantation. However, key issue for isolation and manipulation of MSCs is adhesion in ex-vivo culture systems. Biomaterials engineered for mimicking natural extracellular matrix (ECM) conditions which support stem cell adhesion, proliferation and differentiation represent a main area of research in tissue engineering. Some of them successfully enhanced cells adhesion and proliferation because of their biocompatibility, biomimetic texture, and chemistry. However, it is still in its infancy, therefore intensification and optimization of in vitro, in vivo, and preclinical studies is needed to clarify efficacies as well as applicability of those bioengineered constructs. The aim of this review is to discuss mechanisms related to the in-vitro adhesion of MSCs, surfaces biochemical, biophysical, and other factors (of cell's natural and artificial micro-environment) which could affect it and a review of previous research attempting for its bio-chemo-optimization. - Highlights: • The main materials utilized for fabrication of biomimetic polymers are presented. • MSCs cell-material adhesion mechanism and involved molecules are reviewed. • Surface modifications of polymers in terms of MSC adhesion improving are discussed.

  12. Eccentric exercise facilitates mesenchymal stem cell appearance in skeletal muscle.

    Directory of Open Access Journals (Sweden)

    M Carmen Valero

    Full Text Available Eccentric, or lengthening, contractions result in injury and subsequently stimulate the activation and proliferation of satellite stem cells which are important for skeletal muscle regeneration. The discovery of alternative myogenic progenitors in skeletal muscle raises the question as to whether stem cells other than satellite cells accumulate in muscle in response to exercise and contribute to post-exercise repair and/or growth. In this study, stem cell antigen-1 (Sca-1 positive, non-hematopoetic (CD45⁻ cells were evaluated in wild type (WT and α7 integrin transgenic (α7Tg mouse muscle, which is resistant to injury yet liable to strain, 24 hr following a single bout of eccentric exercise. Sca-1⁺CD45⁻ stem cells were increased 2-fold in WT muscle post-exercise. The α7 integrin regulated the presence of Sca-1⁺ cells, with expansion occurring in α7Tg muscle and minimal cells present in muscle lacking the α7 integrin. Sca-1⁺CD45⁻ cells isolated from α7Tg muscle following exercise were characterized as mesenchymal-like stem cells (mMSCs, predominantly pericytes. In vitro multiaxial strain upregulated mMSC stem cells markers in the presence of laminin, but not gelatin, identifying a potential mechanistic basis for the accumulation of these cells in muscle following exercise. Transplantation of DiI-labeled mMSCs into WT muscle increased Pax7⁺ cells and facilitated formation of eMHC⁺DiI⁻ fibers. This study provides the first demonstration that mMSCs rapidly appear in skeletal muscle in an α7 integrin dependent manner post-exercise, revealing an early event that may be necessary for effective repair and/or growth following exercise. The results from this study also support a role for the α7 integrin and/or mMSCs in molecular- and cellular-based therapeutic strategies that can effectively combat disuse muscle atrophy.

  13. Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy.

    Science.gov (United States)

    Filosto, Massimiliano; Scarpelli, Mauro; Tonin, Paola; Lucchini, Giovanna; Pavan, Fabio; Santus, Francesca; Parini, Rossella; Donati, Maria Alice; Cotelli, Maria Sofia; Vielmi, Valentina; Todeschini, Alice; Canonico, Francesco; Tomelleri, Giuliano; Padovani, Alessandro; Rovelli, Attilio

    2012-12-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele-matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant-related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us

  14. Suitability of human mesenchymal stem cells for gene therapy depends on the expansion medium

    International Nuclear Information System (INIS)

    Apel, Anja; Groth, Ariane; Schlesinger, Sabine; Bruns, Helge; Schemmer, Peter; Buechler, Markus W.; Herr, Ingrid

    2009-01-01

    Great hope is set in the use of mesenchymal stem cells for gene therapy and regenerative medicine. Since the frequency of this subpopulation of stem cells in bone marrow is low, mesenchymal stem cells are expanded ex vivo and manipulated prior to experimental or clinical use. Different methods for isolation and expansion are available, but the particular effect on the stem cell character is unclear. While the isolation of mesenchymal stem cells by density centrifugation followed by selection of the plastic adherent fraction is frequently used, the composition of expansion media differs. Thus, in the present study we cultured mesenchymal stem cells isolated from five healthy young volunteers in three widely used expansion media and performed a detailed analysis of the effect on morphology, proliferation, clonogenicity, passaging, differentiation and senescence. By this way we clearly show that the type of expansion medium used determines the stem cell character and time of senescence which is critical for future gene therapeutic and regenerative approaches using mesenchymal stem cells

  15. Low-level laser irradiation induces in vitro proliferation of mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Barboza, Carlos Augusto Galvão; Ginani, Fernanda [Universidade Federal do Rio Grande do Norte, Natal, RN (Brazil); Soares, Diego Moura [Universidade Federal de Pernambuco, Recife, PE (Brazil); Henriques, Águida Cristina Gomes; Freitas, Roseana de Almeida [Universidade Federal do Rio Grande do Norte, Natal, RN (Brazil)

    2014-07-01

    To evaluate the effect of low-level laser irradiation on the proliferation and possible nuclear morphological changes of mouse mesenchymal stem cells. Mesenchymal stem cells derived from bone marrow and adipose tissue were submitted to two applications (T0 and T48 hours) of low-level laser irradiation (660nm; doses of 0.5 and 1.0J/cm{sup 2}). The trypan blue assay was used to evaluate cell viability, and growth curves were used to analyze proliferation at zero, 24, 48, and 72 hours. Nuclear alterations were evaluated by staining with DAPI (4'-6-diamidino-2-phenylindole) at 72 hours. Bone marrow-derived mesenchymal stem cells responded to laser therapy in a dose-dependent manner. Higher cell growth was observed when the cells were irradiated with a dose of 1.0J/cm{sup 2}, especially after 24 hours (p<0.01). Adipose-derived mesenchymal stem cells responded better to a dose of 1.0J/cm{sup 2}, but higher cell proliferation was observed after 48 hours (p<0.05) and 72 hours (p<0.01). Neither nuclear alterations nor a significant change in cell viability was detected in the studied groups. Low-level laser irradiation stimulated the proliferation of mouse mesenchymal stem cells without causing nuclear alterations. The biostimulation of mesenchymal stem cells using laser therapy might be an important tool for regenerative therapy and tissue engineering.

  16. Low-level laser irradiation induces in vitro proliferation of mesenchymal stem cells

    International Nuclear Information System (INIS)

    Barboza, Carlos Augusto Galvão; Ginani, Fernanda; Soares, Diego Moura; Henriques, Águida Cristina Gomes; Freitas, Roseana de Almeida

    2014-01-01

    To evaluate the effect of low-level laser irradiation on the proliferation and possible nuclear morphological changes of mouse mesenchymal stem cells. Mesenchymal stem cells derived from bone marrow and adipose tissue were submitted to two applications (T0 and T48 hours) of low-level laser irradiation (660nm; doses of 0.5 and 1.0J/cm 2 ). The trypan blue assay was used to evaluate cell viability, and growth curves were used to analyze proliferation at zero, 24, 48, and 72 hours. Nuclear alterations were evaluated by staining with DAPI (4'-6-diamidino-2-phenylindole) at 72 hours. Bone marrow-derived mesenchymal stem cells responded to laser therapy in a dose-dependent manner. Higher cell growth was observed when the cells were irradiated with a dose of 1.0J/cm 2 , especially after 24 hours (p<0.01). Adipose-derived mesenchymal stem cells responded better to a dose of 1.0J/cm 2 , but higher cell proliferation was observed after 48 hours (p<0.05) and 72 hours (p<0.01). Neither nuclear alterations nor a significant change in cell viability was detected in the studied groups. Low-level laser irradiation stimulated the proliferation of mouse mesenchymal stem cells without causing nuclear alterations. The biostimulation of mesenchymal stem cells using laser therapy might be an important tool for regenerative therapy and tissue engineering

  17. Acupoint Injection of Autologous Stromal Vascular Fraction and Allogeneic Adipose-Derived Stem Cells to Treat Hip Dysplasia in Dogs

    Directory of Open Access Journals (Sweden)

    Camila Marx

    2014-01-01

    Full Text Available Stem cells isolated from adipose tissue show great therapeutic potential in veterinary medicine, but some points such as the use of fresh or cultured cells and route of administration need better knowledge. This study aimed to evaluate the effect of autologous stromal vascular fraction (SVF, n=4 or allogeneic cultured adipose-derived stem cells (ASCs, n=5 injected into acupuncture points in dogs with hip dysplasia and weak response to drug therapy. Canine ASCs have proliferation and differentiation potential similar to ASCs from other species. After the first week of treatment, clinical evaluation showed marked improvement compared with baseline results in all patients treated with autologous SVF and three of the dogs treated with allogeneic ASCs. On days 15 and 30, all dogs showed improvement in range of motion, lameness at trot, and pain on manipulation of the joints, except for one ASC-treated patient. Positive results were more clearly seen in the SVF-treated group. These results show that autologous SVF or allogeneic ASCs can be safely used in acupoint injection for treating hip dysplasia in dogs and represent an important therapeutic alternative for this type of pathology. Further studies are necessary to assess a possible advantage of SVF cells in treating joint diseases.

  18. Weight Loss and Decrease of Body Mass Index during Allogeneic Stem Cell Transplantation Are Common Events with Limited Clinical Impact.

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    Christina T Rieger

    Full Text Available Weight loss in cancer patients has been attributed with significant morbidity and mortality. During allogeneic stem cell transplantation (SCT, oral nutrition is often hampered and hence total parenteral nutrition (TPN is necessary. We therefore investigated the course of weight during stem cell transplantation and the clinical consequences of weight change.180 consecutive patients who received allogeneic SCT between January 2010 and December 2011 at our center were analyzed for weight loss, laboratory and clinical parameters.During SCT, a median decrease of 6.6% of body mass index (BMI was observed for the whole population (from 25.3 at admission to 23.6 at discharge, and a 1.6fold increase of malnutrition despite use of TPN (28.3% to 45.0%. 55.6% of patients experienced a significant weight loss of ≥5% with a median decrease of 9.2% in BMI. Serum levels of albumin, total protein and cholesterol rapidly decreased during conditioning therapy. After a median of 2.4 years, the median BMI was still only 23.4 (not different from discharge. However, we did not observe a meaningful difference in side effects and survival between patients that did or did not lose weight.Weight loss is commonly observed during allogeneic SCT despite TPN, but the clinical consequences thereof seem limited: we observed no significant impact on patients with a decrease ≥ 5% in BMI on transplant outcome, side effects or survival.

  19. INFLUENCE OF BONE MARROW ALLOGENEIC MULTIPOTENT MESENCHYMAL STROMAL CELLS ON THE FORMATION OF ANTI-ISCHEMIC KIDNEY PROTECTION

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    S. S. Mescherin

    2015-01-01

    Full Text Available Аim of this work was to study the influence of intravenous injection times of bone marrow allogeneic multipotent mesenchymal stromal cells (BM MMSCs on kidney function and morphology in modeled ischemicreperfusion injury of kidney (IRIK. Materials and methods. The study was conducted on 90 male Wistar rats. On the original IRI model of a single kidney (60 min, warm ischemia 4 groups of experiments were performed: in the first group the dose of 5 × 106 of BM MMSCs was administered intravenously 14 days before IRIK modeling; in the second group, the same dose of BM MMSCs was administered 7 days before IRIK; in the third group, the same dose of BM MMSCs was administered during kidney reperfusion after IRIK modeling; the fourth group served as the control group (IRIK without BM МMSCs. The study duration was 21 days since the start of IRIK modeling. In all groups the nitrogen secretory function of kidneys was examined and the histological condition of kidneys during the entire recovery period was evaluated. Besides, blood of rats of the first and the fourth groups was examined for proand anti-inflammatory cytokine levels and phagocytosis indices using the suspension of inactivated St. aureus. The significance of differences in these two groups was evaluated by Student's test at p < 0.05. Results. It has been demonstrated that the pretreatment with BM MMSCs (1 and 2 weeks before IRIK modeling increased the anti-ischemic resistance of kidney while the administration of BM MMSCs on the day of IRIK modeling (during reperfusion enhanced kidney damage, characterized by increased mortality, elevated levels of urea and creatinine in blood and structural injury of renal tissue, as compared to other groups. The comparative analysis of the first and fourth groups shows that BM MMSCs decrease the levels of pro-inflammatory cytokines and increase the levels of anti-inflammatory cytokines, as well as enhance potential of antimicrobial protection. Conclusion

  20. Mesenchymal Stromal/stem Cell-derived Extracellular Vesicles Promote Human Cartilage RegenerationIn Vitro.

    Science.gov (United States)

    Vonk, Lucienne A; van Dooremalen, Sanne F J; Liv, Nalan; Klumperman, Judith; Coffer, Paul J; Saris, Daniël B F; Lorenowicz, Magdalena J

    2018-01-01

    Osteoarthritis (OA) is a rheumatic disease leading to chronic pain and disability with no effective treatment available. Recently, allogeneic human mesenchymal stromal/stem cells (MSC) entered clinical trials as a novel therapy for OA. Increasing evidence suggests that therapeutic efficacy of MSC depends on paracrine signalling. Here we investigated the role of extracellular vesicles (EVs) secreted by human bone marrow derived MSC (BMMSC) in human OA cartilage repair. To test the effect of BMMSC-EVs on OA cartilage inflammation, TNF-alpha-stimulated OA chondrocyte monolayer cultures were treated with BMMSC-EVs and pro-inflammatory gene expression was measured by qRT-PCR after 48 h. To assess the impact of BMMSC-EVs on cartilage regeneration, BMMSC-EVs were added to the regeneration cultures of human OA chondrocytes, which were analyzed after 4 weeks for glycosaminoglycan content by 1,9-dimethylmethylene blue (DMMB) assay. Furthermore, paraffin sections of the regenerated tissue were stained for proteoglycans (safranin-O) and type II collagen (immunostaining). We show that BMMSC-EVs inhibit the adverse effects of inflammatory mediators on cartilage homeostasis. When co-cultured with OA chondrocytes, BMMSC-EVs abrogated the TNF-alpha-mediated upregulation of COX2 and pro-inflammatory interleukins and inhibited TNF-alpha-induced collagenase activity. BMMSC-EVs also promoted cartilage regeneration in vitro . Addition of BMMSC-EVs to cultures of chondrocytes isolated from OA patients stimulated production of proteoglycans and type II collagen by these cells. Our data demonstrate that BMMSC-EVs can be important mediators of cartilage repair and hold great promise as a novel therapeutic for cartilage regeneration and osteoarthritis.

  1. Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants.

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    Anabel S de la Garza-Rodea

    Full Text Available BACKGROUND: Mesenchymal stem cells (MSCs are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected. METHODOLOGY/PRINCIPAL FINDINGS: We aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID mice could be attained provided that recipients' natural killer (NK cells were depleted prior to cell transplantation. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable.

  2. Mesenchymal stem cells in obesity: insights for translational applications.

    Science.gov (United States)

    Matsushita, Kenichi; Dzau, Victor J

    2017-10-01

    Obesity is now a major public health problem worldwide. Lifestyle modification to reduce the characteristic excess body adiposity is important in the treatment of obesity, but effective therapeutic intervention is still needed to control what has become an obesity epidemic. Unfortunately, many anti-obesity drugs have been withdrawn from market due to adverse side effects. Bariatric surgery therefore remains the most effective therapy for severe cases, although such surgery is invasive and researchers continue to seek new control strategies for obesity. Mesenchymal stem cells (MSCs) are a major source of adipocyte generation, and studies have been conducted into the potential roles of MSCs in treating obesity. However, despite significant progress in stem cell research and its potential applications for obesity, adipogenesis is a highly complex process and the molecular mechanisms governing MSC adipogenesis remain ill defined. In particular, successful clinical application of MSCs will require extensive identification and characterization of the transcriptional regulators controlling MSC adipogenesis. Since obesity is associated with the incidence of multiple important comorbidities, an in-depth understanding of the relationship between MSC adipogenesis and the comorbidities of obesity is also necessary to evaluate the potential of effective and safe MSC-based therapies for obesity. In addition, brown adipogenesis is an attractive topic from the viewpoint of therapeutic innovation and future research into MSC-based brown adipogenesis could lead to a novel breakthrough. Ongoing stem cell studies and emerging research fields such as epigenetics are expected to elucidate the complicated mechanisms at play in MSC adipogenesis and develop novel MSC-based therapeutic options for obesity. This review discusses the current understanding of MSCs in adipogenesis and their potential clinical applications for obesity.

  3. Clinical Trials With Mesenchymal Stem Cells: An Update.

    Science.gov (United States)

    Squillaro, Tiziana; Peluso, Gianfranco; Galderisi, Umberto

    2016-01-01

    In the last year, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. Currently the most commonly used adult stem cells in regenerative medicine, MSCs, can be isolated from several tissues, exhibit a strong capacity for replication in vitro, and can differentiate into osteoblasts, chondrocytes, and adipocytes. However, heterogeneous procedures for isolating and cultivating MSCs among laboratories have prompted the International Society for Cellular Therapy (ISCT) to issue criteria for identifying unique populations of these cells. Consequently, the isolation of MSCs according to ISCT criteria has produced heterogeneous, nonclonal cultures of stromal cells containing stem cells with different multipotent properties, committed progenitors, and differentiated cells. Though the nature and functions of MSCs remain unclear, nonclonal stromal cultures obtained from bone marrow and other tissues currently serve as sources of putative MSCs for therapeutic purposes, and several findings underscore their effectiveness in treating different diseases. To date, 493 MSC-based clinical trials, either complete or ongoing, appear in the database of the US National Institutes of Health. In the present article, we provide a comprehensive review of MSC-based clinical trials conducted worldwide that scrutinizes biological properties of MSCs, elucidates recent clinical findings and clinical trial phases of investigation, highlights therapeutic effects of MSCs, and identifies principal criticisms of the use of these cells. In particular, we analyze clinical trials using MSCs for representative diseases, including hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, and diseases in the liver, kidney

  4. Role of mesenchymal stem cells in osteoarthritis treatment

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    Ling Kong

    2017-04-01

    Full Text Available As the most common form of joint disorder, osteoarthritis (OA imposes a tremendous burden on health care systems worldwide. Without effective cure, OA represents a unique opportunity for innovation in therapeutic development. In contrast to traditional treatments based on drugs, proteins, or antibodies, stem cells are poised to revolutionize medicine as they possess the capacity to replace and repair tissues and organs such as osteoarthritic joints. Among different types of stem cells, mesenchymal stem cells (MSCs are of mesoderm origin and have been shown to generate cells for tissues of the mesoderm lineage, thus, raising the hope for them being used to treat diseases such as OA. However, given their ability to differentiate into other cell types, MSCs have also been tested in treating a myriad of conditions from diabetes to Parkinson's disease, apparently of the ectoderm and endoderm lineages. There are ongoing debates whether MSCs can differentiate into lineages outside of the mesoderm and consequently their effectiveness in treating conditions from the ectoderm and endoderm lineages. In this review, we discuss the developmental origin of MSCs, their differentiation potential and immunomodulatory effects, as well as their applications in treating OA. We suggest further investigations into new therapies or combination therapies that may provide more effective treatment for bone and joint diseases. Furthermore, cell-based therapy and its associated safety and effectiveness should be carefully evaluated before clinical translation. This review provides updated information on recent approval of clinical trials and related applications of MSCs, and discusses additional efforts on cell-based therapy for treating OA and other joint and bone diseases.

  5. The endometrium as a source of mesenchymal stem cells for regenerative medicine.

    Science.gov (United States)

    Mutlu, Levent; Hufnagel, Demetra; Taylor, Hugh S

    2015-06-01

    Stem cell therapies have opened new frontiers in medicine with the possibility of regenerating lost or damaged cells. Embryonic stem cells, induced pluripotent stem cells, hematopoietic stem cells, and mesenchymal stem cells have been used to derive mature cell types for tissue regeneration and repair. However, the endometrium has emerged as an attractive, novel source of adult stem cells that are easily accessed and demonstrate remarkable differentiation capacity. In this review, we summarize our current understanding of endometrial stem cells and their therapeutic potential in regenerative medicine. © 2015 by the Society for the Study of Reproduction, Inc.

  6. Mast Cell Leukemia: Review of a Rare Disease and Case Report of Prolonged Survival after Allogeneic Stem Cell Transplant

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    James Bauer, MD, PhD

    2017-11-01

    Full Text Available Mast cell leukemia is a rare and aggressive form of mastocytosis characterized by >20% mast cells found in the bone marrow aspirates of patients with signs of systemic mastocytosis-related organ damage. The prognosis for patients with mast cell leukemia is extremely poor, with resistance to both cytoreductive therapies and tyrosine kinase inhibitors being relatively common. While allogeneic hematopoietic stem cell transplantation has been associated with long-term survival in patients with advanced systemic mastocytosis, reports regarding its effectiveness in mast cell leukemia are limited to fewer than 20 cases described in the literature. Here, we report a patient with mast cell leukemia who remains in complete remission 24 months after allogeneic HSCT at the time of this writing, and briefly review the clinical, diagnostic, and therapeutic approaches to this rare disease.

  7. Experimental study on therapy of acute radiation sickness with transplantation of allogeneic peripheral blood hemopoietic stem cells

    International Nuclear Information System (INIS)

    Ma Enpu; Bi Jianjin; Zhan Aiqin

    1995-01-01

    In the study, 10 beagles were used. All the dogs were irradiated with 6.5 Gy of γ-rays from a 60 Co source (dose rate, 95.6-107.9 R/min) and divided into three groups. All the three dogs in the control group died, having survived 7.5 days on the average after irradiation. In the second group, four dogs were transplanted with allogeneic peripheral blood hemopoietic stem cells (PBHSC) without removing T lymphocytes. The results of sex chromosome tests after irradiation and transplantation showed that the cells were of donor type. All the four dogs died of severe graft versus-host disease (GVHD) and survived 41.6 days on the average after irradiation. In the third group, three dogs received transplantation of allogeneic PBHSC without T lymphocytes. Two of them died, and the third developed mild GVHD and survived over 4 years

  8. Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Gorshein, Elan; Wei, Catherine; Ambrosy, Susan; Budney, Shanna; Vivas, Juliana; Shenkerman, Angelika; Manago, Jacqueline; McGrath, Mary Kate; Tyno, Anne; Lin, Yong; Patel, Vimal; Gharibo, Mecide; Schaar, Dale; Jenq, Robert R; Khiabanian, Hossein; Strair, Roger

    2017-05-01

    Graft-versus-host disease (GVHD) is a major adverse effect associated with allogeneic stem cell transplant. Previous studies in mice indicated that administration of the probiotic Lactobacillus rhamnosus GG can reduce the incidence of GVHD after hematopoietic stem cell transplant. Here we report results from the first randomized probiotic enteric regimen trial in which allogenic hematopoietic stem cell patients were supplemented with Lactobacillus rhamnosus GG. Gut microbiome analysis confirmed a previously reported gut microbiome association with GVHD. However, the clinical trial was terminated when interim analysis did not detect an appreciable probiotic-related change in the gut microbiome or incidence of GVHD. Additional studies are necessary to determine whether probiotics can alter the incidence of GVHD after allogeneic stem cell transplant. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Invariant Natural Killer T Cells As Suppressors of Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation

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    Melissa Mavers

    2017-07-01

    Full Text Available Invariant natural killer T (iNKT cells serve as a bridge between innate and adaptive immunity and have been shown to play an important role in immune regulation, defense against pathogens, and cancer immunity. Recent data also suggest that this compartment of the immune system plays a significant role in reducing graft-versus-host disease (GVHD in the setting of allogeneic hematopoietic stem cell transplantation. Murine studies have shown that boosting iNKT numbers through certain conditioning regimens or adoptive transfer leads to suppression of acute or chronic GVHD. Preclinical work reveals that iNKT cells exert their suppressive function by expanding regulatory T cells in vivo, though the exact mechanism by which this occurs has yet to be fully elucidated. Human studies have demonstrated that a higher number of iNKT cells in the graft or in the peripheral blood of the recipient post-transplantation are associated with a reduction in GVHD risk, importantly without a loss of graft-versus-tumor effect. In two separate analyses of many immune cell subsets in allogeneic grafts, iNKT cell dose was the only parameter associated with a significant improvement in GVHD or in GVHD-free progression-free survival. Failure to reconstitute iNKT cells following allogeneic transplantation has also been associated with an increased risk of relapse. These data demonstrate that iNKT cells hold promise for future clinical application in the prevention of GVHD in allogeneic stem cell transplantation and warrant further study of the immunoregulatory functions of iNKT cells in this setting.

  10. Preclinical Evaluation of the Immunomodulatory Properties of Cardiac Adipose Tissue Progenitor Cells Using Umbilical Cord Blood Mesenchymal Stem Cells: A Direct Comparative Study

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    Isaac Perea-Gil

    2015-01-01

    Full Text Available Cell-based strategies to regenerate injured myocardial tissue have emerged over the past decade, but the optimum cell type is still under scrutiny. In this context, human adult epicardial fat surrounding the heart has been characterized as a reservoir of mesenchymal-like progenitor cells (cardiac ATDPCs with potential clinical benefits. However, additional data on the possibility that these cells could trigger a deleterious immune response following implantation are needed. Thus, in the presented study, we took advantage of the well-established low immunogenicity of umbilical cord blood-derived mesenchymal stem cells (UCBMSCs to comparatively assess the immunomodulatory properties of cardiac ATDPCs in an in vitro allostimulatory assay using allogeneic mature monocyte-derived dendritic cells (MDDCs. Similar to UCBMSCs, increasing amounts of seeded cardiac ATDPCs suppressed the alloproliferation of T cells in a dose-dependent manner. Secretion of proinflammatory cytokines (IL6, TNFα, and IFNγ was also specifically modulated by the different numbers of cardiac ATDPCs cocultured. In summary, we show that cardiac ATDPCs abrogate T cell alloproliferation upon stimulation with allogeneic mature MDDCs, suggesting that they could further regulate a possible harmful immune response in vivo. Additionally, UCBMSCs can be considered as valuable tools to preclinically predict the immunogenicity of prospective regenerative cells.

  11. Transplantation of neurotrophin-3-transfected bone marrow mesenchymal stem cells for the repair of spinal cord injury

    OpenAIRE

    Dong, Yuzhen; Yang, Libin; Yang, Lin; Zhao, Hongxing; Zhang, Chao; Wu, Dapeng

    2014-01-01

    Bone marrow mesenchymal stem cell transplantation has been shown to be therapeutic in the repair of spinal cord injury. However, the low survival rate of transplanted bone marrow mesenchymal stem cells in vivo remains a problem. Neurotrophin-3 promotes motor neuron survival and it is hypothesized that its transfection can enhance the therapeutic effect. We show that in vitro transfection of neurotrophin-3 gene increases the number of bone marrow mesenchymal stem cells in the region of spinal ...

  12. Células-tronco mesenquimais Mesenchymal stem cell

    Directory of Open Access Journals (Sweden)

    Betânia Souza Monteiro

    2010-02-01

    Full Text Available Dentre todas as células-tronco estudadas até o presente momento, as mesenquimais (MSC destacam-se por sua elevada plasticidade, podendo originar tecidos mesodermais e não mesodermais. Além disso, possuem características imunomoduladoras e imunossupressoras que ampliam as possibilidades de utilização terapêutica. As MSC secretam uma grande variedade de citocinas pró e anti-inflamatórias e fatores de crescimento e, por meio dessas moléculas bioativas, proporcionam a modulação da resposta inflamatória, o restabelecimento do suprimento vascular e a reparação adequada do tecido, contribuindo para a homeostasia tissular e imunológica sob condições fisiológicas. Também podem induzir as demais células presentes no nicho tecidual a secretarem outros fatores solúveis que estimulam a diferenciação dessas células indiferenciadas, favorecendo o processo de reparação. A terapia celular com MSC é uma alternativa terapêutica promissora, porém a compreensão da biologia dessas células ainda é uma ciência em formação. Este artigo tem por objetivo realizar uma breve revisão sobre as células mesenquimais indiferenciadas.Of all the stem cells studied so far, the mesenchymal stem cells (MSC stand out for their high plasticity and capacity of generating mesodermal and non-mesodermal tissues. In addition, immunomodulatory and immunosuppressive features that expand possibilities for therapeutic use are present in these cells. A variety of pro and anti-inflammatory cytokines and growth factors are secrete for MSC and provide a modulation of inflammatory response, re-establishment of vascular supply and adequate repair of the tissue, contributing to tissue homeostasis under physiologic conditions. Therefore, they can induce secretion of soluble factors that stimulate their differentiation by other cells present at the niche's tissue, promoting the repair process. Cell therapy using MSC is a promises therapeutic alternative, but

  13. Inspiratory muscle training in allogeneic hematopoietic stem cell transplantation recipients: a randomized controlled trial.

    Science.gov (United States)

    Barğı, Gülşah; Güçlü, Meral Boşnak; Arıbaş, Zeynep; Akı, Şahika Zeynep; Sucak, Gülsan Türköz

    2016-02-01

    Respiratory muscles are known to be weakened and are a cause of reduced exercise capacity in both recipients and candidates of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effects of inspiratory muscle training (IMT) in this patient population have not been comprehensively investigated so far. The current study was planned to investigate the effects of IMT during allo-HSCT on early transplantation-related outcomes. This is a prospective, randomized controlled, double-blinded study. Thirty-eight allo-HSCT recipients, 20 of whom were allocated to the treatment group (40 % of maximal inspiratory pressure (MIP)) and 18 to the control group (5 % of MIP), received IMT for 6 weeks. Pulmonary functions, dyspnea, respiratory (MIP, maximal expiratory pressure (MEP)) and peripheral muscle strength, maximal exercise capacity using modified incremental shuttle walking test (MISWT) and submaximal exercise capacity using 6-min walking test (6-MWT), fatigue, depression, and quality of life were evaluated before and after IMT. The distance covered during MISWT (61.94 m) and 6-MWT (29.30 m), respiratory muscle strength (MIP 34.99 cmH2O, MEP 12.69 cmH2O), depression (-0.95), and modified Borg dyspnea scores (-0.11) showed a significant improvement in the treatment group compared to controls (p ≤ 0.05). Inspiratory muscle training is a safe and effective intervention which improves respiratory muscle strength and exercise capacity and decreases depression and dyspnea in allo-HSCT recipients. These positive changes might be further enhanced by prolonging the duration of training or inclusion of more recipients with inspiratory muscle weakness. NCT02270346.

  14. TREATMENT OF SEVERE AUTOIMMUNE CYTOPENIAS AFTER ALLOGENEIC STEM CELL TRANSPLANTATION – REPORT OF TWO CASES

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    Irena Preložnik Zupan

    2004-12-01

    Full Text Available Background. Autoimmune cytopenias, thrombocytopenia, anemia and neutropenia, are rare but serious complications after stem cell transplantation (SCT. There are only a few reports concerning their treatment. We performed splenectomy in two patients with severe autoimmune cytopenias after allogeneic SCT resistant to immunosuppressive treatment.Patients, methods and results. First patient had unrelated alloSCT at Royal Free Hospital London for chronic granulocytic leukemia (CGL in July 2000. Post-transplant period was complicated with cytomegalovirus reactivation and septicemia. Seven months later RBC and platelet counts went down. Direct Coomb’s test was intermittently positive. She was resistant to steroids and high dose immunoglobulin. Splenectomy was performed in February 2001. After splenectomy hemoglobin concentration and platelet count improved. Her blood counts remained stable with hemoglobin about 110 g/L and platelets over 100 x109/L. She continued therapy with Itraconazol, Valacyclovir and Penicillin. Three months later she was readmitted for E. Coli fulminated septic infection with fatal outcome.Second patient had related alloSCT at University Medical Centre Ljubljana for CGL in January 2003. Post-transplant course was uneventful. Seven months later he was readmitted for retinal bleeding with severe thrombocytopenia with positive anti-platelet antibodies. He was resistant to steroids and high dose immunoglobulin. Splenectomy was performed in September 2003. His platelet count normalized and remains stable so far. He continues therapy with Itraconazol, Valacyclovir and Penicillin and didn’t experience any serious infection.Conclusions. We assume that splenectomy is an efficient treatment for resistant immune cytopenias after alloSCT. However, severe late infections may compromise the outcome.

  15. SEVERE (GRADE III-IV ACUTE GRAFT VERSUS HOST DISEASE AFTER ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION

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    Irena Preložnik-Zupan

    2002-09-01

    Full Text Available Background. Beside greater susceptibility to infections, acute graft host disease is a consequence of the activation of donor T-cells against host antigens. Most common target organs are skin, liver and intestinal mucosis.Methods. In the 6-year period between January 1995 and December 2000, 49 patients were treated with allogeneic haematopoietic stem cell transplantation (allo-HSCT in Transplant unit, Department of Hematology, Clinical Centre Ljubljana. The standard GVHD prophylaxis regimen consisted of cyclosporine and short-course methotrexate. Severe, grade III-IV aGVHD with skin and/or gastrointestinal and/or liver involvement appeared in 16 (32% of the 49 patients.Results. Among the 16 patients with severe aGVHD, 14 had liver involvement, ten gastrointestinal and eight skin involvement. One patient had skin involvement only, the rest of them had combined involvement of two or three organ systems. Routine first-line treatment for aGVHD, given to all 16 pts with severe forms of the disease, was methylprednisolone (MP 2mg/ kg. Six patients with predominant skin involvement responded to MP. Other ten patients with mainly liver and gastrointestinal involvement needed second or even third line aGVHD treatment. These were anti-thymocyte globulin (ATG and/or monoclonal antibodies (OKT3 and/or mycophenolate mofetil (MMF and/or FK506 (tacrolimus. Seven patients died of advanced aGVHD and treatment related infection.Conclusions. Based on our experiences, we conclude that in critically ill patients with severe aGVHD, neutropenia and high risk for opportunistic infection, each day of ineffective MP therapy may have fatal consequences. Simultaneous institution of a combination of corticosteroids and a second-line drug might prove more appropriate for patients with a severe form of aGVHD.

  16. Risk factor analysis of autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation in children.

    Science.gov (United States)

    Chang, Tsung-Yen; Jaing, Tang-Her; Wen, Yu-Chuan; Huang, I-Anne; Chen, Shih-Hsiang; Tsay, Pei-Kwei

    2016-11-01

    Autoimmune hemolytic anemia (AIHA) is a clinically relevant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, there is no established consensus regarding the optimal therapeutic approach. Whether AIHA contributes to increased mortality is still somewhat controversial.We investigated the incidence, risk factors, and outcome of post-transplant AIHA in 265 consecutive pediatric patients undergoing allo-HSCT over a 17-year period. Onset of AIHA was calculated from the first documented detection of AIHA by either clinical symptoms or positive direct agglutinin test. Resolution of AIHA was defined as normalization of hemoglobin and biochemical markers of hemolysis with sustained transfusion independence.We identified 15 cases of AIHA after allo-HSCT (incidence rate, 6%). Ten (67%) of these patients had a positive direct antiglobulin test. Data were obtained for 9 boys and 6 girls after a median follow-up of 53 months (range 4-102). The median age was 5.1 years (range 0.5-15.4) at the time of HSCT and the median time to emergence was 149 days (range 42-273). No significant risk factor for post-transplant AIHA has emerged from our data to date. In the majority (14 of 15; 93%) of AIHA patients, multiple agents for treatment were required, with 12 of 15 (80%) patients achieving complete resolution of AIHA. No splenectomy was performed in any of our patients.For various reasons, post-transplantation AIHA poses an extraordinary challenge to transplant physicians. Despite the advancements in diagnostic tools, therapeutic challenges remain due to the myriad interacting pathways in AIHA.

  17. Effect of Cytomegalovirus Reactivation on Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Leukemia.

    Science.gov (United States)

    Inagaki, Jiro; Noguchi, Maiko; Kurauchi, Koichiro; Tanioka, Shinji; Fukano, Reiji; Okamura, Jun

    2016-02-01

    Recent studies have demonstrated the protective effect of cytomegalovirus (CMV) reactivation against relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for adult myeloid malignancies. We assessed the association of CMV reactivation, defined as the development of CMV antigenemia (at least 1 pp65 antigen-positive cell per 5.0 × 10(4) WBCs) within 100 days after HSCT, with the risk of relapse in 143 patients with pediatric acute leukemia. The median age at HSCT was 7 years, and underlying diseases included acute lymphoblastic leukemia in 101 patients and acute myeloid leukemia in 42. The cumulative incidence of CMV reactivation at day 100 after HSCT was 45.4%. At a median follow-up of 88 months, patients with CMV reactivation had significantly lower 5-year cumulative incidence of relapse compared with patients without CMV reactivation. In a multivariate analysis, high-level CMV reactivation (≥10 pp65 antigen-positive cells) was an independent factor associated with reduced relapse. However, CMV reactivation was also associated with higher nonrelapse mortality (NRM), mostly caused by opportunistic infection after grades II to IV acute graft-versus-host disease (GVHD), which resulted in decreased probability of survival. High-level CMV reactivation was a risk factor for increased NRM and worse overall survival in multivariate analysis. Although CMV reactivation may reduce the risk of relapse after HSCT for pediatric acute leukemia, effective management of severe acute GVHD and better prophylaxis and treatment of opportunistic infections are required to reduce the incidence of NRM and improve survival. Further studies on pediatric HSCT that include a larger number of patients and more homogenous patient cohorts are desirable. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Onset of ocular graft-versus-host disease symptoms after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Shikari, Hasanain; Amparo, Francisco; Saboo, Ujwala; Dana, Reza

    2015-03-01

    To study the factors affecting the time to onset of ocular graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). A retrospective chart review of 200 patients with ocular GVHD was performed to evaluate the association between various donor-recipient characteristics and the time to onset of ocular GVHD after allo-HSCT. The median time to onset of chronic ocular GVHD after allo-HSCT was 293 days (range, 26-2308 days). Patients receiving fully human leukocyte antigen (HLA)-matched transplants had a delayed onset of ocular GVHD (median, 294 days) compared with mismatched transplants (219 days; P = 0.029). HLA-matched transplants from related donors had delayed onset of ocular GVHD (307 days) compared with HLA-matched (286 days; P = 0.168) and HLA-mismatched (231 days; P = 0.015) transplants from unrelated donors. Ocular GVHD followed systemic GVHD in 76% of patients but preceded systemic disease in 7%, occurred concurrently in 15%, and was not associated with systemic GVHD in 2% of patients. The time elapsed between the occurrence of systemic and ocular GVHD was significantly longer in matched-related transplants (250 days) than in matched-unrelated transplants (120 days; P = 0.004). The onset of ocular GVHD after allo-HSCT is variable and is influenced by donor-recipient matching characteristics. In the majority of patients with GVHD, ocular involvement follows the occurrence of systemic manifestations; however, importantly, it can also precede or develop independently of systemic disease in a minority of patients. Regular ophthalmic follow-up is recommended after allo-HSCT regardless of concurrent systemic GVHD status.

  19. Hypothyroidism following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.

    Science.gov (United States)

    Medinger, Michael; Zeiter, Deborah; Heim, Dominik; Halter, Jörg; Gerull, Sabine; Tichelli, André; Passweg, Jakob; Nigro, Nicole

    2017-07-01

    Hypothyroidism may complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT); we therefore analyzed risk factors in this study. We studied 229 patients with acute myeloid leukemia (AML) who underwent an allo-HSCT between 2003 and 2013 with different conditioning regimens (myeloablative, reduced-intensity, chemotherapy-based, or total body irradiation-based). Thyroid-stimulating hormone (TSH) and free thyroxine levels (fT4) were available in 104 patients before and after allo-HSCT. The median age at transplantation (n=104) was 47 (IQR 40-59)], 37 (35.6%) patients were female, and the overall mortality was 34.6% (n=36). After a median follow-up period of 47 (IQR 25-84) months, overt hypothyroidism (basal TSH>4.49mIU/l, FT4hypothyroidism (basal TSH>4.49mIU/l, normal fT4) was observed in 20 patients (19.2%). Positive thyroperoxidase (TPO) antibodies were found in 5 (4.8%) patients. A total of 13 patients (12.5%) were treated with thyroid hormone replacement. Acute graft-versus-host disease (aGvHD) ≥grade 2 occurred in 55 (52.9%) and chronic GvHD (cGvHD) in 74 (71.2%) of the patients. The risk of developing hypothyroidism was higher in the patients with repeated allo-HSCTs (P=0.024) and with positive TPO antibodies (P=0.045). Furthermore, the development of overt hypothyroidism was inversely proportional to age (P=0.043). No correlation was found with GvHD, HLA-mismatch, total body irradiation, and gender. After allo-HSCT, a significant number of patients experience thyroid dysfunction, including subclinical and overt hypothyroidism. Long-term and continuous follow-up for thyroid function after HSCT is important to provide timely and appropriate treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation.

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    Werner Wunderli

    Full Text Available Infants with severe primary combined immunodeficiency (SCID and children post-allogeneic hematopoietic stem cell transplantation (HSCT are extremely susceptible to unusual infections. The lack of generic tools to detect disease-causing viruses among more than 200 potential human viral pathogens represents a major challenge to clinicians and virologists. We investigated retrospectively the causes of a fatal disseminated viral infection with meningoencephalitis in an infant with gamma C-SCID and of chronic gastroenteritis in 2 other infants admitted for HSCT during the same time period. Analysis was undertaken by combining cell culture, electron microscopy and sequence-independent single primer amplification (SISPA techniques. Caco-2 cells inoculated with fecal samples developed a cytopathic effect and non-enveloped viral particles in infected cells were detected by electron microscopy. SISPA led to the identification of astrovirus as the pathogen. Both sequencing of the capsid gene and the pattern of infection suggested nosocomial transmission from a chronically excreting index case to 2 other patients leading to fatal infection in 1 and to transient disease in the others. Virus-specific, real-time reverse transcription polymerase chain reaction was then performed on different stored samples to assess the extent of infection. Infection was associated with viremia in 2 cases and contributed to death in 1. At autopsy, viral RNA was detected in the brain and different other organs, while immunochemistry confirmed infection of gastrointestinal tissues. This report illustrates the usefulness of the combined use of classical virology procedures and modern molecular tools for the diagnosis of unexpected infections. It illustrates that astrovirus has the potential to cause severe disseminated lethal infection in highly immunocompromised pediatric patients.

  1. Prolonged outbreak of adenovirus A31 in allogeneic stem cell transplant recipients.

    Science.gov (United States)

    Swartling, L; Allard, A; Törlen, J; Ljungman, P; Mattsson, J; Sparrelid, E

    2015-12-01

    An outbreak of human adenovirus (HAdV) A31 occurred from December 2011 to March 2012 at the Center for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital in Sweden. We analyzed the outbreak, the routes of transmission, and report the medical consequences. The medical records of all patients admitted to CAST during the outbreak period were studied. Phylogenetic analysis of the patient HAdV strains was performed by sequencing the hexon gene and the more variable E3 gene. We identified 9 cases of HAdV A31. Hygiene measures were implemented, but transmission continued for 2 months. All 9 patients had been admitted to the ward, but 2 had no connection in time to other known HAdV A31 cases. DNA sequencing of the patient strains strongly suggested nosocomial transmission. Transplantation was postponed and then cancelled in 1 patient, and 5 patients were treated with cidofovir because of high levels of viremia. In 7 patients, concomitant graft-versus-host disease (GVHD) grade II-V complicated the clinical picture, as it was difficult to distinguish symptoms of GVHD from those of HAdV infection. An outbreak of HAdV in HSCT recipients can be difficult to control. Although none of the patients had severe disease, the medical consequences were significant. It is possible that unidentified cases with mild symptoms may have caused continuous transmission at the unit. Regular testing of all patients several weeks beyond the last case identified may be an important measure to control transmission. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation.

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    Zhilong Li

    Full Text Available BACKGROUND: Mesenchymal stem cells (MSCs hold great promise for the treatment of difficult diseases. As MSCs represent a rare cell population, ex vivo expansion of MSCs is indispensable to obtain sufficient amounts of cells for therapies and tissue engineering. However, spontaneous differentiation and aging of MSCs occur during expansion and the molecular mechanisms involved have been poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Human MSCs in early and late passages were examined for their expression of genes involved in osteogenesis to determine their spontaneous differentiation towards osteoblasts in vitro, and of genes involved in self-renewal and proliferation for multipotent differentiation potential. In parallel, promoter DNA methylation and hostone H3 acetylation levels were determined. We found that MSCs underwent aging and spontaneous osteogenic differentiation upon regular culture expansion, with progressive downregulation of TERT and upregulation of osteogenic genes such as Runx2 and ALP. Meanwhile, the expression of genes associated with stem cell self-renewal such as Oct4 and Sox2 declined markedly. Notably, the altered expression of these genes were closely associated with epigenetic dysregulation of histone H3 acetylation in K9 and K14, but not with methylation of CpG islands in the promoter regions of most of these genes. bFGF promoted MSC proliferation and suppressed its spontaneous osteogenic differentiation, with corresponding changes in histone H3 acetylation in TERT, Oct4, Sox2, Runx2 and ALP genes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that histone H3 acetylation, which can be modulated by extrinsic signals, plays a key role in regulating MSC aging and differentiation.

  3. Osteogenic Potency of Nacre on Human Mesenchymal Stem Cells

    Science.gov (United States)

    Green, David W.; Kwon, Hyuk-Jae; Jung, Han-Sung

    2015-01-01

    Nacre seashell is a natural osteoinductive biomaterial with strong effects on osteoprogenitors, osteoblasts, and osteoclasts during bone tissue formation and morphogenesis. Although nacre has shown, in one study, to induce bridging of new bone across large non-union bone defects in 8 individual human patients, there have been no succeeding human surgical studies to confirm this outstanding potency. But the molecular mechanisms associated with nacre osteoinduction and the influence on bone marrow-derived mesenchymal stem cells (BMSC’s), skeletal stem cells or bone marrow stromal cells remain elusive. In this study we highlight the phenotypic and biochemical effects of Pinctada maxima nacre chips and the global nacre soluble protein matrix (SPM) on primary human bone marrow-derived stromal cells (hBMSCs) in vitro. In static co-culture with nacre chips, the hBMSCs secreted Alkaline phosphatase (ALP) at levels that exceeded bone morphogenetic protein (rhBMP-2) treatment. Concentrated preparation of SPM applied to Stro-1 selected hBMSC’s led to rapid ALP secretions, at concentrations exceeding the untreated controls even in osteogenic conditions. Within 21 days the same population of Stro-1 selected hBMSCs proliferated and secreted collagens I–IV, indicating the premature onset of an osteoblast phenotype. The same SPM was found to promote unselected hBMSC differentiation with osteocalcin detected at 7 days, and proliferation increased at 7 days in a dose-dependent manner. In conclusion, nacre particles and nacre SPM induced the early stages of human bone cell differentiation, indicating that they may be promising soluble factors with osteoinductive capacity in primary human bone cell progenitors such as, hBMSC’s. PMID:25666352

  4. Derivation of Stromal (Skeletal, Mesenchymal) Stem-like cells from Human Embryonic Stem Cells

    DEFF Research Database (Denmark)

    Mahmood, Amer; Harkness, Linda; Abdallah, Basem

    2012-01-01

    Derivation of bone forming cells (osteoblasts) from human embryonic stem cells (hESC) is a pre-requisite for their use in clinical applications. However, there is no standard protocol for differentiating hESC into osteoblastic cells. The aim of this study was to identify the emergence of a human...... stromal (mesenchymal, skeletal) stem cell (hMSC)-like population, known to be osteoblastic cell precursors and to test their osteoblastic differentiation capacity in ex vivo cultures and in vivo. We cultured hESC in a feeder-free environment using serum replacement and as suspension aggregates (embryoid...... bodies; hEBs). Over a 20 day developmental period, the hEBs demonstrated increasing enrichment for cells expressing hMSC markers: CD29, CD44, CD63, CD56, CD71, CD73, CD105, CD106 and CD166 as revealed by immunohistochemical staining and flow cytometry (FACS) analysis. Ex vivo differentiation of h...

  5. Umbilical Cord-Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation

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    Yu-Hua Chao

    2012-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is becoming an effective therapeutic modality for a variety of diseases. Mesenchymal stem cells (MSCs can be used to enhance hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, prevent and treat graft-versus-host disease, and repair tissue damage in patients receiving HSCT. Till now, most MSCs for human clinical application have been derived from bone marrow. However, acquiring bone-marrow-derived MSCs involves an invasive procedure. Umbilical cord is rich with MSCs. Compared to bone-marrow-derived MSCs, umbilical cord-derived MSCs (UCMSCs are easier to obtain without harm to the donor and can proliferate faster. No severe adverse effects were noted in our previous clinical application of UCMSCs in HSCT. Accordingly, application of UCMSCs in humans appears to be feasible and safe. Further studies are warranted.

  6. Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients

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    V. Wiegering

    2017-03-01

    Conclusion: Children undergoing a HSCT show a different pattern of immune reconstitution in the allogeneic and autologous setting. This might influence the outcome and should affect the clinical handling of infectious prophylaxis and re-vaccinations.

  7. Visual bone marrow mesenchymal stem cell transplantation in the repair of spinal cord injury.

    Science.gov (United States)

    Zhang, Rui-Ping; Xu, Cheng; Liu, Yin; Li, Jian-Ding; Xie, Jun

    2015-03-01

    An important factor in improving functional recovery from spinal cord injury using stem cells is maximizing the number of transplanted cells at the lesion site. Here, we established a contusion model of spinal cord injury by dropping a weight onto the spinal cord at T7-8. Superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells were transplanted into the injured spinal cord via the subarachnoid space. An outer magnetic field was used to successfully guide the labeled cells to the lesion site. Prussian blue staining showed that more bone marrow mesenchymal stem cells reached the lesion site in these rats than in those without magnetic guidance or superparamagnetic iron oxide labeling, and immunofluorescence revealed a greater number of complete axons at the lesion site. Moreover, the Basso, Beattie and Bresnahan (BBB) locomotor rating scale scores were the highest in rats with superparamagnetic labeling and magnetic guidance. Our data confirm that superparamagnetic iron oxide nanoparticles effectively label bone marrow mesenchymal stem cells and impart sufficient magnetism to respond to the external magnetic field guides. More importantly, superparamagnetic iron oxide-labeled bone marrow mesenchymal stem cells can be dynamically and non-invasively tracked in vivo using magnetic resonance imaging. Superparamagnetic iron oxide labeling of bone marrow mesenchymal stem cells coupled with magnetic guidance offers a promising avenue for the clinical treatment of spinal cord injury.

  8. Titanium phosphate glass microcarriers induce enhanced osteogenic cell proliferation and human mesenchymal stem cell protein expression

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    Nilay J Lakhkar

    2015-11-01

    Full Text Available In this study, we have developed 50- to 100-µm-sized titanium phosphate glass microcarriers (denoted as Ti5 that show enhanced proliferation of human mesenchymal stem cells and MG63 osteosarcoma cells, as well as enhanced human mesenchymal stem cell expression of bone differentiation markers, in comparison with commercially available glass microspheres at all time points. We also demonstrate that these microcarriers provide superior human mesenchymal stem cell proliferation with conventional Dulbecco’s Modified Eagle medium than with a specially developed commercial stem cell medium. The microcarrier proliferative capacity is revealed by a 24-fold increase in MG63 cell numbers in spinner flask bioreactor studies performed over a 7-day period, versus only a 6-fold increase in control microspheres under the same conditions; the corresponding values of Ti5 and control microspheres under static culture are 8-fold and 7-fold, respectively. The capability of guided osteogenic differentiation is confirmed by ELISAs for bone morphogenetic protein-2 and osteopontin, which reveal significantly greater expression of these markers, especially osteopontin, by human mesenchymal stem cells on the Ti5 microspheres than on the control. Scanning electron microscopy and confocal laser scanning microscopy images reveal favorable MG63 and human mesenchymal stem cell adhesion on the Ti5 microsphere surfaces. Thus, the results demonstrate the suitability of the developed microspheres for use as microcarriers in bone tissue engineering applications.

  9. 12 hours after cerebral ischemia is the optimal time for bone marrow mesenchymal stem cell transplantation

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    Seyed Mojtaba Hosseini

    2015-01-01

    Full Text Available Cell therapy using stem cell transplantation against cerebral ischemia has been reported. However, it remains controversial regarding the optimal time for cell transplantation and the transplantation route. Rat models of cerebral ischemia were established by occlusion of the middle cerebral artery. At 1, 12 hours, 1, 3, 5 and 7 days after cerebral ischemia, bone marrow mesenchymal stem cells were injected via the tail vein. At 28 days after cerebral ischemia, rat neurological function was evaluated using a 6-point grading scale and the pathological change of ischemic cerebral tissue was observed by hematoxylin-eosin staining. Under the fluorescence microscope, the migration of bone marrow mesenchymal stem cells was examined by PKH labeling. Caspase-3 activity was measured using spectrophotometry. The optimal neurological function recovery, lowest degree of ischemic cerebral damage, greatest number of bone marrow mesenchymal stem cells migrating to peri-ischemic area, and lowest caspase-3 activity in the ischemic cerebral tissue were observed in rats that underwent bone marrow mesenchymal stem cell transplantation at 12 hours after cerebral ischemia. These findings suggest that 12 hours after cerebral ischemia is the optimal time for tail vein injection of bone marrow mesenchymal stem cell transplantation against cerebral ischemia, and the strongest neuroprotective effect of this cell therapy appears at this time.

  10. Factors affecting directional migration of bone marrow mesenchymal stem cells to the injured spinal cord.

    Science.gov (United States)

    Xia, Peng; Pan, Su; Cheng, Jieping; Yang, Maoguang; Qi, Zhiping; Hou, Tingting; Yang, Xiaoyu

    2014-09-15

    Microtubule-associated protein 1B plays an important role in axon guidance and neuronal migration. In the present study, we sought to discover the mechanisms underlying microtubule-associated protein 1B mediation of axon guidance and neuronal migration. We exposed bone marrow mesenchymal stem cells to okadaic acid or N-acetyl-D-erythro-sphingosine (an inhibitor and stimulator, respectively, of protein phosphatase 2A) for 24 hours. The expression of the phosphorylated form of type I microtubule-associated protein 1B in the cells was greater after exposure to okadaic acid and lower after N-acetyl-D-erythro-sphingosine. We then injected the bone marrow mesenchymal stem cells through the ear vein into rabbit models of spinal cord contusion. The migration of bone marrow mesenchymal stem cells towards the injured spinal cord was poorer in cells exposed to okadaic acid- and N-acetyl-D-erythro-sphingosine than in non-treated bone marrow mesenchymal stem cells. Finally, we blocked phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways in rabbit bone marrow mesenchymal stem cells using the inhibitors LY294002 and U0126, respectively. LY294002 resulted in an elevated expression of phosphorylated type I microtubule-associated protein 1B, whereas U0126 caused a reduction in expression. The present data indicate that PI3K and ERK1/2 in bone marrow mesenchymal stem cells modulate the phosphorylation of microtubule-associated protein 1B via a cross-signaling network, and affect the migratory efficiency of bone marrow mesenchymal stem cells towards injured spinal cord.

  11. Impact of mesenchymal stem cell secreted PAI-1 on colon cancer cell migration and proliferation.

    Science.gov (United States)

    Hogan, Niamh M; Joyce, Myles R; Murphy, J Mary; Barry, Frank P; O'Brien, Timothy; Kerin, Michael J; Dwyer, Roisin M

    2013-06-14

    Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cell (MSC) and colon cancer cell (CCC) interactions. Mesenchymal Stem Cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3-dimensional scaffolds. Conditioned media containing all secreted factors was harvested at day 1, 3 and 7. Chemokine secretion and expression were analyzed by Chemi-array, ELISA (Macrophage migration inhibitory factor (MIF), plasminogen activator inhibitor type 1 (PAI-1)) and RQ-PCR. Colon cancer cell migration and proliferation in response to recombinant PAI-1, MSCs and MSCs+antibody to PAI-1 was analyzed using Transwell inserts and an MTS proliferation assay respectively. Chemi-array revealed secretion of a wide range of factors by each cell population, including PAI-1 and MIF. ELISA analysis revealed Mesenchymal Stem Cells to secrete the highest levels of PAI-1 (MSC mean 10.6 ng/mL, CCC mean 1.01 ng/mL), while colon cancer cells were the principal source of MIF. MSC-secreted PAI-1 stimulated significant migration of both CCC lines, with an antibody to the chemokine shown to block this effect (67-88% blocking,). A cell-line dependant effect on CCC proliferation was shown for Mesenchymal Stem Cell-secreted PAI-1 with HCT-116 cells showing decreased proliferation at all concentrations, and HT29 cells showing increased proliferation in the presence of higher PAI-1 levels. This is the first study to identify PAI-1 as an important mediator of Mesenchymal Stem Cell/colon cancer cell interactions and highlights the significant functional impact of Mesenchymal Stem Cell-secreted PAI-1 on colon cancer cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Factors affecting directional migration of bone marrow mesenchymal stem cells to the injured spinal cord

    Science.gov (United States)

    Xia, Peng; Pan, Su; Cheng, Jieping; Yang, Maoguang; Qi, Zhiping; Hou, Tingting; Yang, Xiaoyu

    2014-01-01

    Microtubule-associated protein 1B plays an important role in axon guidance and neuronal migration. In the present study, we sought to discover the mechanisms underlying microtubule-associated protein 1B mediation of axon guidance and neuronal migration. We exposed bone marrow mesenchymal stem cells to okadaic acid or N-acetyl-D-erythro-sphingosine (an inhibitor and stimulator, respectively, of protein phosphatase 2A) for 24 hours. The expression of the phosphorylated form of type I microtubule-associated protein 1B in the cells was greater after exposure to okadaic acid and lower after N-acetyl-D-erythro-sphingosine. We then injected the bone marrow mesenchymal stem cells through the ear vein into rabbit models of spinal cord contusion. The migration of bone marrow mesenchymal stem cells towards the injured spinal cord was poorer in cells exposed to okadaic acid- and N-acetyl-D-erythro-sphingosine than in non-treated bone marrow mesenchymal stem cells. Finally, we blocked phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways in rabbit bone marrow mesenchymal stem cells using the inhibitors LY294002 and U0126, respectively. LY294002 resulted in an elevated expression of phosphorylated type I microtubule-associated protein 1B, whereas U0126 caused a reduction in expression. The present data indicate that PI3K and ERK1/2 in bone marrow mesenchymal stem cells modulate the phosphorylation of microtubule-associated protein 1B via a cross-signaling network, and affect the migratory efficiency of bone marrow mesenchymal stem cells towards injured spinal cord. PMID:25374590

  13. Changes in expression pattern of selected endometrial proteins following mesenchymal stem cells infusion in mares with endometrosis.

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    Lisley I Mambelli

    Full Text Available Mesenchymal stem cells (MSCs due to their self-renewal potential and differentiation capacity are useful for tissue regeneration. Immunomodulatory and trophic properties of MSCs were demonstrated suggesting their use as medicinal signaling cells able to positively change local environment in injured tissue. Equine endometrosis is a progressive degenerative disease responsible for glandular alterations and endometrial fibrosis which causes infertility in mares. More precisely, this disease is characterized by phenotypic changes in the expression pattern of selected endometrial proteins. Currently, no effective treatment is available for endometrosis. Herein, we aimed at the evaluation of expression pattern of these proteins after allogeneic equine adipose tissue-derived multipotent mesenchymal stem cells (eAT-MSCs infusion as well as at testing the capacity of these cells to promote endometrial tissue remodeling in mares with endometrosis. eAT-MSC (2 × 10(7/animal were transplanted into mares' uterus and control animals received only placebo. Uterine biopsies were collected before (day 0 and after (days 7, 21 and 60 cells transplantation. Conventional histopathology as well as expression analysis of such proteins as laminin, vimentin, Ki-67-antigen, α-smooth muscle actin (α-SMA and cytokeratin 18 (CK18 have been performed before and after eAT-MSCs transplantation. We demonstrated that eAT-MSCs induced early (at day 7 remodeling of endometrial tissue microenvironment through changes observed in intra cellular and intra glandular localization of aforementioned proteins. We demonstrated that eAT-MSCs were able to positively modulate the expression pattern of studied secretory proteins as well as, to promote the induction of glandular epithelial cells proliferation suggesting local benefits to committed endometrial tissue environment after eAT-MSCs transplantation.

  14. Cellular Therapeutics for Heart Failure: Focus on Mesenchymal Stem Cells

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    Amitabh C. Pandey

    2017-01-01

    Full Text Available Resulting from a various etiologies, the most notable remains ischemia; heart failure (HF manifests as the common end pathway of many cardiovascular processes and remains among the top causes for hospitalization and a major cause of morbidity and mortality worldwide. Current pharmacologic treatment for HF utilizes pharmacologic agents to control symptoms and slow further deterioration; however, on a cellular level, in a patient with progressive disease, fibrosis and cardiac remodeling can continue leading to end-stage heart failure. Cellular therapeutics have risen as the new hope for an improvement in the treatment of HF. Mesenchymal stem cells (MSCs have gained popularity given their propensity of promoting endogenous cellular repair of a myriad of disease processes via paracrine signaling through expression of various cytokines, chemokines, and adhesion molecules resulting in activation of signal transduction pathways. While the exact mechanism remains to be completely elucidated, this remains the primary mechanism identified to date. Recently, MSCs have been incorporated as the central focus in clinical trials investigating the role how MSCs can play in the treatment of HF. In this review, we focus on the characteristics of MSCs that give them a distinct edge as cellular therapeutics and present results of clinical trials investigating MSCs in the setting of ischemic HF.

  15. Concave microwell plate facilitates chondrogenesis from mesenchymal stem cells.

    Science.gov (United States)

    Ko, Ji-Yun; Im, Gun-Il

    2016-11-01

    To compare in vitro chondrogenesis from bone marrow-derived mesenchymal stem cells using concave microwell plates with those obtained using culture tubes. Pellets cultured in concave microwell plates had a significantly higher level of GAG per DNA content and greater proteoglycan content than those cultured in tubes at day 7 and 14. Three chondrogenic markers, SOX-9, COL2A1 and aggrecan, showed significantly higher expression in pellets cultured in concave microwell plates than those cultured in tubes at day 7 and 14. At day 21, there was not a significant difference in the expression of these markers. COL10A1, the typical hypertrophy marker, was significantly lower in concave microwell plates during the whole culture period. Runx-2, a marker of hypertrophy and osteogenesis, was significantly lower at day 7 in pellets cultured in concave microwell plates than those cultured in tubes. Concave microwell plates provide a convenient and effective tool for the study of in vitro chondrogenesis and may replace the use of propylene culture tube.

  16. Mesenchymal Stem Cells Mitigate Cirrhosis through BMP7

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    Bing Li

    2015-01-01

    Full Text Available Background/Aims: Transplantation of mesenchymal stem cells (MSCs has therapeutic effects on various diseases, while its effect on developing cirrhosis as well as the underlying mechanism remained largely unknown. Methods: Twenty C57BL/6 mice were randomly separated into 2 groups of ten each. One group received transplantation of MSCs, while the other group received saline as control. The mice then received intraperitoneal injection of carbon tetrachloride (CCl4 twice per week for 8 weeks to develop cirrhosis. After another 4 weeks, the levels of cirrhosis in these mice were evaluated by liver fibrosis area, portal pressure, sodium balance and excretion. Transcripts of transforming growth factor β 1 (TGFβ1 and bone morphogenic protein 7 (BMP7 in the mouse livers were quantified by RT-qPCR. BMP7-depleted MSCs were prepared and applied in this model, and compared to MSCs. Results: Liver fibrosis, portal hypertension and sodium retention that were developed by CCl4, were all significantly alleviated by MSCs transplantation, which decreased TGFβ1 levels and increased BMP7 levels in the injured liver. MSCs were found to express extremely high levels of BMP7. Knockdown of BMP7 in MSCs completely abolished the protective effect of MSCs against CCl4-induced cirrhosis. Conclusions: MSCs mitigate cirrhosis through their production of BMP7 against the fibrogenic effect of TGFβ1 in the injured liver.

  17. Mesenchymal Stem Cells for Treating Articular Cartilage Defects and Osteoarthritis.

    Science.gov (United States)

    Wang, Yu; Yuan, Mei; Guo, Quan-yi; Lu, Shi-bi; Peng, Jiang

    2015-01-01

    Articular cartilage damage and osteoarthritis are the most common joint diseases. Joints are prone to damage caused by sports injuries or aging, and such damage regularly progresses to more serious joint disorders, including osteoarthritis, which is a degenerative disease characterized by the thinning and eventual wearing out of articular cartilage, ultimately leading to joint destruction. Osteoarthritis affects millions of people worldwide. Current approaches to repair of articular cartilage damage include mosaicplasty, microfracture, and injection of autologous chondrocytes. These treatments relieve pain and improve joint function, but the long-term results are unsatisfactory. The long-term success of cartilage repair depends on development of regenerative methodologies that restore articular cartilage to a near-native state. Two promising approaches are (i) implantation of engineered constructs of mesenchymal stem cell (MSC)-seeded scaffolds, and (ii) delivery of an appropriate population of MSCs by direct intra-articular injection. MSCs may be used as trophic producers of bioactive factors initiating regenerative activities in a defective joint. Current challenges in MSC therapy are the need to overcome current limitations in cartilage cell purity and to in vitro engineer tissue structures exhibiting the required biomechanical properties. This review outlines the current status of MSCs used in cartilage tissue engineering and in cell therapy seeking to repair articular cartilage defects and related problems. MSC-based technologies show promise when used to repair cartilage defects in joints.

  18. Therapeutic application of mesenchymal stem cells in osteoarthritis.

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    Ruiz, Maxime; Cosenza, Stella; Maumus, Marie; Jorgensen, Christian; Noël, Danièle

    2016-01-01

    Osteoarthritis (OA) is a degenerative disease characterized by cartilage degradation and subchondral bone alterations. This disease represents a global public health problem whose prevalence is rapidly growing with the increasing aging of the population. With the discovery of mesenchymal stem cells (MSC) as possible therapeutic agents, their potential for repairing cartilage damage in OA is under investigation. Characterization of MSCs and their functional properties are mentioned with an insight into their trophic function and secretory profile. We present a special focus on the types of extracellular vesicles (EVs) that are produced by MSCs and their role in the paracrine activity of MSCs. We then discuss the therapeutic approaches that have been evaluated in pre-clinical models of OA and the results coming out from the clinical trials in patients with OA. MSC-based therapy seems a promising approach for the treatment of patients with OA. Further research is still needed to demonstrate their efficacy in clinical trials using controlled, prospective studies. However, the emergence of MSC-derived EVs as possible therapeutic agents could be an alternative to cell-based therapy.

  19. The Role of Mesenchymal Stem Cell in Cancer Development

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    Hiroshi eYagi

    2013-11-01

    Full Text Available The role of mesenchymal stem cells (MSCs in cancer development is still controversial. MSCs may promote tumor progression through immune modulation, but other tumor suppressive effects of MSCs have also been described. The discrepancy between these results may arise from issues related to different tissue sources, individual donor variability, and injection timing of MSCs. The expression of critical receptors such as Toll-like receptor (TLR is variable at each time point of treatment, which may also determine the effects of MSCs on tumor progression. However, factors released from malignant cells, as well as surrounding tissues and the vasculature, are still regarded as a black box. Thus, it is still difficult to clarify the specific role of MSCs in cancer development. Whether MSCs support or suppress tumor progression is currently unclear, but it is clear that systemically administered MSCs can be recruited and migrate toward tumors. These findings are important because they can be used as a basis for initiating studies to explore the incorporation of engineered MSCs as novel anti-tumor carriers, for the development of tumor-targeted therapies.

  20. Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate

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    Cristina Sobacchi

    2017-05-01

    Full Text Available Mesenchymal stem cells (MSCs are multipotent stromal cells that are identified by in vitro plastic adherence, colony-forming capacity, expression of a panel of surface molecules, and ability to differentiate at least toward osteogenic, adipogenic, and chondrogenic lineages. They also produce trophic factors with immunomodulatory, proangiogenic, and antiapoptotic functions influencing the behavior of neighboring cells. On the other hand, a reciprocal regulation takes place; in fact, MSCs can be isolated from several tissues, and depending on the original microenvironment and the range of stimuli received from there, they can display differences in their essential characteristics. Here, we focus mainly on the bone tissue and how soluble factors, such as growth factors, cytokines, and hormones, present in this microenvironment can orchestrate bone marrow-derived MSCs fate. We also briefly describe the alteration of MSCs behavior in pathological settings such as hematological cancer, bone metastasis, and bone marrow failure syndromes. Overall, the possibility to modulate MSCs plasticity makes them an attractive tool for diverse applications of tissue regeneration in cell therapy. Therefore, the comprehensive understanding of the microenvironment characteristics and components better suited to obtain a specific MSCs response can be extremely useful for clinical use.

  1. Oxidative stress induces senescence in human mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Brandl, Anita [Department of Anesthesiology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Meyer, Matthias; Bechmann, Volker [Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Nerlich, Michael [Department of Anesthesiology, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany); Angele, Peter, E-mail: Peter.Angele@klinik.uni-regensburg.de [Department of Trauma Surgery, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93042 Regensburg (Germany)

    2011-07-01

    Mesenchymal stem cells (MSCs) contribute to tissue repair in vivo and form an attractive cell source for tissue engineering. Their regenerative potential is impaired by cellular senescence. The effects of oxidative stress on MSCs are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of MSCs, subject to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by rtPCR. Sub-lethal doses of oxidative stress reduced proliferation rates and induced senescent-morphological features and senescence-associated {beta}-galactosidase positivity. Prolonged low dose treatment with hydrogen peroxide had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. Following acute oxidant insult p21 was up-regulated prior to returning to initial levels. TRF1 was significantly reduced, TRF2 showed a slight up-regulation. SIRT1 and XRCC5 were up-regulated after oxidant insult and expression levels increased in aging cells. Compared to fibroblasts and chondrocytes, MSCs showed an increased tolerance to oxidative stress regarding proliferation, telomere biology and gene expression with an impaired stress tolerance in aged cells.

  2. Mesenchymal stem cells for the treatment of neurodegenerative disease.

    Science.gov (United States)

    Joyce, Nanette; Annett, Geralyn; Wirthlin, Louisa; Olson, Scott; Bauer, Gerhard; Nolta, Jan A

    2010-11-01

    Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.

  3. Mesenchymal stem cells: potential in treatment of neurodegenerative diseases.

    Science.gov (United States)

    Tanna, Tanmay; Sachan, Vatsal

    2014-01-01

    Mesenchymal Stem Cells or Marrow Stromal Cells (MSCs) have long been viewed as a potent tool for regenerative cell therapy. MSCs are easily accessible from both healthy donor and patient tissue and expandable in vitro on a therapeutic scale without posing significant ethical or procedural problems. MSC based therapies have proven to be effective in preclinical studies for graft versus host disease, stroke, myocardial infarction, pulmonary fibrosis, autoimmune disorders and many other conditions and are currently undergoing clinical trials at a number of centers all over the world. MSCs are also being extensively researched as a therapeutic tool against neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD) and Multiple Sclerosis (MS). MSCs have been discussed with regard to two aspects in the context of neurodegenerative diseases: their ability to transdifferentiate into neural cells under specific conditions and their neuroprotective and immunomodulatory effects. When transplanted into the brain, MSCs produce neurotrophic and growth factors that protect and induce regeneration of damaged tissue. Additionally, MSCs have also been explored as gene delivery vehicles, for example being genetically engineered to over express glial-derived or brain-derived neurotrophic factor in the brain. Clinical trials involving MSCs are currently underway for MS, ALS, traumatic brain injuries, spinal cord injuries and stroke. In the present review, we explore the potential that MSCs hold with regard to the aforementioned neurodegenerative diseases and the current scenario with reference to the same.

  4. Immunomodulatory effect of Mesenchymal Stem Cells on B cells

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    Marcella eFranquesa

    2012-07-01

    Full Text Available The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches.Mesenchymal Stem Cells (MSC are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field.

  5. The Modulatory Effects of Mesenchymal Stem Cells on Osteoclastogenesis

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    Wessam E. Sharaf-Eldin

    2016-01-01

    Full Text Available The effect of mesenchymal stem cells (MSCs on bone formation has been extensively demonstrated through several in vitro and in vivo studies. However, few studies addressed the effect of MSCs on osteoclastogenesis and bone resorption. Under physiological conditions, MSCs support osteoclastogenesis through producing the main osteoclastogenic cytokines, RANKL and M-CSF. However, during inflammation, MSCs suppress osteoclast formation and activity, partly via secretion of the key anti-osteoclastogenic factor, osteoprotegerin (OPG. In vitro, co-culture of MSCs with osteoclasts in the presence of high concentrations of osteoclast-inducing factors might reflect the in vivo inflammatory pathology and prompt MSCs to exert an osteoclastogenic suppressive effect. MSCs thus seem to have a dual effect, by stimulating or inhibiting osteoclastogenesis, depending on the inflammatory milieu. This effect of MSCs on osteoclast formation seems to mirror the effect of MSCs on other immune cells, and may be exploited for the therapeutic potential of MSCs in bone loss associated inflammatory diseases.

  6. Novel supplier of mesenchymal stem cell: subacromial bursa.

    Science.gov (United States)

    Lhee, S-H; Jo, Y H; Kim, B Y; Nam, B M; Nemeno, J G; Lee, S; Yang, W; Lee, J I

    2013-10-01

    Mesenchymal stem cells (MSCs) are multipotent stromal elements that can differentiate into a variety of cell types. MSCs are good sources of therapeutic cells for degenerative diseases. For these reason, many researchers have focused on searching for other sources of MSCs. To obtain MSCs for clinical use requires surgery of the donor that therefore can induce donor morbidity, since the common sources at present are bone marrow and adipose tissues. In this study, we investigated the existence of MSCs in postoperative discarded tissues. Subacromial bursal tissues were obtained from the shoulders of 3 injured patients. The cells from the bursa tissues were isolated through treatment with collagenase. The isolated cells were then seeded and expanded by serial passaging under normal culture system. To evaluate MSC characteristics of the cells, their MSC markers were confirmed by mRNA and protein expression. Multipotent ability was assessed using differentiation media and immunohistochemistry. Cells from the bursa expressed MSCs markers-CD29, CD73, CD90, and PDGFRB (platelet-derived growth factor receptor-beta). Moreover, as to their multipotency, bursal cells differentiated into adipocytes (fat cells), osteocytes (bone cells), and chondrocytes (cartilage cells). In summary, we showed that MSCs could be generated from the subacromial bursa, which is medical waste after surgery. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  7. Cell Fate and Differentiation of Bone Marrow Mesenchymal Stem Cells

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    Shoichiro Kokabu

    2016-01-01

    Full Text Available Osteoblasts and bone marrow adipocytes originate from bone marrow mesenchymal stem cells (BMMSCs and there appears to be a reciprocal relationship between adipogenesis and osteoblastogenesis. Alterations in the balance between adipogenesis and osteoblastogenesis in BMMSCs wherein adipogenesis is increased relative to osteoblastogenesis are associated with decreased bone quality and quantity. Several proteins have been reported to regulate this reciprocal relationship but the exact nature of the signals regulating the balance between osteoblast and adipocyte formation within the bone marrow space remains to be determined. In this review, we focus on the role of Transducin-Like Enhancer of Split 3 (TLE3, which was recently reported to regulate the balance between osteoblast and adipocyte formation from BMMSCs. We also discuss evidence implicating canonical Wnt signalling, which plays important roles in both adipogenesis and osteoblastogenesis, in regulating TLE3 expression. Currently, there is demand for new effective therapies that target the stimulation of osteoblast differentiation to enhance bone formation. We speculate that reducing TLE3 expression or activity in BMMSCs could be a useful approach towards increasing osteoblast numbers and reducing adipogenesis in the bone marrow environment.

  8. Tissue distribution and engraftment of human mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene

    DEFF Research Database (Denmark)

    Bentzon, J.F.; Stenderup, K.; Hansen, F.D.

    2005-01-01

    Engraftment of mesenchymal stem cells (MSC) in peripheral tissues for replenishing of local stem cell function has been proposed as a therapeutic approach to degenerative diseases. We have previously reported the development of an immortalized human telomerase reverse transcriptase transduced MSC...

  9. Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies?

    DEFF Research Database (Denmark)

    Lepperdinger, Günter; Brunauer, Regina; Jamnig, Angelika

    2008-01-01

    The prospective clinical use of multipotent mesenchymal stromal stem cells (MSC) holds enormous promise for the treatment of a large number of degenerative and age-related diseases. However, the challenges and risks for cell-based therapies are multifaceted. The risks for patients receiving stem...

  10. Mesenchymal stem cells in human placental chorionic villi reside in a vascular Niche

    NARCIS (Netherlands)

    Castrechini, N. M.; Murthi, P.; Gude, N. M.; Erwich, J. J. H. M.; Gronthos, S.; Zannettino, A.; Brennecke, S. R.; Kalionis, B.; Brennecke, S.P.

    The chorionic villi of human term placentae are a rich source of mesenchymal stem cells (PMSCs) The stem cell "niche" within the chorionic villi regulates how PMSCs participate in placental tissue generation, maintenance and repair, but the anatomic location of the niche has not been defined A

  11. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review.

    Science.gov (United States)

    Freitag, Julien; Bates, Dan; Boyd, Richard; Shah, Kiran; Barnard, Adele; Huguenin, Leesa; Tenen, Abi

    2016-05-26

    Osteoarthritis is a leading cause of pain and disability across the world. With an aging population its prevalence is likely to further increase. Current accepted medical treatment strategies are aimed at symptom control rather than disease modification. Surgical options including joint replacement are not without possible significant complications. A growing interest in the area of regenerative medicine, led by an improved understanding of the role of mesenchymal stem cells in tissue homeostasis and repair, has seen recent focused efforts to explore the potential of stem cell therapies in the active management of symptomatic osteoarthritis. Encouragingly, results of pre-clinical and clinical trials have provided initial evidence of efficacy and indicated safety in the therapeutic use of mesenchymal stem cell therapies for the treatment of knee osteoarthritis. This paper explores the pathogenesis of osteoarthritis and how mesenchymal stem cells may play a role in future management strategies of this disabling condition.

  12. Mesenchymal stem cells as a therapeutic tool in tissue and organ regeneration

    Directory of Open Access Journals (Sweden)

    Anna Bajek

    2011-01-01

    Full Text Available Tissue engineering is an interdisciplinary field that offers new opportunities for regeneration of diseased and damaged tissue with the use of many different cell types,including adult stem cells. In tissue engineering and regenerative medicine the most popular are mesenchymal stem cells (MSCs isolated from bone marrow. Bone marrow mesenchymal stem cells are a potential source of progenitor cells for osteoblasts, chondroblasts, adipocytes, skeletal muscles and cardiomyocytes. It has also been shown that these cells can differentiate into ecto- and endodermal cells, e.g. neuronal cells, glial cells, keratinocytes and hepatocytes. The availability of autologous MSCs, their proliferative potential and multilineage differentiation capacity make them an excellent tool for tissue engineering and regenerative medicine. The aim of this publication is to present characteristic and biological properties of mesenchymal stem cells isolated from bone marrow.

  13. [Clinical Summarization of Allogeneic Hematopoietic Stem Cell Transplantation for Leukemia: A Report of 100 Cases].

    Science.gov (United States)

    Huang, Qing-Xin; Tu, San-Fang; Huang, Rui; Huang, Yu-Xian; Deng, Lan; Wu, Bing-Yi; Song, Chao-Yang; Li, Yu-Hua

    2016-04-01

    To analyze the treatment outcome of a consecutive series of 100 leukemia patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical data of leukemia patients received allo-HSCT were analyzed retrospectively, the therapeutic efficacy was summarized. 100 evaluable cases of leukemia included 47 cases of AML, 33 cases of ALL, 2 cases of AL (biphenotypic), 16 CML and 2 CMML. Before transplantation, 76 cases were in first complete remission, 9 cases in second or greater complete remission and 15 cases in non-remission or relapse. All the patients received peripheral blood hematopoietic stem cell transplantation (PBHSCT). The conditioning regimen of human leukocyte antigen (HLA)-matched allo-HSCT group was modified BuCy, but in HLA-mismatched group Fludarabine and anti-human thymocyte globulin (ATG) was added. CsA+MTX regimen was used for prophylaxis of graft-versus-host disease (GVHD) in HLA-identical allo-HSCT, while additional MMF was added in HLA-mismatched group. The average time of follow-up was 13 months. At the last follow-up, 66.0% (66/100) patients survived, 53.0% (53/100) patients survived without leukemia, 28.0% (28/100) patients relapsed and 34.0% (34/100) patients died, 44.1% patients of them died from infectious pulmonary complications. During transplantation, 65.0% of the patients were suffered from lung infection. The overall survival (OS) and disease-free survival (DFS) of all cases was 60.9% and 48.8%, respectively. The recurrence rate was significantly higher in non-remission (66.7%) than in CR (21.2%) patients (P < 0.05). The cumulative incidence of GVHD in HLA-mismatched transplantation was 60.8%, which was significantly higher than that of HLA-matched transplantation (38.8%) (P < 0.05). Allo-HSCT can cure a significant proportion of leukemia patients, especially for those in CR status. Since the incidence of infectious pulmonary complications after allo-HSCT is still high, much more attention should be paid to it

  14. Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation

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    Busemann Christoph

    2012-10-01

    Full Text Available Abstract Therapy of indolent lymphomas with involvement of the central nervous system (CNS has not been standardized so far. A 42-year old male patient presented with neurological signs because of leukemic splenic marginal zone lymphoma (SMZL manifested in bone marrow, lymph nodes and CNS. Due to the aggressiveness of the disease and the young age of the patient, an intensive immunochemotherapy followed by high-dose therapy with busulfan, thiotepa and fludarabine and subsequent unrelated allogeneic stem cell transplantation (alloSCT was performed. The haemopoietic stem cells engrafted in time and the patient is doing well (ECOG 0 without evidence for active lymphoma three years after transplantation. Highly sensitive tests by specific quantitative real-time polymerase chain reaction for presence of lymphoma cells in blood and bone marrow indicated also a molecular remission. The reported case shows the feasibility of high-dose therapy and allogeneic stem cell transplantation in high-risk patients with CNS-involvement of indolent non-Hodgkin’s lymphoma. In addition, the case supports the hypothesis that the graft-versus lymphoma effect after alloSCT is also active within the CNS.

  15. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

    Science.gov (United States)

    Goodyear, Oliver C; Dennis, Mike; Jilani, Nadira Y; Loke, Justin; Siddique, Shamyla; Ryan, Gordon; Nunnick, Jane; Khanum, Rahela; Raghavan, Manoj; Cook, Mark; Snowden, John A; Griffiths, Mike; Russell, Nigel; Yin, John; Crawley, Charles; Cook, Gordon; Vyas, Paresh; Moss, Paul; Malladi, Ram; Craddock, Charles F

    2012-04-05

    Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.

  16. Response to intravenous allogeneic equine cord-blood-derived mesenchymal stromal cells administered from chilled or frozen state in serum and protein free media

    Directory of Open Access Journals (Sweden)

    Lynn Brandon Williams

    2016-07-01

    Full Text Available Equine Mesenchymal stromal cells (MSC are commonly transported, chilled or frozen, to veterinary clinics. These MSC must remain viable and minimally affected by culture, transport, or injection processes. The safety of two carrier solutions developed for optimal viability and excipient use were evaluated in ponies, with and without allogeneic cord blood-derived (CB MSC. We hypothesized that neither the carrier solutions nor CB-MSC would elicit measurable changes in clinical, hematological, or biochemical parameters. In 9 ponies (study 1 a bolus of HypoThermosol® FRS (HTS-FRS, CryoStor® CS10 (CS10 or saline was injected IV (n=3/treatment. Study 2, following a one week washout period 5x107 pooled allogeneic CB-MSC were administered IV in HTS-FRS following 24h simulated chilled transport. Study 3, following another one week washout period 5x107 pooled allogeneic CB-MSC were administered IV in CS10 immediately after thawing. Nine ponies received CB-MSCs in study 2 and 3 and three ponies received the cell carrier media without cells. CB-MSCs were pooled in equal numbers from five unrelated donors. In all studies ponies were monitored with physical examination, and blood collection for 7 days following injection. CD4 and CD8 lymphocyte populations were also evaluated in each blood sample.In all three studies, physical exam, complete blood cell count, serum biochemistry, and coagulation panel did not deviate from established normal ranges. Proportions of CD4+ and CD8+ lymphocytes increased at 168h post injection in CB-MSC treatment groups regardless of the carrier solution. Decreases in CD4+/CD8+ double positive populations were observed at 24 h and 72 h in CB-MSC treated animals. There was no difference in viability between CB-MSC suspended in HTS-FRS or CS10.HTS-FRS and CS10 used for low volume excipient injection of MSC suspensions was not associated with short-term adverse reactions. HTS-FRS and CS10 both adequately maintain CB-MSC viability

  17. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia

    DEFF Research Database (Denmark)

    Baron, F; Labopin, M; Niederwieser, D

    2012-01-01

    This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of rela...... of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P...

  18. Associations between levels of insulin-like growth factor 1 and sinusoidal obstruction syndrome after allogeneic haematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Weischendorff, Sarah; Kielsen, Katrine; Sengeløv, H

    2017-01-01

    Allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) is challenged by severe adverse events, as cytotoxic effects of the conditioning may result in systemic inflammation, leaky epithelial barriers and organ toxicities, contributing to treatment-related morbidity and mortality...... SDS decrease in IGF-1 (95% CI: 1.45-16.67), P=0.011 and OR=5.00 (1.37-20.00), P=0.015, respectively). Furthermore, low pre-transplant levels of IGF-1 and IGFBP-3 were associated with increased fluid retention during the first 21 days post transplant (OR=7.69 (95% CI: 1.59-33.33), P=0.012, and OR=2...

  19. Bone marrow-derived mesenchymal stem cells versus adipose-derived mesenchymal stem cells for peripheral nerve regeneration

    Directory of Open Access Journals (Sweden)

    Marcela Fernandes

    2018-01-01

    Full Text Available Studies have confirmed that bone marrow-derived mesenchymal stem cells (MSCs can be used for treatment of several nervous system diseases. However, isolation of bone marrow-derived MSCs (BMSCs is an invasive and painful process and the yield is very low. Therefore, there is a need to search for other alterative stem cell sources. Adipose-derived MSCs (ADSCs have phenotypic and gene expression profiles similar to those of BMSCs. The production of ADSCs is greater than that of BMSCs, and ADSCs proliferate faster than BMSCs. To compare the effects of venous grafts containing BMSCs or ADSCs on sciatic nerve injury, in this study, rats were randomly divided into four groups: sham (only sciatic nerve exposed, Matrigel (MG; sciatic nerve injury + intravenous transplantation of MG vehicle, ADSCs (sciatic nerve injury + intravenous MG containing ADSCs, and BMSCs (sciatic nerve injury + intravenous MG containing BMSCs groups. Sciatic functional index was calculated to evaluate the function of injured sciatic nerve. Morphologic characteristics of nerves distal to the lesion were observed by toluidine blue staining. Spinal motor neurons labeled with Fluoro-Gold were quantitatively assessed. Compared with sham-operated rats, sciatic functional index was lower, the density of small-diameter fibers was significantly increased, and the number of motor neurons significantly decreased in rats with sciatic nerve injury. Neither ADSCs nor BMSCs significantly improved the sciatic nerve function of rats with sciatic nerve injury, increased fiber density, fiber diameters, axonal diameters, myelin sheath thickness, and G ratios (axonal diameter/fiber diameter ratios in the sciatic nerve distal to the lesion site. There was no significant difference in the number of spinal motor neurons among ADSCs, BMSCs and MG groups. These results suggest that neither BMSCs nor ADSCs provide satisfactory results for peripheral nerve repair when using MG as the conductor for

  20. Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways.

    Directory of Open Access Journals (Sweden)

    Roy Blum

    2010-09-01

    Full Text Available Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system.We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2, lipid metabolism (e.g., Srebp1 and cell migration (e.g., Areb6 and Rreb1. Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche.We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may be common to mammalian niches in general. This study provides a

  1. Mesenchymal stem cell like (MSCl) cells generated from human embryonic stem cells support pluripotent cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Varga, Nora [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary); Vereb, Zoltan; Rajnavoelgyi, Eva [Department of Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen (Hungary); Nemet, Katalin; Uher, Ferenc; Sarkadi, Balazs [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary); Apati, Agota, E-mail: apati@kkk.org.hu [Membrane Research Group of the Hungarian Academy of Sciences, Semmelweis University, Budapest (Hungary)

    2011-10-28

    Highlights: Black-Right-Pointing-Pointer MSC like cells were derived from hESC by a simple and reproducible method. Black-Right-Pointing-Pointer Differentiation and immunosuppressive features of MSCl cells were similar to bmMSC. Black-Right-Pointing-Pointer MSCl cells as feeder cells support the undifferentiated growth of hESC. -- Abstract: Mesenchymal stem cell like (MSCl) cells were generated from human embryonic stem cells (hESC) through embryoid body formation, and isolated by adherence to plastic surface. MSCl cell lines could be propagated without changes in morphological or functional characteristics for more than 15 passages. These cells, as well as their fluorescent protein expressing stable derivatives, efficiently supported the growth of undifferentiated human embryonic stem cells as feeder cells. The MSCl cells did not express the embryonic (Oct4, Nanog, ABCG2, PODXL, or SSEA4), or hematopoietic (CD34, CD45, CD14, CD133, HLA-DR) stem cell markers, while were positive for the characteristic cell surface markers of MSCs (CD44, CD73, CD90, CD105). MSCl cells could be differentiated toward osteogenic, chondrogenic or adipogenic directions and exhibited significant inhibition of mitogen-activated lymphocyte proliferation, and thus presented immunosuppressive features. We suggest that cultured MSCl cells can properly model human MSCs and be applied as efficient feeders in hESC cultures.

  2. Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells: Influence in Cancer Development

    Science.gov (United States)

    Papaccio, Federica; Paino, Francesca; Regad, Tarik; Desiderio, Vincenzo; Tirino, Virginia

    2017-01-01

    Abstract Tumors are composed of different types of cancer cells that contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) play an important role in cancer initiation and progression. Like their stem cells counterpart, CSCs are also characterized by self‐renewal and the capacity to differentiate. A particular population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into cells of mesodermal characteristics. Several studies have reported the potential pro‐or anti‐tumorigenic influence of MSCs on tumor initiation and progression. In fact, MSCs are recruited to the site of wound healing to repair damaged tissues, an event that is also associated with tumorigenesis. In other cases, resident or migrating MSCs can favor tumor angiogenesis and increase tumor aggressiveness. This interplay between MSCs and cancer cells is fundamental for cancerogenesis, progression, and metastasis. Therefore, an interesting topic is the relationship between cancer cells, CSCs, and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of normal and CSCs in cancer development. The understanding of the role of MSCs in cancer is also important in cancer management. Stem Cells Translational Medicine 2017;6:2115–2125 PMID:29072369

  3. Adipose Stem Cells as Alternatives for Bone Marrow Mesenchymal Stem Cells in Oral Ulcer Healing

    Science.gov (United States)

    Aziz Aly, Lobna Abdel; Menoufy, Hala El-; Ragae, Alyaa; Rashed, Laila Ahmed; Sabry, Dina

    2012-01-01

    Background and Objectives Adipose tissue is now recognized as an accessible, abundant, and reliable site for the isolation of adult stem cells suitable for tissue engineering and regenerative medicine applications. Methods and Results Oral ulcers were induced by topical application of formocresol in the oral cavity of dogs. Transplantation of undifferentiated GFP-labeled Autologous Bone Marrow Stem Cell (BMSCs), Adipose Derived Stem Cell (ADSCs) or vehicle (saline) was injected around the ulcer in each group. The healing process of the ulcer was monitored clinically and histopathologically. Gene expression of vascular endothelial growth factor (VEGF) was detected in MSCs by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Expression of VEGF and collagen genes was detected in biopsies from all ulcers. Results: MSCs expressed mRNA for VEGF MSCs transplantation significantly accelerated oral ulcer healing compared with controls. There was increased expression of both collagen and VEGF genes in MSCs-treated ulcers compared to controls. Conclusions MSCs transplantation may help to accelerate oral ulcer healing, possibly through the induction of angiogenesis by VEGF together with increased intracellular matrix formation as detected by increased collagen gene expression. This body of work has provided evidence supporting clinical applications of adipose-derived cells in safety and efficacy trials as an alternative for bone marrow mesenchymal stem cells in oral ulcer healing. PMID:24298363

  4. Characteristics and Outcome of Patients After Allogeneic Hematopoietic Stem Cell Transplantation Treated With Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome.

    Science.gov (United States)

    Wohlfarth, Philipp; Beutel, Gernot; Lebiedz, Pia; Stemmler, Hans-Joachim; Staudinger, Thomas; Schmidt, Matthieu; Kochanek, Matthias; Liebregts, Tobias; Taccone, Fabio Silvio; Azoulay, Elie; Demoule, Alexandre; Kluge, Stefan; Svalebjørg, Morten; Lueck, Catherina; Tischer, Johanna; Combes, Alain; Böll, Boris; Rabitsch, Werner; Schellongowski, Peter

    2017-05-01

    The acute respiratory distress syndrome is a frequent condition following allogeneic hematopoietic stem cell transplantation. Extracorporeal membrane oxygenation may serve as rescue therapy in refractory acute respiratory distress syndrome but has not been assessed in allogeneic hematopoietic stem cell transplantation recipients. Multicenter, retrospective, observational study. ICUs in 12 European tertiary care centers (Austria, Germany, France, and Belgium). All allogeneic hematopoietic stem cell transplantation recipients treated with venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome between 2010 and 2015. None. Thirty-seven patients, nine of whom underwent noninvasive ventilation at the time of extracorporeal membrane oxygenation initiation, were analyzed. ICU admission occurred at a median of 146 (interquartile range, 27-321) days after allogeneic hematopoietic stem cell transplantation. The main reason for acute respiratory distress syndrome was pneumonia in 81% of patients. All but one patient undergoing noninvasive ventilation at extracorporeal membrane oxygenation initiation had to be intubated thereafter. Overall, seven patients (19%) survived to hospital discharge and were alive and in remission of their hematologic disease after a follow-up of 18 (range, 5-30) months. Only one of 24 patients (4%) initiated on extracorporeal membrane oxygenation within 240 days after allogeneic hematopoietic stem cell transplantation survived compared to six of 13 (46%) of those treated thereafter (p syndrome in this group. On the contrary, long-term allogeneic hematopoietic stem cell transplantation recipients otherwise eligible for full-code ICU management may be potential candidates for extracorporeal membrane oxygenation therapy in case of severe acute respiratory distress syndrome failing conventional measures.

  5. In vitro cardiomyogenic potential of human umbilical vein-derived mesenchymal stem cells

    International Nuclear Information System (INIS)

    Kadivar, Mehdi; Khatami, Shohreh; Mortazavi, Yousef; Shokrgozar, Mohammad Ali; Taghikhani, Mohammad; Soleimani, Masoud

    2006-01-01

    Cardiomyocyte loss in the ischemically injured human heart often leads to irreversible defects in cardiac function. Recently, cellular cardiomyoplasty with mesenchymal stem cells, which are multipotent cells with the ability to differentiate into specialized cells under appropriate stimuli, has emerged as a new approach for repairing damaged myocardium. In the present study, the potential of human umbilical cord-derived mesenchymal stem cells to differentiate into cells with characteristics of cardiomyocyte was investigated. Mesenchymal stem cells were isolated from endothelial/subendothelial layers of the human umbilical cords using a method similar to that of human umbilical vein endothelial cell isolation. Isolated cells were characterized by transdifferentiation ability to adipocytes and osteoblasts, and also with flow cytometry analysis. After treatment with 5-azacytidine, the human umbilical cord-derived mesenchymal stem cells were morphologically transformed into cardiomyocyte-like cells and expressed cardiac differentiation markers. During the differentiation, cells were monitored by a phase contrast microscope and their morphological changes were demonstrated. Immunostaining of the differentiated cells for sarcomeric myosin (MF20), desmin, cardiac troponin I, and sarcomeric α-actinin was positive. RT-PCR analysis showed that these differentiated cells express cardiac-specific genes. Transmission electron microscopy revealed a cardiomyocyte-like ultrastructure and typical sarcomers. These observations confirm that human umbilical cord-derived mesenchymal stem cells can be chemically transformed into cardiomyocytes and can be considered as a source of cells for cellular cardiomyoplasty

  6. Cotransplantation of bone marrow mononuclear cells and umbilical cord mesenchymal stem cells in avascular necrosis of the femoral head.

    Science.gov (United States)

    Cai, J; Wu, Z; Huang, L; Chen, J; Wu, C; Wang, S; Deng, Z; Wu, W; Luo, F; Tan, J

    2014-01-01

    We sought to investigate the therapeutic effects of cotransplantation of autologous bone marrow mononuclear cells (BMMNCs) and allogeneic umbilical cord mesenchymal stem cells (UC-MSCs) on avascular necrosis of the femoral head (ANFH). In all, 30 patients (49 hips; 24 males and 6 females) with ANFH were enrolled. According to the system of the Association Research Circulation Osseous, there were 24 hips in phase II and 25 hips in phase Ⅲ. Blood supply to the femoral head was evaluated by using digital subtraction angiography. Generally, 60 to 80 mL of autologous BMMNCs and 30 to 50 mL of UC-MSCs were infused into the femoral head artery. Harris scores including pain and joint function were used to evaluate the effects before and 3, 6, 9, and 12 months after transplantation. Computed tomography and radiographs were performed before and 12 months after the treatment. Clinical symptoms of pain and claudication were gradually improved. After the treatment, 93.3% (28/30), 86.7% (26/30), and 86.7% (26/30) of patients showed relief of hip pain, improvement of joint function, and extended walking distances, respectively. The Harris scores were increased significantly at 3, 6, and 12 months posttransplant compared with those pretransplant. In addition, the bone lesions in 89.7% of hips (44/49) were improved as showed on computed tomography after transplantation. Cotransplantation of autologous BMMNCs and allogeneic UC-MSCs showed therapeutic effect on ANFH without severe adverse effects. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Frequent induction of chromosomal aberrations in in vivo skin fibroblasts after allogeneic stem cell transplantation: hints to chromosomal instability after irradiation

    International Nuclear Information System (INIS)

    Massenkeil, G.; Zschieschang, P.; Thiel, G.; Hemmati, P. G.; Budach, V.; Dörken, B.; Pross, J.; Arnold, R.

    2015-01-01

    Total body irradiation (TBI) has been part of standard conditioning regimens before allogeneic stem cell transplantation for many years. Its effect on normal tissue in these patients has not been studied extensively. We studied the in vivo cytogenetic effects of TBI and high-dose chemotherapy on skin fibroblasts from 35 allogeneic stem cell transplantation (SCT) patients. Biopsies were obtained prospectively (n = 18 patients) before, 3 and 12 months after allogeneic SCT and retrospectively (n = 17 patients) 23–65 months after SCT for G-banded chromosome analysis. Chromosomal aberrations were detected in 2/18 patients (11 %) before allogeneic SCT, in 12/13 patients (92 %) after 3 months, in all patients after 12 months and in all patients in the retrospective group after allogeneic SCT. The percentage of aberrant cells was significantly higher at all times after allogeneic SCT compared to baseline analysis. Reciprocal translocations were the most common aberrations, but all other types of stable, structural chromosomal aberrations were also observed. Clonal aberrations were observed, but only in three cases they were detected in independently cultured flasks. A tendency to non-random clustering throughout the genome was observed. The percentage of aberrant cells was not different between patients with and without secondary malignancies in this study group. High-dose chemotherapy and TBI leads to severe chromosomal damage in skin fibroblasts of patients after SCT. Our long-term data suggest that this damage increases with time, possibly due to in vivo radiation-induced chromosomal instability

  8. Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition

    OpenAIRE

    Morel, Anne-Pierre; Lièvre, Marjory; Thomas, Clémence; Hinkal, George; Ansieau, Stéphane; Puisieux, Alain

    2008-01-01

    Recently, two novel concepts have emerged in cancer biology: the role of so-called "cancer stem cells" in tumor initiation, and the involvement of an epithelial-mesenchymal transition (EMT) in the metastatic dissemination of epithelial cancer cells. Using a mammary tumor progression model, we show that cells possessing both stem and tumorigenic characteristics of "cancer stem cells" can be derived from human mammary epithelial cells following the activation of the Ras-MAPK pathway. The acquis...

  9. Evidence for Kaposi Sarcoma Originating from Mesenchymal Stem Cell through KSHV-induced Mesenchymal-to-Endothelial Transition.

    Science.gov (United States)

    Li, Yuqing; Zhong, Canrong; Liu, Dawei; Yu, Wenjing; Chen, Weikang; Wang, Yan; Shi, Songtao; Yuan, Yan

    2018-01-01

    The major transmission route for Kaposi sarcoma-associated herpesvirus (KSHV) infection is the oral cavity through saliva. Kaposi sarcoma (KS) frequently occurs in the oral cavity in HIV-positive individuals and is often the first presenting sign of AIDS. However, the oral target cells for KSHV infection and the cellular origin of Kaposi sarcoma remain unknown. Here we present clinical and experimental evidences that Kaposi sarcoma spindle cells may originate from virally modified oral mesenchymal stem cells (MSC). AIDS-KS spindle cells expressed neuroectodermal stem cell marker (Nestin) and oral MSC marker CD29, suggesting an oral/craniofacial MSC lineage of AIDS-associated Kaposi sarcoma. Furthermore, oral MSCs were highly susceptible to KSHV infection, and infection promoted multilineage differentiation and mesenchymal-to-endothelial transition (MEndT). KSHV infection of oral MSCs resulted in expression of a large number of cytokines, a characteristic of Kaposi sarcoma, and upregulation of Kaposi sarcoma signature and MEndT-associated genes. These results suggest that Kaposi sarcoma may originate from pluripotent MSC and KSHV infection transforms MSC to Kaposi sarcoma-like cells through MEndT. Significance: These findings indicate that Kaposi sarcomas, which arise frequently in AIDS patients, originate from neural crest-derived mesenchymal stem cells, with possible implications for improving the clnical treatment of this malignancy. Cancer Res; 78(1); 230-45. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Microscale versus nanoscale scaffold architecture for mesenchymal stem cell chondrogenesis.

    Science.gov (United States)

    Shanmugasundaram, Shobana; Chaudhry, Hans; Arinzeh, Treena Livingston

    2011-03-01

    Nanofiber scaffolds, produced by the electrospinning technique, have gained widespread attention in tissue engineering due to their morphological similarities to the native extracellular matrix. For cartilage repair, studies have examined their feasibility; however these studies have been limited, excluding the influence of other scaffold design features. This study evaluated the effect of scaffold design, specifically examining a range of nano to micron-sized fibers and resulting pore size and mechanical properties, on human mesenchymal stem cells (MSCs) derived from the adult bone marrow during chondrogenesis. MSC differentiation was examined on these scaffolds with an emphasis on temporal gene expression of chondrogenic markers and the pluripotent gene, Sox2, which has yet to be explored for MSCs during chondrogenesis and in combination with tissue engineering scaffolds. Chondrogenic markers of aggrecan, chondroadherin, sox9, and collagen type II were highest for cells on micron-sized fibers (5 and 9 μm) with pore sizes of 27 and 29 μm, respectively, in comparison to cells on nano-sized fibers (300 nm and 600 to 1400 nm) having pore sizes of 2 and 3 μm, respectively. Undifferentiated MSCs expressed high levels of the Sox2 gene but displayed negligible levels on all scaffolds with or without the presence of inductive factors, suggesting that the physical features of the scaffold play an important role in differentiation. Micron-sized fibers with large pore structures and mechanical properties comparable to the cartilage ECM enhanced chondrogenesis, demonstrating architectural features as well as mechanical properties of electrospun fibrous scaffolds enhance differentiation.

  11. Sodium Tungstate for Promoting Mesenchymal Stem Cell Chondrogenesis.

    Science.gov (United States)

    Khader, Ateka; Sherman, Lauren S; Rameshwar, Pranela; Arinzeh, Treena L

    2016-12-15

    Articular cartilage has a limited ability to heal. Mesenchymal stem cells (MSCs) derived from the bone marrow have shown promise as a cell type for cartilage regeneration strategies. In this study, sodium tungstate (Na 2 WO 4 ), which is an insulin mimetic, was evaluated for the first time as an inductive factor to enhance human MSC chondrogenesis. MSCs were seeded onto three-dimensional electrospun scaffolds in growth medium (GM), complete chondrogenic induction medium (CCM) containing insulin, and CCM without insulin. Na 2 WO 4 was added to the media leading to final concentrations of 0, 0.01, 0.1, and 1 mM. Chondrogenic differentiation was assessed by biochemical analyses, immunostaining, and gene expression. Cytotoxicity using human peripheral blood mononuclear cells (PBMCS) was also investigated. The chondrogenic differentiation of MSCs was enhanced in the presence of low concentrations of Na 2 WO 4 compared to control, without Na 2 WO 4 . In the induction medium containing insulin, cells in 0.01 mM Na 2 WO 4 produced significantly higher sulfated glycosaminoglycans, collagen type II, and chondrogenic gene expression than all other groups at day 28. Cells in 0.1 mM Na 2 WO 4 had significantly higher collagen II production and significantly higher sox-9 and aggrecan gene expression compared to control at day 28. Cells in GM and induction medium without insulin containing low concentrations of Na 2 WO 4 also expressed chondrogenic markers. Na 2 WO 4 did not stimulate PBMC proliferation or apoptosis. The results demonstrate that Na 2 WO 4 enhances chondrogenic differentiation of MSCs, does not have a toxic effect, and may be useful for MSC-based approaches for cartilage repair.

  12. Isolation of Mesenchymal Stem Cells from Human Deciduous Teeth Pulp

    Directory of Open Access Journals (Sweden)

    Aileen I. Tsai

    2017-01-01

    Full Text Available This study aimed to identify predictors of success rate of mesenchymal stem cell (MSC isolation from human deciduous teeth pulp. A total of 161 deciduous teeth were extracted at the dental clinic of Chang Gung Memorial Hospital. The MSCs were isolated from dental pulps using a standard protocol. In total, 128 colonies of MSCs were obtained and the success rate was 79.5%. Compared to teeth not yielding MSCs successfully, those successfully yielding MSCs were found to have less severe dental caries (no/mild-to-moderate/severe: 63.3/24.2/12.5% versus 12.5/42.4/42.4%, P<0.001 and less frequent pulpitis (no/yes: 95.3/4.7% versus 51.5/48.5%, P<0.001. In a multivariate regression model, it was confirmed that the absence of dental caries (OR = 4.741, 95% CI = 1.564–14.371, P=0.006 and pulpitis (OR = 9.111, 95% CI = 2.921–28.420, P<0.001 was significant determinants of the successful procurement of MSCs. MSCs derived from pulps with pulpitis expressed longer colony doubling time than pulps without pulpitis. Furthermore, there were higher expressions of proinflammatory cytokines, interleukin- (IL- 6 and monocyte chemoattractant protein- (MCP- 1, P<0.01, and innate immune response [toll-like receptor 1 (TLR1 and TLR8, P<0.05; TLR2, TLR3, and TLR6, P<0.01] in the inflamed than noninflamed pulps. Therefore, a carious deciduous tooth or tooth with pulpitis was relatively unsuitable for MSC processing and isolation.

  13. Mesenchymal stem cell therapy in the treatment of hip osteoarthritis

    Science.gov (United States)

    Mardones, Rodrigo; Jofré, Claudio M.; Tobar, L.

    2017-01-01

    Abstract This study was performed to investigate the safety and efficacy of the intra-articular infusion of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (BM-MSC) to a cohort of patients with articular cartilage defects in the hip. The above rationale is sustained by the notion that MSCs express a chondrocyte differential potential and produce extracellular matrix molecules as well as regulatory signals, that may well contribute to cure the function of the damaged hip joint. A cohort of 10 patients with functional and radiological evidences of hip osteoarthritis, either in one or both legs, was included in the study. BM-MSC (the cell product) were prepared and infused into the damaged articulation(s) of each patient (60 × 106 cells in 3 weekly/doses). Before and after completion of the cell infusion scheme, patients were evaluated (hip scores for pain, stiffness, physical function, range of motion), to assess whether the infusion of the respective cell product was beneficial. The intra-articular injection of three consecutive weekly doses of ex vivo expanded autologous BM-MSC to patients with articular cartilage defects in the hip and proved to be a safe and clinically effective treatment in the restoration of hip function and range of motion. In addition, the statistical significance of the above data is in line with the observation that the radiographic scores (Tönnis Classification of Osteoarthritis) of the damaged leg(s) remained without variation in 9 out of 10 patients, after the administration of the cell product. PMID:28630737

  14. Lipopolysaccharides priming mesenchymal stem cells accelerate diabetic wound healing viaexosomes

    Directory of Open Access Journals (Sweden)

    Dong-dong TI

    2016-08-01

    Full Text Available Objective  To study the therapeutic effect of exosome derived from lipopolysaccharides (LPS priming mesenchymal stem cells (MSCs for diabetic wound healing. Methods  Human umbilical cord MSCs were treated with LPS (100ng/ml for 2 days, the supernatant were then collected, and exosomes were harvested by density gradient centrifugation and identified. Diabetic cutaneous wounds were prepared and the animals were divided into the following three groups: control group, untreated MSCs derived exosome (un-exosome treatment group and LPS primed MSCs derived exosome (LPS-exosome treatment group. Exosomes (60μg were injected dispersively into the wound edge daily for 10 days. After treatment, the therapeutic results were evaluated by gross observation of the wounds, the expression levels of inflammation related factors and macrophage subtype markers in the injured sites were detected by qRT-PCR at day 3, 7 and 14 after treatment. Results  Compared with control group, the diabetic wound healing was obviously improved in LPS-exosome treatment group after treatment for 7 and 14 days, with faster wound close, depressed expression of pro-inflammatory factors IL -1, IL -12 and M1 macrophage surface marker iNOS, and up-regulation of anti-inflammatory factors IL-10, TGF-βand M2 macrophage surface marker CD163, the differences were significant (P<0.05. Conclusions  LPS-exosome may balance macrophage plasticity, restrain chronic inflammation and accelerate diabetic cutaneous wound healing. DOI: 10.11855/j.issn.0577-7402.2016.07.02

  15. Mesenchymal Stem Cell Treatment of Inflammation-Induced Cancer.

    Science.gov (United States)

    Prakash, Monica D; Miller, Sarah; Randall-Demllo, Sarron; Nurgali, Kulmira

    2016-11-01

    Cancer development is often associated with chronic inflammation. To date, research into inflammation-induced cancer has largely focused on chemokines, cytokines, and their downstream targets. These inflammatory mediators may promote tumor growth, invasion, metastasis, and facilitate angiogenesis. However, the exact mechanisms by which inflammation promotes neoplasia remain unclear. Inflammatory bowel disease (IBD) is characterized by recurrent, idiopathic intestinal inflammation, the complications of which are potentially fatal. IBD incidence in Australia is 24.2 per 100,000 and its peak onset is in people aged 15 to 24 years. Symptoms include abdominal pain, cramps, bloody stool, and persistent diarrhoea or constipation and so seriously compromise quality of life. However, due to its unknown etiology, current treatment strategies combat the symptoms rather than the disease and are limited by inefficacy, toxicity, and adverse side-effects. IBD is also associated with an increased risk of colorectal cancer, for which treatment options are similarly limited. In recent years, there has been much interest in the therapeutic potential of mesenchymal stem cells (MSCs). However, whether MSCs suppress or promote tumor development is still contentious within the literature. Many studies indicate that MSCs exert anti-tumor effects and suppress tumor growth, whereas other studies report pro-tumor effects. Studies using MSCs as treatment for IBD have shown promising results in both animal models and human trials. However, as MSC treatment is still novel, the long-term risks remain unknown. This review aims to summarize the current literature on MSC treatment of inflammation-induced cancer, with a focus on colorectal cancer resulting from IBD.

  16. Mesenchymal stem cells cancel azoxymethane-induced tumor initiation.

    Science.gov (United States)

    Nasuno, Masanao; Arimura, Yoshiaki; Nagaishi, Kanna; Isshiki, Hiroyuki; Onodera, Kei; Nakagaki, Suguru; Watanabe, Shuhei; Idogawa, Masashi; Yamashita, Kentaro; Naishiro, Yasuyoshi; Adachi, Yasushi; Suzuki, Hiromu; Fujimiya, Mineko; Imai, Kohzoh; Shinomura, Yasuhisa

    2014-04-01

    The role of mesenchymal stem cells (MSCs) in tumorigenesis remains controversial. Therefore, our goal was to determine whether exogenous MSCs possess intrinsic antineoplastic or proneoplastic properties in azoxymethane (AOM)-induced carcinogenesis. Three in vivo models were studied: an AOM/dextran sulfate sodium colitis-associated carcinoma model, an aberrant crypt foci model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). We also performed in vitro coculture experiments. As a result, we found that MSCs partially canceled AOM-induced tumor initiation but not tumor promotion. Moreover, MSCs inhibited the AARGC in colonic epithelial cells because of the removal of O(6)-methylguanine (O(6) MeG) adducts through O(6) MeG-DNA methyltransferase activation. Furthermore, MSCs broadly affected the cell-cycle machinery, potentially leading to G1 arrest in vivo. Coculture of IEC-6 rat intestinal cells with MSCs not only arrested the cell cycle at the G1 phase, but also induced apoptosis. The anti-carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)-β signaling because such properties were completely abrogated by absorption of TGF-β under indirect coculture conditions. MSCs inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped from the AARGC. Furthermore, tumor initiation perturbed by MSCs might potentially dysregulate WNT and TGF-β-Smad signaling pathways in subsequent tumorigenesis. Obtaining a better understanding of MSC functions in colon carcinogenesis is essential before commencing the broader clinical application of promising MSC-based therapies for cancer-prone patients with inflammatory bowel disease. © AlphaMed Press.

  17. Mesenchymal stem cells promote formation of colorectal tumors in mice.

    Science.gov (United States)

    Tsai, Kuo-Shu; Yang, Shung-Haur; Lei, Yen-Ping; Tsai, Chih-Chien; Chen, Hsin-Wei; Hsu, Chih-Yuan; Chen, Ling-Lan; Wang, Hsei-Wei; Miller, Stephanie A; Chiou, Shih-Hwa; Hung, Mien-Chie; Hung, Shih-Chieh

    2011-09-01

    Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation. Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation. A small number (≤ 10) of unsorted, CD133⁻, CD166⁻, epithelial cell adhesion molecule⁻(EpCAM⁻), or CD133⁻/CD166⁻/EpCAM⁻ colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2-signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation. IL-6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Role of Slug transcription factor in human mesenchymal stem cells.

    Science.gov (United States)

    Torreggiani, Elena; Lisignoli, Gina; Manferdini, Cristina; Lambertini, Elisabetta; Penolazzi, Letizia; Vecchiatini, Renata; Gabusi, Elena; Chieco, Pasquale; Facchini, Andrea; Gambari, Roberto; Piva, Roberta

    2012-04-01

    The pathways that control mesenchymal stem cells (MSCs) differentiation are not well understood, and although some of the involved transcription factors (TFs) have been characterized, the role of others remains unclear. We used human MSCs from tibial plateau (TP) trabecular bone, iliac crest (IC) bone marrow and Wharton's jelly (WJ) umbilical cord demonstrating a variability in their mineral matrix deposition, and in the expression levels of TFs including Runx2, Sox9, Sox5, Sox6, STAT1 and Slug, all involved in the control of osteochondroprogenitors differentiation program. Because we reasoned that the basal expression level of some TFs with crucial role in the control of MSC fate may be correlated with osteogenic potential, we considered the possibility to affect the hMSCs behaviour by using gene silencing approach without exposing cells to induction media. In this study we found that Slug-silenced cells changed in morphology, decreased in their migration ability, increased Sox9 and Sox5 and decreased Sox6 and STAT1 expression. On the contrary, the effect of Slug depletion on Runx2 was influenced by cell type. Interestingly, we demonstrated a direct in vivo regulatory action of Slug by chromatin immunoprecipitation, showing a specific recruitment of this TF in the promoter of Runx2 and Sox9 genes. As a whole, our findings have important potential implication on bone tissue engineering applications, reinforcing the concept that manipulation of specific TF expression levels may elucidate MSC biology and the molecular mechanisms, which promote osteogenic differentiation. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  19. Human dental pulp mesenchymal stem cells isolation and osteoblast differentiation

    Directory of Open Access Journals (Sweden)

    Moustafa Alkhalil

    2015-02-01

    Full Text Available Aim This study was focused on the isolation and characterization of mesenchymal stem cells (MSCs from human dental pulp (DPSC. Methods The study was performed in the Department for Oral and Cranio-Maxillo- Facial Surgey Hamad Medical Corporation, Doha, Qatar and Weill Cornell Medical Colleague Doha, Qatar, in period 2010-2011. Dental pulp was extracted from premolars and third molars of 19 healthy patients. The pulp was digested in a solution of 3 mg/mL collagenase type I and 4 mg/mL dispase for 1 hour at 37C. After filtration, cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM Low Glucoses with 20% Fetal Bovine Serum (FBS, 2mM L-glutamine and antibiotics (100 U/mL penicillin, 100 ug/mL streptomycin at 37 °C under 5% CO2. Cultures were treated with osteoinductive medium for differentiation MSC in to the osteoblast cell line. Staining with Alizarin red were used for the detection of the osteoblast production and calcification new formed tissue. Results On the total of three out of 19 patients it was possible to isolate DPMSCs after 2 to 3 weeks: in one patient it was not possible to expand MSCs because of infection, and in other two patients positive Alizarin red staining reaction showed osteogenic differentiation capability and strong mineralization in vitro. Conclusion The main advantage of using DPSC is absence of morbidity. MSCs could be isolated noninvasively from teeth, routinely extracted in the clinic and discarded as medical waste. Standardization of clinical and laboratory protocols for DPMSCs isolation and team work coordination could lead to significantly improved result.

  20. Tracking mesenchymal stem cells using magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Jens T Rosenberg

    2016-01-01

    Full Text Available Recent translational studies in the fields of tissue regeneration and cell therapy have characterized mesenchymal stem cells (MSCs as a potentially effective and accessible measure for treating ischemic cerebral and neurodegenerative disorders such as stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Developing more efficient cell tracking techniques bear the potential to optimize MSC transplantation therapies by providing a more accurate picture of the fate and area of effect of implanted cells. Currently, determining the location of transplanted MSCs involves a histological approach, but magnetic resonance imaging (MRI presents a noninvasive paradigm that permits repeat evaluations. To visualize MSCs using MRI, the implanted cells must be treated with an intracellular contrast agent. These are commonly paramagnetic compounds, many of which are based on superparamagnetic iron oxide (SPIO nanoparticles. Recent research has set out characterize the effects of SPIO-uptake on the cellular activity of in vitro human MSCs and the resultant influence that respective SPIO concentration has on MRI sensitivity. As these studies reveal, SPIO-uptake has no effect on the cellular processes of proliferation and differentiation while producing high contrast MRI signals. Moreover, transplantation of SPIO-labeled MSCs in animal models encouragingly showed no loss in MRI contrast, suggesting that SPIO labeling may be an appealing regime for lasting MRI detection. This study is a review article. Referred literature in this study has been listed in the reference part. The datasets supporting the conclusions of this article are available online by searching the PubMed. Some original points in this article come from the laboratory practice in our research centers and the authors' experiences.

  1. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation.

    Science.gov (United States)

    Eirin, Alfonso; Zhu, Xiang-Yang; Puranik, Amrutesh S; Tang, Hui; McGurren, Kelly A; van Wijnen, Andre J; Lerman, Amir; Lerman, Lilach O

    2017-07-01

    Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue-derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle-based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  2. Mesenchymal stem cell secretome and regenerative therapy after cancer.

    Science.gov (United States)

    Zimmerlin, Ludovic; Park, Tea Soon; Zambidis, Elias T; Donnenberg, Vera S; Donnenberg, Albert D

    2013-12-01

    Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro-angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bi-directional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFβ, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus

  3. Mesenchymal stem cells cultured on magnetic nanowire substrates

    Science.gov (United States)

    Perez, Jose E.; Ravasi, Timothy; Kosel, Jürgen

    2017-02-01

    Stem cells have been shown to respond to extracellular mechanical stimuli by regulating their fate through the activation of specific signaling pathways. In this work, an array of iron nanowires (NWs) aligned perpendicularly to the surface was fabricated by pulsed electrodepositon in porous alumina templates followed by a partial removal of the alumina to reveal 2-3 μm of the NWs. This resulted in alumina substrates with densely arranged NWs of 33 nm in diameter separated by 100 nm. The substrates were characterized by scanning electron microscopy (SEM) energy dispersive x-ray analysis and vibrating sample magnetometer. The NW array was then used as a platform for the culture of human mesenchymal stem cells (hMSCs). The cells were stained for the cell nucleus and actin filaments, as well as immuno-stained for the focal adhesion protein vinculin, and then observed by fluorescence microscopy in order to characterize their spreading behavior. Calcein AM/ethidium homodimer-1 staining allowed the determination of cell viability. The interface between the cells and the NWs was studied using SEM. Results showed that hMSCs underwent a re-organization of actin filaments that translated into a change from an elongated to a spherical cell shape. Actin filaments and vinculin accumulated in bundles, suggesting the attachment and formation of focal adhesion points of the cells on the NWs. Though the overall number of cells attached on the NWs was lower compared to the control, the attached cells maintained a high viability (>90%) for up to 6 d. Analysis of the interface between the NWs and the cells confirmed the re-organization of F-actin and revealed the adhesion points of the cells on the NWs. Additionally, a net of filopodia surrounded each cell, suggesting the probing of the array to find additional adhesion points. The cells maintained their round shape for up to 6 d of culture. Overall, the NW array is a promising nanostructured platform for studying and influencing h

  4. Mesenchymal stem cells cultured on magnetic nanowire substrates

    KAUST Repository

    Perez, Jose E.

    2016-12-28

    Stem cells have been shown to respond to extracellular mechanical stimuli by regulating their fate through the activation of specific signaling pathways. In this work, an array of iron nanowires (NWs) aligned perpendicularly to the surface was fabricated by pulsed electrodepositon in porous alumina templates followed by a partial removal of the alumina to reveal 2-3 μm of the NWs. This resulted in alumina substrates with densely arranged NWs of 33 nm in diameter separated by 100 nm. The substrates were characterized by scanning electron microscopy (SEM) energy dispersive x-ray analysis and vibrating sample magnetometer. The NW array was then used as a platform for the culture of human mesenchymal stem cells (hMSCs). The cells were stained for the cell nucleus and actin filaments, as well as immuno-stained for the focal adhesion protein vinculin, and then observed by fluorescence microscopy in order to characterize their spreading behavior. Calcein AM/ethidium homodimer-1 staining allowed the determination of cell viability. The interface between the cells and the NWs was studied using SEM. Results showed that hMSCs underwent a re-organization of actin filaments that translated into a change from an elongated to a spherical cell shape. Actin filaments and vinculin accumulated in bundles, suggesting the attachment and formation of focal adhesion points of the cells on the NWs. Though the overall number of cells attached on the NWs was lower compared to the control, the attached cells maintained a high viability (>90%) for up to 6 d. Analysis of the interface between the NWs and the cells confirmed the re-organization of F-actin and revealed the adhesion points of the cells on the NWs. Additionally, a net of filopodia surrounded each cell, suggesting the probing of the array to find additional adhesion points. The cells maintained their round shape for up to 6 d of culture. Overall, the NW array is a promising nanostructured platform for studying and influencing h

  5. Pluripotent stem cells isolated from umbilical cord form embryonic like bodies in a mesenchymal layer culture.

    Science.gov (United States)

    Tsagias, Nikos; Kouzi-Koliakos, Kokkona; Karagiannis, Vasileios; Tsikouras, P; Koliakos, George G

    2015-03-01

    Recently the matrix of umbilical cord began to use as an alternative source of stem cells additionally to the blood of umbilical cord. Umbilical cord has been used mainly for mesenchymal stem cell banking. The immunological characteristics of mesenchymal stem cells in combination with their ability to avoid rejection make them an attractive biological material for transplantations. In this study the isolation of small in size pluripotent stem cells from umbilical cord expressing early transcription factors with characteristics that resemble to embryonic stem cells is investigated. Pluripotent stem cells were isolated from human umbilical cords, by a new strategy method based on unique characteristics such as the small size and the positivity on early transcription factors OCT and Nanog. An enriched population of CXCR4(+) OCT(+) Nanog(+) CD45(-) small stem cells from the cord was isolated. This fraction was able to create alkaline phosphatase positive like spheres forms in a mesenchymal layer with multilineage differentiation capacity. Our results were assessed by RT PCR and electophoresis for the pluripotent genes. These data suggest that umbilical cord provides an attractive source not only of mesenchymal stem cells but moreover of pluripotent stem cells. The method described herein should be applied in the field of stem cell banking in addition to the classical umbilical cord harvesting method. Isolation of a population of cells with pluripotent characteristics from umbilical cord. Adoption of a second centrifugation step for the pluripotent stem isolation. Increasing the value of the cord and explaining the pluripotency. This work will enhance the value of umbilical cord harvesting.

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  16. Bone marrow mesenchymal stem cells repair spinal cord ischemia/reperfusion injury by promoting axonal growth and anti-autophagy.

    Science.gov (United States)

    Yin, Fei; Meng, Chunyang; Lu, Rifeng; Li, Lei; Zhang, Ying; Chen, Hao; Qin, Yonggang; Guo, Li

    2014-09-15

    Bone marrow mesenchymal stem cells can differentiate into neurons and astrocytes after transplantation in the spinal cord of rats with ischemia/reperfusion injury. Although bone marrow mesenchymal stem cells are known to protect against spinal cord ischemia/reperfusion injury through anti-apoptotic effects, the precise mechanisms remain unclear. In the present study, bone marrow mesenchymal stem cells were cultured and proliferated, then transplanted into rats with ischemia/reperfusion injury via retro-orbital injection. Immunohistochemistry and immunofluorescence with subsequent quantification revealed that the expression of the axonal regeneration marker, growth associated protein-43, and the neuronal marker, microtubule-associated protein 2, significantly increased in rats with bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Furthermore, the expression of the autophagy marker, microtubule-associated protein light chain 3B, and Beclin 1, was significantly reduced in rats with the bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Western blot analysis showed that the expression of growth associated protein-43 and neurofilament-H increased but light chain 3B and Beclin 1 decreased in rats with the bone marrow mesenchymal stem cell transplantation. Our results therefore suggest that bone marrow mesenchymal stem cell transplantation promotes neurite growth and regeneration and prevents autophagy. These responses may likely be mechanisms underlying the protective effect of bone marrow mesenchymal stem cells against spinal cord ischemia/reperfusion injury.

  17. Bone marrow mesenchymal stem cells repair spinal cord ischemia/reperfusion injury by promoting axonal growth and anti-autophagy

    Science.gov (United States)

    Yin, Fei; Meng, Chunyang; Lu, Rifeng; Li, Lei; Zhang, Ying; Chen, Hao; Qin, Yonggang; Guo, Li

    2014-01-01

    Bone marrow mesenchymal stem cells can differentiate into neurons and astrocytes after transplantation in the spinal cord of rats with ischemia/reperfusion injury. Although bone marrow mesenchymal stem cells are known to protect against spinal cord ischemia/reperfusion injury through anti-apoptotic effects, the precise mechanisms remain unclear. In the present study, bone marrow mesenchymal stem cells were cultured and proliferated, then transplanted into rats with ischemia/reperfusion injury via retro-orbital injection. Immunohistochemistry and immunofluorescence with subsequent quantification revealed that the expression of the axonal regeneration marker, growth associated protein-43, and the neuronal marker, microtubule-associated protein 2, significantly increased in rats with bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Furthermore, the expression of the autophagy marker, microtubule-associated protein light chain 3B, and Beclin 1, was significantly reduced in rats with the bone marrow mesenchymal stem cell transplantation compared with those in rats with spinal cord ischemia/reperfusion injury. Western blot analysis showed that the expression of growth associated protein-43 and neurofilament-H increased but light chain 3B and Beclin 1 decreased in rats with the bone marrow mesenchymal stem cell transplantation. Our results therefore suggest that bone marrow mesenchymal stem cell transplantation promotes neurite growth and regeneration and prevents autophagy. These responses may likely be mechanisms underlying the protective effect of bone marrow mesenchymal stem cells against spinal cord ischemia/reperfusion injury. PMID:25374587

  18. A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia

    Directory of Open Access Journals (Sweden)

    Simona Piemontese

    2017-01-01

    Full Text Available Abstract Background In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo versus matched (MUD 10/10 or mismatched unrelated donor at a single HLA-locus (MMUD 9/10 for patients with acute leukemia in remission. Methods Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups. Results The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS and overall survival (OS were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease. Conclusions Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD. Key point 1 Better outcomes using fully (10/10 matched unrelated donor for allo-SCT in acute leukemia in remission. Key point 2 Similar outcomes after allo

  19. Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India

    Directory of Open Access Journals (Sweden)

    Abhijeet Ganapule

    2017-12-01

    Full Text Available Purpose: There are limited data from developing countries on the role and cost-effectiveness of allogeneic stem cell transplantation (allo-SCT for patients with acute myeloid leukemia (AML. Patients and Methods: We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost-effectiveness of this therapeutic modality. Results: Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%. The 5-year overall survival (OS and event-free survival for the entire cohort was 40.1 ± 3.5% and 38.7 ± 3.4%, respectively. The 5-year OS for patients in first (CR1, second, and third complete remission and with disease/refractory AML was 53.1 ± 5.2%, 48.2 ± 8.3%, 31.2 ± 17.8%, and 16.0 ± 4.4%, respectively (P < .001. From 2007, reduced intensity conditioning (RIC with fludarabine and melphalan (Flu/Mel was used in a majority of patients in CR1 (n = 67. Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38. Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 ± 6.6% versus 38.1 ± 8.1% (P = .003 and 63.8 ± 6.4% versus 32.3 ± 7.9% (P = .002, respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion: In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients.

  20. Prophylactic antiviral therapy in allogeneic hematopoietic stem cell transplantation in hepatitis B virus patients.

    Science.gov (United States)

    Liao, Ya-Ping; Jiang, Jia-Lu; Zou, Wai-Yi; Xu, Duo-Rong; Li, Juan

    2015-04-14

    To investigate the timing, safety and efficacy of prophylactic antiviral therapy in patients with hepatitis B virus (HBV) infection undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This prospective study recruited a total of 57 patients diagnosed with malignant hematological diseases and HBV infection at the First Affiliated Hospital of Sun Yat-sen University between 2006 and 2013. The patients were classified as hepatitis B surface antigen (HBsAg)-positive or HBsAg-negative/ antiHBc-positive. Patients were treated with chemotherapy followed by antiviral therapy with nucleoside analogues. Patients underwent allo-HSCT when serum HBV DNA was antiviral therapy was continued for 1 year after the discontinuation of immunosuppressive therapy. A total of 105 patients who underwent allo-HSCT and had no HBV infection were recruited as controls. The three groups were compared for incidence of graft-vs-host disease (GVHD), drug-induced liver injury, hepatic veno-occlusive disease, death and survival time. A total of 29 of the 41 subjects with chronic GVHD exhibited extensive involvement and 12 exhibited focal involvement. Ten of the 13 subjects with chronic GVHD in the HBsAg(-)/hepatitis B core antibody(+) group exhibited extensive involvement and 3 exhibited focal involvement. Five of the 10 subjects with chronic GVHD in the HBsAg(+) group exhibited extensive involvement and 5 exhibited focal involvement. The non HBV-infected group did not differ significantly from the HBsAg-negative/antiHBc-positive and the HBsAg-positive groups which were treated with nucleoside analogues in the incidence of graft-vs-host disease (acute GVHD; 37.1%, 46.9% and 40%, respectively; P = 0.614; chronic GVHD; 39%, 40.6% and 40%, respectively; P = 0.98), drug-induced liver injury (25.7%, 18.7% and 28%, respectively; P = 0.7), death (37.1%, 40.6% and 52%, respectively; P = 0.4) and survival times (P = 0.516). One patient developed HBV reactivation (HBsAg-positivity) due to

  1. Migration capacity of human umbilical cord mesenchymal stem cells towards glioma in vivo

    Science.gov (United States)

    Fan, Cungang; Wang, Dongliang; Zhang, Qingjun; Zhou, Jingru

    2013-01-01

    High-grade glioma is the most common malignant primary brain tumor in adults. The poor prognosis of glioma, combined with a resistance to currently available treatments, necessitates the ment of more effective tumor-selective therapies. Stem cell-based therapies are emerging as novel cell-based delivery vehicle for therapeutic agents. In the present study, we successfully isolated human umbilical cord mesenchymal stem cells by explant culture. The human umbilical cord senchymal stem cells were adherent to plastic surfaces, expressed specific surface phenotypes of mesenchymal stem cells as demonstrated by flow cytometry, and possessed multi-differentiation potentials in permissive induction media in vitro. Furthermore, human umbilical cord mesenchymal stem cells demonstrated excellent glioma-specific targeting capacity in established rat glioma models after intratumoral injection or contralateral ventricular administration in vivo. The excellent glioma-specific targeting ability and extensive intratumoral distribution of human umbilical cord mesenchymal stem cells indicate that they may serve as a novel cellular vehicle for delivering therapeutic molecules in glioma therapy. PMID:25206518

  2. Gastrocnemius tendon strain in a dog treated with autologous mesenchymal stem cells and a custom orthosis.

    Science.gov (United States)

    Case, J Brad; Palmer, Ross; Valdes-Martinez, Alex; Egger, Erick L; Haussler, Kevin K

    2013-05-01

    To report clinical findings and outcome in a dog with gastrocnemius tendon strain treated with autologous mesenchymal stem cells and a custom orthosis. Clinical report. A 4-year-old spayed female Border Collie. Bone-marrow derived, autologous mesenchymal stem cells were transplanted into the tendon core lesion. A custom, progressive, dynamic orthosis was fit to the tarsus. Serial orthopedic examinations and ultrasonography as well as long-term force-plate gait analysis were utilized for follow up. Lameness subjectively resolved and peak vertical force increased from 43% to 92% of the contralateral pelvic limb. Serial ultrasonographic examinations revealed improved but incomplete restoration of normal linear fiber pattern of the gastrocnemius tendon. Findings suggest that autologous mesenchymal stem cell transplantation with custom, progressive, dynamic orthosis may be a viable, minimally invasive technique for treatment of calcaneal tendon injuries in dogs. © Copyright 2013 by The American College of Veterinary Surgeons.

  3. Does mesenchymal stem cell improve the liver regeneration after the 70% hepatectomy?

    Science.gov (United States)

    Alves, Ana Karina Soares; Lanzoni, Valéria; Fuziy, Rogério Aoki; Franco, Rita Maria Aparecida Monteiro Moura; Maeda, Carlos Toshinori; Lopes, Gaspar de Jesus; Linhares, Marcelo Moura

    2017-07-01

    To evaluate the effects of mesenchymal stem cells on liver regeneration in rats following a 70% hepatectomy. Forty rats were subjected to 70% hepatectomy and then ~106 mesenchymal stem cells (test group), or saline solution (control group), were infused into their livers via the portal vein. Each treatment group was divided into early and late subgroups (euthanized 3 d and 5 d following the operation, respectively). Group comparisons of Albumin, aminotransaminases (AST, ALT), and Alcaline Phosphatase (AP) levels, proliferative index (ki-67+ straining), and mitotic cell counts were conducted. No significant differences in liver regeneration rate, number of mitoses, proliferative index, or serum levels of albumin, AST, or AP were observed. ALT levels were higher in the test group than in the control group (p<.05). Mesenchymal stem-cell therapy did not improve liver regeneration rate 3 d or 5 d after 70% hepatectomy in rats. Likewise, the therapy appeared not to affect liver function, proliferative index, or number of mitoses significantly.

  4. Granulocytic Sarcoma by AML M4eo (inv16 after Allogeneic Stem Cell Transplantation without Bone Marrow Involvement

    Directory of Open Access Journals (Sweden)

    Stephan Zaenker

    2011-01-01

    Full Text Available Granulocytic sarcoma (GS represents a rare type of extramedullar manifestation from the acute myeloid leukaemia (AML. We report the case of a patient with recurrences of AML M4eo leukaemia in the uterus and the small intestine at 3 and 5 years, respectively, after matched related peripheral blood stem cell transplantation (PBSCT. The patient underwent the withdrawal of immunosuppression, hysterectomy, and local irradiation at first relapse, as well as systemic chemotherapy and donor lymphocyte infusions at second recurrence, inducing a second and third complete remission, respectively. At year six after transplantation, the patient experienced disease progression by meningeosis leukaemia to which she succumbed despite intrathecal chemotherapy. Following allogeneic stem cell transplantation, awareness for atypical manifestations of granulocytic sarcoma appears prudent, the cellular immunotherapy should aim at immunological disease control.

  5. The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate

    Directory of Open Access Journals (Sweden)

    Hamze Timari

    2017-12-01

    Full Text Available Hematopoietic stem cells (HSCs are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs. Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT and inhibition of graft versus host disease (GVHD. HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.

  6. Spontaneous transformation of adult mesenchymal stem cells from cynomolgus macaques in vitro

    International Nuclear Information System (INIS)

    Ren, Zhenhua; Wang, Jiayin; Zhu, Wanwan; Guan, Yunqian; Zou, Chunlin; Chen, Zhiguo; Zhang, Y. Alex

    2011-01-01

    Mesenchymal stem cells (MSCs) have shown potential clinical utility in cell therapy and tissue engineering, due to their ability to proliferate as well as to differentiate into multiple lineages, including osteogenic, adipogenic, and chondrogenic specifications. Therefore, it is crucial to assess the safety of MSCs while extensive expansion ex vivo is a prerequisite to obtain the cell numbers for cell transplantation. Here we show that MSCs derived from adult cynomolgus monkey can undergo spontaneous transformation following in vitro culture. In comparison with MSCs, the spontaneously transformed mesenchymal cells (TMCs) display significantly different growth pattern and morphology, reminiscent of the characteristics of tumor cells. Importantly, TMCs are highly tumorigenic, causing subcutaneous tumors when injected into NOD/SCID mice. Moreover, no multiple differentiation potential of TMCs is observed in vitro or in vivo, suggesting that spontaneously transformed adult stem cells may not necessarily turn into cancer stem cells. These data indicate a direct transformation of cynomolgus monkey MSCs into tumor cells following long-term expansion in vitro. The spontaneous transformation of the cultured cynomolgus monkey MSCs may have important implications for ongoing clinical trials and for models of oncogenesis, thus warranting a more strict assessment of MSCs prior to cell therapy. -- Highlights: ► Spontaneous transformation of cynomolgus monkey MSCs in vitro. ► Transformed mesenchymal cells lack multipotency. ► Transformed mesenchymal cells are highly tumorigenic. ► Transformed mesenchymal cells do not have the characteristics of cancer stem cells.

  7. Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity

    Directory of Open Access Journals (Sweden)

    Evelyne Beerling

    2016-03-01

    Full Text Available Forced overexpression and/or downregulation of proteins regulating epithelial-to-mesenchymal transition (EMT has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial-mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences.

  8. Spontaneous transformation of adult mesenchymal stem cells from cynomolgus macaques in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Zhenhua [Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing (China); Key Laboratory of Neurodegeneration, Ministry of Education, Beijing (China); Department of Anatomy, Anhui Medical University, Hefei, 230032 (China); Wang, Jiayin; Zhu, Wanwan; Guan, Yunqian; Zou, Chunlin [Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing (China); Key Laboratory of Neurodegeneration, Ministry of Education, Beijing (China); Chen, Zhiguo, E-mail: chenzhiguo@gmail.com [Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing (China); Key Laboratory of Neurodegeneration, Ministry of Education, Beijing (China); Stanford Institute for Stem Cell Biology and Regenerative Medicine and Department of Neurosurgery, Stanford, CA (United States); Zhang, Y. Alex, E-mail: yaz@bjsap.org [Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing (China); Key Laboratory of Neurodegeneration, Ministry of Education, Beijing (China)

    2011-12-10

    Mesenchymal stem cells (MSCs) have shown potential clinical utility in cell therapy and tissue engineering, due to their ability to proliferate as well as to differentiate into multiple lineages, including osteogenic, adipogenic, and chondrogenic specifications. Therefore, it is crucial to assess the safety of MSCs while extensive expansion ex vivo is a prerequisite to obtain the cell numbers for cell transplantation. Here we show that MSCs derived from adult cynomolgus monkey can undergo spontaneous transformation following in vitro culture. In comparison with MSCs, the spontaneously transformed mesenchymal cells (TMCs) display significantly different growth pattern and morphology, reminiscent of the characteristics of tumor cells. Importantly, TMCs are highly tumorigenic, causing subcutaneous tumors when injected into NOD/SCID mice. Moreover, no multiple differentiation potential of TMCs is observed in vitro or in vivo, suggesting that spontaneously transformed adult stem cells may not necessarily turn into cancer stem cells. These data indicate a direct transformation of cynomolgus monkey MSCs into tumor cells following long-term expansion in vitro. The spontaneous transformation of the cultured cynomolgus monkey MSCs may have important implications for ongoing clinical trials and for models of oncogenesis, thus warranting a more strict assessment of MSCs prior to cell therapy. -- Highlights: Black-Right-Pointing-Pointer Spontaneous transformation of cynomolgus monkey MSCs in vitro. Black-Right-Pointing-Pointer Transformed mesenchymal cells lack multipotency. Black-Right-Pointing-Pointer Transformed mesenchymal cells are highly tumorigenic. Black-Right-Pointing-Pointer Transformed mesenchymal cells do not have the characteristics of cancer stem cells.

  9. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells.

    Science.gov (United States)

    Chow, Lyndah; Johnson, Valerie; Regan, Dan; Wheat, William; Webb, Saiphone; Koch, Peter; Dow, Steven

    2017-12-01

    Mesenchymal stem cells (MSCs) exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC); as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC), including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders. Copyright © 2017. Published by Elsevier B.V.

  10. Towards Personalized Regenerative Cell Therapy: Mesenchymal Stem Cells Derived from Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Lin, Lin; Bolund, Lars; Luo, Yonglun

    2016-01-01

    Mesenchymal stem cells (MSCs) are adult stem cells with the capacity of self-renewal and multilineage differentiation, and can be isolated from several adult tissues. However, isolating MSCs from adult tissues for cell therapy is hampered by the invasive procedure, the rarity of the cells and their attenuated proliferation capacity when cultivated and expanded in vitro. Human MSCs derived from induced pluripotent stem cells (iPSC-MSCs) have now evolved as a promising alternative cell source for MSCs and regenerative medicine. Several groups, including ours, have reported successful derivation of functional iPSC-MSCs and applied these cells in MSC-based therapeutic testing. Still, the current experience and understanding of iPSC-MSCs with respect to production methods, safety and efficacy are primitive. In this review, we highlight the methodological progress in iPSC-MSC research, describing the importance of choosing the right sources of iPSCs, iPSC reprogramming methods, iPSC culture systems, embryoid body intermediates, pathway inhibitors, basal medium, serum, growth factors and culture surface coating. We also highlight some progress in the application of iPSC-MSCs in direct cell therapy, tissue engineering and gene therapy.

  11. Safety and immune regulatory properties of canine induced pluripotent stem cell-derived mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Lyndah Chow

    2017-12-01

    Full Text Available Mesenchymal stem cells (MSCs exhibit broad immune modulatory activity in vivo and can suppress T cell proliferation and dendritic cell activation in vitro. Currently, most MSC for clinical usage are derived from younger donors, due to ease of procurement and to the superior immune modulatory activity. However, the use of MSC from multiple unrelated donors makes it difficult to standardize study results and compare outcomes between different clinical trials. One solution is the use of MSC derived from induced pluripotent stem cells (iPSC; as iPSC-derived MSC have nearly unlimited proliferative potential and exhibit in vitro phenotypic stability. Given the value of dogs as a spontaneous disease model for pre-clinical evaluation of stem cell therapeutics, we investigated the functional properties of canine iPSC-derived MSC (iMSC, including immune modulatory properties and potential for teratoma formation. We found that canine iMSC downregulated expression of pluripotency genes and appeared morphologically similar to conventional MSC. Importantly, iMSC retained a stable phenotype after multiple passages, did not form teratomas in immune deficient mice, and did not induce tumor formation in dogs following systemic injection. We concluded therefore that iMSC were phenotypically stable, immunologically potent, safe with respect to tumor formation, and represented an important new source of cells for therapeutic modulation of inflammatory disorders.

  12. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Espinoza I

    2013-09-01

    Full Text Available Ingrid Espinoza,1,2 Radhika Pochampally,1,2 Fei Xing,1 Kounosuke Watabe,1,3 Lucio Miele1,4 1Cancer Institute, 2Department of Biochemistry, 3Department of Microbiology, 4Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA Abstract: Notch signaling is an evolutionarily conserved pathway involved in cell fate control during development, stem cell self-renewal, and postnatal tissue differentiation. Roles for Notch in carcinogenesis, the biology of cancer stem cells, tumor angiogenesis, and epithelial-to-mesenchymal transition (EMT have been reported. This review describes the role of Notch in the “stemness” program in cancer cells and in metastases, together with a brief update on the Notch inhibitors currently under investigation in oncology. These agents may be useful in targeting cancer stem cells and to reverse the EMT process. Keywords: Notch signaling, EMT, cancer stem cells, mesenchymal stem cells, metastases, Notch inhibitors

  13. Epigenetic modulation of cancer-germline antigen gene expression in tumorigenic human mesenchymal stem cells: implications for cancer therapy

    DEFF Research Database (Denmark)

    Gjerstorff, Morten; Burns, Jorge S; Nielsen, Ole

    2009-01-01

    Cancer-germline antigens are promising targets for cancer immunotherapy, but whether such therapies will also eliminate the primary tumor stem cell population remains undetermined. We previously showed that long-term cultures of telomerized adult human bone marrow mesenchymal stem cells can...... spontaneously evolve into tumor-initiating, mesenchymal stem cells (hMSC-TERT20), which have characteristics of clinical sarcoma cells. In this study, we used the hMSC-TERT20 tumor stem cell model to investigate the potential of cancer-germline antigens to serve as tumor stem cell targets. We found...... of cancer-germline antigens in hMSC-TERT20 cells, while their expression levels in primary human mesenchymal stem cells remained unaffected. The expression pattern of cancer-germline antigens in tumorigenic mesenchymal stem cells and sarcomas, plus their susceptibility to enhancement by epigenetic...

  14. Use of peripherally inserted central venous catheters (PICCs) in children receiving autologous or allogeneic stem-cell transplantation.

    Science.gov (United States)

    Benvenuti, Stefano; Ceresoli, Rosanna; Boroni, Giovanni; Parolini, Filippo; Porta, Fulvio; Alberti, Daniele

    2018-03-01

    The aim of our study was to present our experience with the use of peripherally inserted central catheters (PICCs) in pediatric patients receiving autologous or allogenic blood stem-cell transplantation. The insertion of the device in older children does not require general anesthesia and does not require a surgical procedure. From January 2014 to January 2017, 13 PICCs were inserted as a central venous device in 11 pediatric patients submitted to 14 autologous or allogeneic stem-cell transplantation, at the Bone Marrow Transplant Unit of the Children's Hospital of Brescia. The mean age of patients at the time of the procedure was 11.3 years (range 3-18 years). PICCs remained in place for an overall period of 4104 days. All PICCs were positioned by the same specifically trained physician and utilized by nurses of our stem-cell transplant unit. No insertion-related complications were observed. Late complications were catheter ruptures and line occlusions (1.2 per 1000 PICC days). No rupture or occlusion required removal of the device. No catheter-related venous thrombosis, catheter-related bloodstream infection (CRBSI), accidental removal or permanent lumen occlusion were observed. Indications for catheter removal were completion of therapy (8 patients) and death (2 patients). Three PICCs are currently being used for blood sampling in follow-up patients after transplantation. Our data suggest that PICCs are a safe and effective alternative to conventional central venous catheters even in pediatric patients with high risk of infectious and hemorrhagic complications such as patients receiving stem-cell transplantation.

  15. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Kühl, Jörn-Sven; Suarez, Felipe; Gillett, Godfrey T; Hemmati, Philipp G; Snowden, John A; Stadler, Michael; Vuong, Giang L; Aubourg, Patrick; Köhler, Wolfgang; Arnold, Renate

    2017-04-01

    The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols. © The Author (2017). Published

  16. Uniaxial cyclic strain of human adipose–derived mesenchymal stem cells and C2C12 myoblasts in coculture

    Directory of Open Access Journals (Sweden)

    James M Dugan

    2014-03-01

    Full Text Available Tissue engineering skeletal muscle in vitro is of great importance for the production of tissue-like constructs for treating tissue loss due to traumatic injury or surgery. However, it is essential to find new sources of cells for muscle engineering as efficient in vitro expansion and culture of primary myoblasts are problematic. Mesenchymal stem cells may be a promising source of myogenic progenitor cells and may be harvested in large numbers from adipose tissue. As skeletal muscle is a mechanically dynamic tissue, we have investigated the effect of cyclic mechanical strain on the myogenic differentiation of a coculture system of murine C2C12 myoblasts and human adipose–derived mesenchymal stem cells. Fusion of mesenchymal stem cells with nascent myotubes and expression of human sarcomeric proteins was observed, indicating the potential for myogenic differentiation of human mesenchymal stem cells. Cyclic mechanical strain did not affect the fusion of mesenchymal stem cells, but maturation of myotubes was perturbed.

  17. Mesenchymal Stem Cell-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Ameliorate Diabetic Polyneuropathy in Mice

    OpenAIRE

    Himeno, Tatsuhito; Kamiya, Hideki; Naruse, Keiko; Cheng, Zhao; Ito, Sachiko; Kondo, Masaki; Okawa, Tetsuji; Fujiya, Atsushi; Kato, Jiro; Suzuki, Hirohiko; Kito, Tetsutaro; Hamada, Yoji; Oiso, Yutaka; Isobe, Kenichi; Nakamura, Jiro

    2013-01-01

    Background. Although pathological involvements of diabetic polyneuropathy (DPN) have been reported, no dependable treatment of DPN has been achieved. Recent studies have shown that mesenchymal stem cells (MSCs) ameliorate DPN. Here we demonstrate a differentiation of induced pluripotent stem cells (iPSCs) into MSC-like cells and investigate the therapeutic potential of the MSC-like cell transplantation on DPN. Research Design and Methods. For induction into MSC-like cells, GFP-expressing iPSC...

  18. Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta-adrenergic stimulation.

    Science.gov (United States)

    Köse, Sevil; Aerts-Kaya, Fatima; Köprü, Çağla Zübeyde; Nemutlu, Emirhan; Kuşkonmaz, Barış; Karaosmanoğlu, Beren; Taşkıran, Ekim Zihni; Altun, Belgin; Uçkan Çetinkaya, Duygu; Korkusuz, Petek

    2018-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a well-known hematopoietic stem cell (HSC)-mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize a sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors CB1 and CB2. We suggest that eCBs may act as mobilizers of HSCs from the bone marrow (BM) under stress conditions as beta-adrenergic receptors (Adrβ). This study demonstrates that BM mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF-treated group compared with BM plasma. BM mononuclear cells (MNCs) and CD34 + HSCs express CB1, CB2, and Adrβ subtypes. CD34 + HSCs had higher CB1 and CB2 receptor expression in G-CSF-untreated and G-CSF-treated groups compared with MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry. AEA- and 2-AG-stimulated HSC migration was blocked by eCB receptor antagonists in an in vitro migration assay. In conclusion, components of the eCB system and their interaction with Adrβ subtypes were demonstrated on HSCs and MSCs of G-CSF-treated and G-CSF-untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  19. Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury

    DEFF Research Database (Denmark)

    Oliveri, Roberto S; Bello, Segun; Biering-Sørensen, Fin

    2013-01-01

    Traumatic spinal cord injury (SCI) is a devastating event with huge personal and societal costs. A limited number of treatments exist to ameliorate the progressive secondary damage that rapidly follows the primary mechanical impact. Mesenchymal stem or stromal cells (MSCs) have anti-inflammatory ......Traumatic spinal cord injury (SCI) is a devastating event with huge personal and societal costs. A limited number of treatments exist to ameliorate the progressive secondary damage that rapidly follows the primary mechanical impact. Mesenchymal stem or stromal cells (MSCs) have anti...

  20. Carriers in mesenchymal stem cell osteoblast mineralization-State-of-the-art

    DEFF Research Database (Denmark)

    Dahl, Morten; Jørgensen, Niklas Rye; Hørberg, Mette

    2014-01-01

    PURPOSE: Tissue engineering is a new way to regenerate bone tissue, where osteogenic capable cells combine with an appropriate scaffolding material. Our aim was in a Medline Search to evaluate osteoblast mineralization in vitro and in vivo including gene expressing combining mesenchymal stem cells...... (MSCs) and five different carriers, titanium, collagen, calcium carbonate, calcium phosphate and polylactic acid-polyglycolic acid copolymer for purpose of a meta-or a descriptive analysis. MATERIALS AND METHODS: The search included the following MeSH words in different combinations-mesenchymal stem...

  1. Transplanted Bone Marrow Mesenchymal Stem Cells Improve Memory in Rat Models of Alzheimer's Disease

    OpenAIRE

    Babaei, Parvin; Soltani Tehrani, Bahram; Alizadeh, Arsalan

    2012-01-01

    The present study aims to evaluate the effect of bone marrow mesenchymal stem cells (MSCs) grafts on cognition deficit in chemically and age-induced Alzheimer's models of rats. In the first experiments aged animals (30 months) were tested in Morris water maze (MWM) and divided into two groups: impaired memory and unimpaired memory. Impaired groups were divided into two groups and cannulated bilaterally at the CA1 of the hippocampus for delivery of mesenchymal stem cells ( 5 0 0 × 1 0 3 / ...

  2. Mesenchymal stem cells expressing baculovirus-engineered BMP-2 and VEGF enhance posterolateral spine fusion in a rabbit model.

    Science.gov (United States)

    Fu, Tsai-Sheng; Chang, Yu-Han; Wong, Chak-Bor; Wang, I-Chun; Tsai, Tsung-Ting; Lai, Po-Liang; Chen, Lih-Huei; Chen, Wen-Jer

    2015-09-01

    Mesenchymal stem cell (MSC)-based cell therapy and gene transfer have converged and show great potential for accelerating bone healing. Gene therapy can provide more sustained expression of osteogenic factors such as bone morphogenetic protein-2 (BMP-2). We previously demonstrated that low-dose BMP-2 enhanced spinal posterolateral fusion by MSCs in a rabbit model. Herein, we genetically modified rabbit MSCs with a recombinant baculovirus encoding BMP-2 (Bac-CB) and vascular endothelial growth factor (Bac-VEGF) seeded into porous scaffolds to enhance spinal fusion. This study evaluates the success rate of the MSC-based cell therapy and gene transfer approach for single-level posterolateral spine fusion. We hypothesize that combining three-dimensional tricalcium phosphate (TCP) scaffolds and genetically modified allogeneic MSCs with baculovirus-mediated growth factor expression would increase the success rate of spinal fusion. The study design was based on an animal model (approved by the Institutional Animal Care and Use Committee) using 18 adult male New Zealand rabbits. This study included 18 male New Zealand rabbits, weighing 3.5 to 4 kg. Allogeneic bone marrow-derived MSCs were isolated and genetically modified with Bac-CB and Bac-CV seeded onto TCP scaffolds (MSC/Bac/TCP). The animals were divided into three groups according to the material implanted into the bilateral L4-L5 intertransverse space: TCP scaffold (n=6), MSC/TCP (n=6), and MSC/Bac/TCP (n=6). After 12 weeks, the rabbits were euthanized for radiographic examination, manual palpation, and histologic study. Bilateral fusion areas in each animal were evaluated independently. The radiographic fusion rates at 12 sites were 0 of 12 in the TCP scaffold group, 4 of 12 in the MSC/TCP group, and 10 of 12 in the MSC/Bac/TCP group. By manual palpation, there were zero solid fusions in the TCP scaffold group, two solid fusions in the MSC/TCP group, and five solid fusions in the MSC/Bac/TCP group. Fusion rates

  3. Comparison among bone marrow mesenchymal stem and mononuclear cells to promote functional recovery after spinal cord injury in rabbits.

    Science.gov (United States)

    Fonseca, Antônio Filipe Braga; Scheffer, Jussara Peters; Giraldi-Guimarães, Arthur; Coelho, Bárbara Paula; Medina, Raphael Mansur; Oliveira, André Lacerda Abreu

    2017-12-01

    To investigate the efficacy of allogeneic mesenchymal stem-cells and autologous mononuclear cells to promote sensorimotor recovery and tissue rescue. Female rabbits were submitted to the epidural balloon inflation method and the intravenous cells administrations were made after 8 hours or seven days after injury induction. Sensorimotor evaluation of the hindlimbs was performed, and the euthanasia was made thirty days after the treatment. Spinal cords were stained with hematoxylin and eosin. Both therapies given 8 hours after the injury promoted the sensorimotor recovery after a week. Only the group treated after a week with mononuclear cells showed no significant recovery at post-injury day 14. In the days 21 and 28, all treatments promoted significant recovery. Histopathological analysis showed no difference among the experimental groups. Our results showed that both bone marrow-derived cell types promoted significant sensorimotor recovery after injury, and the treatment made at least a week after injury is efficient. The possibilities of therapy with bone marrow-derived cells are large, increasing the therapeutic arsenal for the treatment of spinal cord injury.

  4. Cotransplantation of Mesenchymal Stem Cells and Immature Dendritic Cells Potentiates the Blood Glucose Control of Islet Allografts

    Directory of Open Access Journals (Sweden)

    Guanghui Long

    2017-01-01

    Full Text Available Background. Transplantation of islets is a promising alternative to treat type 1 diabetes (T1D, but graft rejection is the major obstacle to its application in clinical practice. We evaluated the effects of mesenchymal stem cells (MSCs and immature dendritic cells (imDCs on islet transplantation in diabetic model. Methods. The streptozotocin T1D model was established in BABL/c mice. Rat islets were isolated and identified with dithizone (DTZ staining. MSCs and imDCs were isolated from bone marrow of syngenic mice. Islets, alone or along with MSCs and/or imDCs, were transplanted to the left kidney capsule of diabetic mice. The blood glucose levels and glycosylated hemoglobin levels after transplantation were monitored. Results. Cotransplantation significantly decreased blood glucose and glycosylated hemoglobin levels in the diabetes mice. Transplantation of 200 islets + 2 × 105 MSCs + 2 × 105 imDCs could not only restore normal blood glucose levels, but also significantly prolong graft survival for 12.6±3.48 days. Conclusions. Cotransplantation of allogenic islets with imDCs and/or MSCs can significantly promote graft survival, reverse hyperglycemia, and effectively control the glycosylated hemoglobin levels.

  5. Enhanced osseointegration of titanium implants in a rat model of osteoporosis using multilayer bone mesenchymal stem cell sheets

    Science.gov (United States)

    Duan, Yan; Ma, Wei; Li, Dehua; Wang, Tongfei; Liu, Baolin

    2017-01-01

    The present study aimed to investigate whether bone marrow-derived mesenchymal stem cell (BMSC) sheets combined with titanium implants enhanced implant osseointegration in an ovariectomized (OVX) rat model of osteoporosis. Sprague-Dawley rats were randomly assigned into a test group and control group. Allogenic BMSCs were collected from the rats, cultured and stored via cryopreservation. At 6 months post-ovariectomy, establishment of the OVX model was confirmed by micro-computed tomography (CT) measurements. BMSC sheets were subsequently layered and wrapped over titanium implants for implantation. Unmodified implants served as the control. At 8 weeks post-implantation, samples were observed by micro-CT reconstruction and histomorphometric evaluation. Micro-CT reconstruction identified a marked improvement in the surrounding bone volume following treatment, with data analyses indicating a significant increase in bone volume in the BMSC-implant group compared with the control implant group (Pimplant contact surrounding the BMSC-implant constructs. These results indicate that the use of BMSC sheets as a novel tissue engineering approach improves the osseointegration of titanium implants in an osteoporosis model. This method may expand the operative indications in patients with osteoporosis and improve the success rate of clinical dental implant treatments. PMID:29250137

  6. Isolation and characterization of exosome from human embryonic stem cell-derived c-myc-immortalized mesenchymal stem cells

    NARCIS (Netherlands)

    Lai, Ruenn Chai; Yeo, Ronne Wee Yeh; Padmanabhan, Jayanthi; Choo, Andre; De Kleijn, Dominique P V; Lim, Sai Kiang

    2016-01-01

    Mesenchymal stem cells (MSC) are currently the cell type of choice in many cell therapy trials. The number of therapeutic applications for MSCs registered as product IND submissions with the FDA and initiation of registered clinical trials has increased substantially in recent years, in particular

  7. Biological conduits combining bone marrow mesenchymal stem cells and extracellular matrix to treat long-segment sciatic nerve defects

    Directory of Open Access Journals (Sweden)

    Yang Wang

    2015-01-01

    Full Text Available The transplantation of polylactic glycolic acid conduits combining bone marrow mesenchymal stem cells and extracellular matrix gel for the repair of sciatic nerve injury is effective in some respects, but few data comparing the biomechanical factors related to the sciatic nerve are available. In the present study, rabbit models of 10-mm sciatic nerve defects were prepared. The rabbit models were repaired with autologous nerve, a polylactic glycolic acid conduit + bone marrow mesenchymal stem cells, or a polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel. After 24 weeks, mechanical testing was performed to determine the stress relaxation and creep parameters. Following sciatic nerve injury, the magnitudes of the stress decrease and strain increase at 7,200 seconds were largest in the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel group, followed by the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells group, and then the autologous nerve group. Hematoxylin-eosin staining demonstrated that compared with the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells group and the autologous nerve group, a more complete sciatic nerve regeneration was found, including good myelination, regularly arranged nerve fibers, and a completely degraded and resorbed conduit, in the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel group. These results indicate that bridging 10-mm sciatic nerve defects with a polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel construct increases the stress relaxation under a constant strain, reducing anastomotic tension. Large elongations under a constant physiological load can limit the anastomotic opening and shift, which is beneficial for the regeneration and functional reconstruction of sciatic nerve. Better

  8. Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibit proliferation of leukemia cells.

    Science.gov (United States)

    Ji, Yuan; Ma, Yongbin; Chen, Xiang; Ji, Xianyan; Gao, Jianyi; Zhang, Lei; Ye, Kai; Qiao, Fuhao; Dai, Yao; Wang, Hui; Wen, Xiangmei; Lin, Jiang; Hu, Jiabo

    2017-08-01

    Human embryonic stem cell derived-mesenchymal stem cells (hESC‑MSCs) are able to inhibit proliferation of leukemia cells. Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells (hESC‑MSC‑MVs) might play an important part in antitumor activity. Microvesicles were isolated by ultracentrifugation and identified under a scanning electron microscopy and transmission electron microscope separately. After 48-h cocultured with hESC‑MSCs and hESC‑MSC‑MVs, the number of K562 and HL60 was counted and tumor cell viability was measured by CCK8 assay. The expression of proteins Bcl-2 and Bax were estimated by western blotting. Transmission electron microscope and western blot analysis were adopted to evaluate the autophagy level. Results showed that both hESC‑MSCs and hESC‑MSC‑MVs inhibited proliferation of leukemia cells in a concentration-dependent manner. hESC‑MSC‑MVs reduced the ratio of Bcl/Bax, enhanced the protein level of Beclin-1 and LC3-II conversion, thus upregulating autophagy and apoptosis. In conclusion, microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibited tumor growth and stimulated autophagy and excessive autophagy might induce apoptosis.

  9. Comparison of periodontal ligament and gingiva-derived mesenchymal stem cells for regenerative therapies.

    Science.gov (United States)

    Santamaría, Silvia; Sanchez, Nerea; Sanz, Mariano; Garcia-Sanz, Jose A

    2017-05-01

    Tissue-engineering therapies using undifferentiated mesenchymal cells (MSCs) from intra-oral origin have been tested in experimental animals. This experimental study compared the characteristics of undifferentiated mesenchymal stem cells from either periodontal ligament or gingival origin, aiming to establish the basis for the future use of these cells on regenerative therapies. Gingiva-derived mesenchymal stem cells (GMSCs) were obtained from de-epithelialized gingival biopsies, enzymatically digested and expanded in conditions of exponential growth. Their growth characteristics, phenotype, and differentiation ability were compared with those of periodontal ligament-derived mesenchymal stem cells (PDLMSCs). Both periodontal ligament- and gingiva-derived cells displayed a MSC-like phenotype and were able to differentiate into osteoblasts, chondroblasts, and adipocytes. These cells were genetically stable following in vitro expansion and did not generate tumors when implanted in immunocompromised mice. Furthermore, under suboptimal growth conditions, GMSCs proliferated with higher rates than PDLMSCs. Stem cells derived from gingival biopsies represent bona fide MSCs and have demonstrated genetic stability and lack of tumorigenicity. Gingiva-derived MSCs may represent an accessible source of messenchymal stem cells to be used in future periodontal regenerative therapies.

  10. Influence of HLA Matching on the Efficacy of Allogeneic Mesenchymal Stromal Cell Therapies for Osteoarthritis and Degenerative Disc Disease

    Directory of Open Access Journals (Sweden)

    Javier García-Sancho, MD, PhD

    2017-09-01

    Conclusions. This lack of reactivity is presumably due to the cooperation of 2 factors, (1 downregulation of the host immune responses by the transplanted MSCs and (2 effective insulation of these cells inside the articular cavity or the intervertebral disc, respectively. Interestingly, better HLA matching did not enhance efficacy. These observations have medical relevance as they support the clinical use of allogeneic cells, at least as a single-dose administration. Multiple-dose applications will require further research to exclude possible sensitization.

  11. Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings

    NARCIS (Netherlands)

    Kroger, N.; Zabelina, T.; Wreede, L. de; Berger, J.; Alchalby, H.; Biezen, A. van; Milpied, N.; Volin, L.; Mohty, M.; Leblond, V.; Blaise, D.; Finke, J.; Schaap, N.P.; Robin, M.; Witte, T.J. de

    2013-01-01

    We investigated whether a young human leukocyte antigen (HLA)-matched unrelated donor (MUD) should be preferred as donor to an HLA-identical sibling (MRD) for older patients with myelodysplastic syndrome (MDS) (>/=50 years) who underwent allogeneic stem cell transplantation (AHSCT). Outcomes of 719

  12. Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma

    NARCIS (Netherlands)

    Lokhorst, H. M.; Sonneveld, P.; Cornelissen, J. J.; Joosten, P.; van Marwijk Kooy, M.; Meinema, J.; Nieuwenhuis, H. K.; van Oers, M. H.; Richel, D. J.; Segeren, C. N.; Veth, G.; Verdonck, L. F.; Wijermans, P. W.

    1999-01-01

    We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77

  13. Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study

    NARCIS (Netherlands)

    Raber-Durlacher, Judith E.; Laheij, Alexa M. G. A.; Epstein, Joel B.; Epstein, Matthew; Geerligs, Gerard M.; Wolffe, Gordon N.; Blijlevens, Nicole M. A.; Donnelly, J. Peter

    2013-01-01

    This study was aimed to investigate whether any association could be found between the presence of an inflamed and infected periodontium (e.g., gingivitis and periodontitis) and the development of bacteremia during neutropenia following allogeneic hematopoietic stem cell transplantation (HSCT).

  14. [Effects of catalase on human umbilical cord mesenchymal stem cells].

    Science.gov (United States)

    Hu, Lin-Ping; Gao, Ying-Dai; Zheng, Guo-Guang; Shi, Ying-Xu; Xie, Yin-Liang; Liu, Yong-Jun; Yuan, Wei-Ping; Cheng, Tao

    2010-04-01

    This study was aimed to investigate the growth and multiple differentiation potential of human umbilical cord tissue derived mesenchymal stem cells (UC-MSCs) transfected by a retroviral vector with catalase (CAT) gene. The UC-MSCs cultured in vitro were transfected by using pMSCV carrying GFP (pMSCV-GFP) and pMSCV carrying CAT (pMSCV-GFP-CAT) respectively, then the MSC-GFP cell line and MSC-GFP-CAT cell line were obtained by sorting of flow cytometry. The GFP expression was observed by a fluorescent microscopy at 48 hours after CAT gene transfection. The GFP+ cells were sorted by flow cytometry. The activity of CAT in GFP+ cells was detected by catalase assay kit. The proliferative capacity of transfected UC-MSCs was determined by cell counting kit-8. The differentiation ability of gene-transfected GFP+ cells into osteogenesis and adipogenesis was observed by von Kossa and oil red O staining. The results indicated that green fluorescence in UC-MSCs was observed at 48 hours after transfection, and the fluorescence gradually enhanced to a steady level on day 3. The percentage of MSCs-GFP was (25.54+/-8.65)%, while the percentage of MSCs-GFP-CAT was (35.4+/-18.57)%. The activity of catalase in UC-MSCs, MSCs-GFP, MSCs-GFP-CAT cells were 19.5, 20.3, 67.2 U, respectively. The transfected MSCs-GFP-CAT could be induced into osteoblasts and adipocytes. After 21 days, von Kossa staining showed induced osteoblasts. Many lipid droplets with high refractivity occurred in cytoplasm of the transfected UC-MSCs, and showed red fat granules in oil red O staining cells. There were no significant differences between transfected and non-transfected UC-MSCs cells (p>0.05). It is concluded that UC-MSCs are successfully transfected by retrovirus carrying GFP or CAT gene, the activity of catalase increased by 3.4-fold. The transfected UC-MSCs maintain proliferation potential and ability of differentiation into osteoblasts and adipocytes.

  15. Effects of sulfur mustard on mesenchymal stem cells.

    Science.gov (United States)

    Schmidt, Annette; Steinritz, Dirk; Rothmiller, Simone; Thiermann, Horst; Scherer, A Michael

    2017-08-14

    Chronic wound healing disorders that occur as a result of a sulfur mustard (SM) exposure present a particular challenge. These chronic wounds are similar to other chronic wounds. In the past, it has been shown that mesenchymal stem cells (MSC) play an important role in the healing of chronic wounds. An important property to support wound healing is their ability to migrate. However, we were able to show that SM leads to a reduction in MSC migration even at low concentrations. Currently, exposed MSCs are still able to differentiate. Further alterations are not known. The current investigation therefore focused onto the question how SM affects MSC. The effect of SM on MSC was investigated. Here, the alkylation of DNA was considered, and DNA adducts were quantified over a period of 48h. The modification of the nuclei under the influence of SM was analyzed as well as proliferation of the cells by immunohistochemical staining with Ki-67 and quantification. For the quantification of the apoptosis rate, antibodies against cleaved Caspase-3, 8, and apoptosis inducing factor (AIF) were used. The senescence analysis was performed after histological staining against β-galactosidase. Quantifications were carried out by using the TissueQuest System and the software TissueFAX. SM exposure of MSC results in a dose dependent formation of nuclear DNA adducts. 4h after exposure the cells display a decreasing concentration of DNA adducts. This process is accompanied by a change of nuclei shape but without an increase of apoptosis induction. In parallel the number of cells undergoing senescence increases as a function of the SM concentration. SM exposure of MSC leads to adduct formation on chromosomal DNA. These DNA adducts can be reduced without MSC are undergoing apoptosis. This indicates an active DNA damage response (DDR) pathway in combination with the formation of persistent nuclear DNA damage foci. This process is accompanied by a reduced capability of proliferation and a

  16. Effect of silver nanoparticles on human mesenchymal stem cell differentiation

    Directory of Open Access Journals (Sweden)

    Christina Sengstock

    2014-11-01

    Full Text Available Background: Silver nanoparticles (Ag-NP are one of the fastest growing products in nano-medicine due to their enhanced antibacterial activity at the nanoscale level. In biomedicine,