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Sample records for receiving hematopoietic stem

  1. 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.

  2. Hematopoietic Stem Cells Therapies.

    Science.gov (United States)

    Chivu-Economescu, Mihaela; Rubach, Martin

    2017-01-01

    Stem cell-based therapies are recognized as a new way to treat various diseases and injuries, with a wide range of health benefits. The goal is to heal or replace diseased or destroyed organs or body parts with healthy new cells provided by stem cell transplantation. The current practical form of stem cell therapy is the hematopoietic stem cells transplant applied for the treatment of hematological disorders. There are over 2100 clinical studies in progress concerning hematopoietic stem cell therapies. All of them are using hematopoietic stem cells to treat various diseases like: cancers, leukemia, lymphoma, cardiac failure, neural disorders, auto-immune diseases, immunodeficiency, metabolic or genetic disorders. Several challenges are to be addressed prior to developing and applying large scale cell therapies: 1) to explain and control the mechanisms of differentiation and development toward a specific cell type needed to treat the disease, 2) to obtain a sufficient number of desired cell type for transplantation, 3) to overcome the immune rejection and 4) to show that transplanted cells fulfill their normal functions in vivo after transplants. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. The Use of Intravenous Antibiotics at the Onset of Neutropenia in Patients Receiving Outpatient-Based Hematopoietic Stem Cell Transplants

    Science.gov (United States)

    Hamadah, Aziz; Schreiber, Yoko; Toye, Baldwin; McDiarmid, Sheryl; Huebsch, Lothar; Bredeson, Christopher; Tay, Jason

    2012-01-01

    Empirical antibiotics at the onset of febrile neutropenia are one of several strategies for management of bacterial infections in patients undergoing Hematopoietic Stem Cell Transplant (HSCT) (empiric strategy). Our HSCT program aims to perform HSCT in an outpatient setting, where an empiric antibiotic strategy was employed. HSCT recipients began receiving intravenous antibiotics at the onset of neutropenia in the absence of fever as part of our institutional policy from 01 Jan 2009; intravenous Prophylactic strategy. A prospective study was conducted to compare two consecutive cohorts [Year 2008 (Empiric strategy) vs. Year 2009 (Prophylactic strategy)] of patients receiving HSCT. There were 238 HSCTs performed between 01 Jan 2008 and 31 Dec 2009 with 127 and 111 in the earlier and later cohorts respectively. Infection-related mortality pre- engraftment was similar with a prophylactic compared to an empiric strategy (3.6% vs. 7.1%; p = 0.24), but reduced among recipients of autologous HSCT (0% vs. 6.8%; p = 0.03). Microbiologically documented, blood stream infections and clinically documented infections pre-engraftment were reduced in those receiving a prophylactic compared to an empiric strategy, (11.7% vs. 28.3%; p = 0.001), (9.9% vs. 24.4%; p = 0.003) and (18.2% vs. 33.9% p = 0.007) respectively. The prophylactic use of intravenous once-daily ceftriaxone in patients receiving outpatient based HSCT is safe and may be particularly effective in patients receiving autologous HSCT. Further studies are warranted to study the impact of this Prophylactic strategy in an outpatient based HSCT program. PMID:23029441

  4. Genotype-Directed Dosing Leads to Optimized Voriconazole Levels in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Teusink, Ashley; Vinks, Alexander; Zhang, Kejian; Davies, Stella; Fukuda, Tsuyoshi; Lane, Adam; Nortman, Shannon; Kissell, Diane; Dell, Sarah; Filipovich, Alexandra; Mehta, Parinda

    2016-03-01

    Invasive fungal infections are a significant cause of morbidity and mortality in recipients of hematopoietic stem cell transplantation (HSCT), warranting antifungal prophylaxis as a standard of care in these patients. Voriconazole is commonly used in this setting because of its broad-spectrum activity and available dosage forms. There is wide well-known inter- and intrapatient variability in voriconazole concentrations, in part because concentrations are affected by common CYP2C19 polymorphisms. In 2 successive studies we have optimized voriconazole dosing to achieve target voriconazole serum concentrations using a genotype-specific dosing algorithm for antifungal prophylaxis in the post-HSCT period. In our pilot study all patients undergoing HSCT who received voriconazole antifungal prophylaxis were prospectively followed. Voriconazole concentrations were monitored weekly and doses adjusted until concentrations reached between 1 and 5.5 μg/L. The most common CYP2C19 polymorphisms were determined and correlated with voriconazole dose and time required to reach the target concentration range. In the subsequent study patients receiving voriconazole prophylaxis were dosed based on their CYP2C19 genotype and followed prospectively. In the pilot study 25 patients received voriconazole as antifungal prophylaxis for a median of 49 days (range, 15 to 196 days). The median time to reach the target concentration was 34 days for extensive metabolizers and 11 days for poor metabolizers. Three patients were genotyped as intermediate metabolizers; they reached the target concentration in a median of 56 days. Similarly, 2 patients who were genotyped as ultrarapid metabolizers reached the target range in 18 and 25 days. The time and dose required to reach the adequate concentration showed a trend toward correlation with individual CYP2C19 genotype, although voriconazole concentrations showed large interpatient variability in wild-type patients (extensive metabolizers). In our

  5. Elevated fluoride levels and periostitis in pediatric hematopoietic stem cell transplant recipients receiving long-term voriconazole.

    Science.gov (United States)

    Tarlock, Katherine; Johnson, Darren; Cornell, Cathy; Parnell, Shawn; Meshinchi, Soheil; Baker, K Scott; Englund, Janet A

    2015-05-01

    Azole therapy is widely utilized in hematopoietic stem cell transplant (HCT) recipients for the treatment of aspergillus. Complications of voriconazole treatment related to its elevated fluoride content have been described in adults, including reports of symptomatic skeletal fluorosis. We review fluoride levels, clinical, and laboratory data in five pediatric HCT recipients on long-term voriconazole therapy, all found to have elevated serum fluoride levels. Two patients had toxic fluoride levels, one infant had symptoms of significant pain with movement and radiographs confirmed skeletal fluorosis. Monitoring fluoride levels in children, especially with skeletal symptoms, should be considered in patients on long-term voriconazole. © 2014 Wiley Periodicals, Inc.

  6. Thrombopoietin and hematopoietic stem cells

    OpenAIRE

    de Graaf, Carolyn A; Metcalf, Donald

    2011-01-01

    Thrombopoietin (TPO) is the cytokine that is chiefly responsible for megakaryocyte production but increasingly attention has turned to its role in maintaining hematopoietic stem cells (HSCs). HSCs are required to initiate the production of all mature hematopoietic cells, but this differentiation needs to be balanced against self-renewal and quiescence to maintain the stem cell pool throughout life. TPO has been shown to support HSC quiescence during adult hematopoiesis, with the loss of TPO s...

  7. Neurocognitive Trajectory of Boys Who Received a Hematopoietic Stem Cell Transplant at an Early Stage of Childhood Cerebral Adrenoleukodystrophy.

    Science.gov (United States)

    Pierpont, Elizabeth I; Eisengart, Julie B; Shanley, Ryan; Nascene, David; Raymond, Gerald V; Shapiro, Elsa G; Ziegler, Rich S; Orchard, Paul J; Miller, Weston P

    2017-06-01

    Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT. To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning. Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity). Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function. Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = -0.340; P = .008), perceptual reasoning (r = -0.419; P = .001), and processing speed (r = -0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment

  8. Thrombopoietin and hematopoietic stem cells

    Science.gov (United States)

    de Graaf, Carolyn A

    2011-01-01

    Thrombopoietin (TPO) is the cytokine that is chiefly responsible for megakaryocyte production but increasingly attention has turned to its role in maintaining hematopoietic stem cells (HSCs). HSCs are required to initiate the production of all mature hematopoietic cells, but this differentiation needs to be balanced against self-renewal and quiescence to maintain the stem cell pool throughout life. TPO has been shown to support HSC quiescence during adult hematopoiesis, with the loss of TPO signaling associated with bone marrow failure and thrombocytopenia. Recent studies have shown that constitutive activation mutations in Mpl contribute to myeloproliferative disease. In this review, we will discuss TPO signaling pathways, regulation of TPO levels and the role of TPO in normal hematopoiesis and during myeloproliferative disease. PMID:21478671

  9. Hematopoietic stem cell mobilization: updated conceptual renditions

    Science.gov (United States)

    Bonig, H; Papayannopoulou, T

    2013-01-01

    Despite its specific clinical relevance, the field of hematopoietic stem cell mobilization has received broad attention, owing mainly to the belief that pharmacologic stem cell mobilization might provide clues as to how stem cells are retained in their natural environment, the bone marrow ‘niche’. Inherent to this knowledge is also the desire to optimally engineer stem cells to interact with their target niche (such as after transplantation), or to lure malignant stem cells out of their protective niches (in order to kill them), and in general to decipher the niche’s structural components and its organization. Whereas, with the exception of the recent addition of CXCR4 antagonists to the armamentarium for mobilization of patients refractory to granulocyte colony-stimulating factor alone, clinical stem cell mobilization has not changed significantly over the last decade or so, much effort has been made trying to explain the complex mechanism(s) by which hematopoietic stem and progenitor cells leave the marrow. This brief review will report some of the more recent advances about mobilization, with an attempt to reconcile some of the seemingly inconsistent data in mobilization and to interject some commonalities among different mobilization regimes. PMID:22951944

  10. Cytokines regulating hematopoietic stem cell function.

    Science.gov (United States)

    Zhang, Cheng C; Lodish, Harvey F

    2008-07-01

    Regulation of the multiple fates of hematopoietic stem cells - including quiescence, self-renewal, differentiation, apoptosis, and mobilization from the niche - requires the cooperative actions of several cytokines and other hormones that bind to receptors on these cells. In this review we discuss recent advances in the identification of novel hematopoietic stem cell supportive cytokines and the mechanisms by which they control hematopoietic stem cell fate decisions. Several extrinsic factors that stimulate ex-vivo expansion of hematopoietic stem cells were recently identified by a number of experimental approaches, including forward genetic screening and transcriptional profiling of supportive stromal cells. Recent experiments in which multiple cytokine signaling pathways are activated or suppressed in hematopoietic stem cells reveal the complexity of signal transduction and cell-fate choice in hematopoietic stem cells in vivo and in vitro. The study of genetically modified mice and improvements in the in-vitro hematopoietic stem cell culture system will be powerful tools to elucidate the functions of cytokines that regulate hematopoietic stem cell function. These will further reveal the complex nature of the mechanisms by which extrinsic factors regulate signal transduction and cell-fate decisions of hematopoietic stem cells.

  11. [Retrospective study of the implementation of the qualitative PCR technique in biological samples for monitoring toxoplasmosis in pediatric patients receiving hematopoietic stem cell transplantation].

    Science.gov (United States)

    Nigro, Mónica G; Figueroa, Carlos; Ledesma, Bibiana A

    2014-01-01

    Toxoplasmosis is an opportunistic infection caused by the parasite Toxoplasma gondii. The infection is severe and difficult to diagnose in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twelve patients receiving HSCT were monitored post-transplant, by qualitative PCR at the Children's Hospital S.A.M.I.C. "Prof. Dr. Juan P. Garrahan". The monitoring of these patients was defined by a history of positive serology for toxoplasmosis in the donor or recipient and because their hematologic condition did not allow the use of trimethoprim-sulfamethoxazole for prophylaxis. During the patients' monitoring, two of them with positive PCR results showed signs of illness by T. gondii and were treated with pyrimethamine-clindamycin. In two other patients, toxoplasmosis was the cause of death and an autopsy finding, showing negative PCR results. Four patients without clinical manifestations received treatment for toxoplasmosis because of positive PCR detection. In four patients there were no signs of toxoplasmosis disease and negative PCR results during follow-up. The qualitative PCR technique proved useful for the detection of toxoplasmosis reactivation in HSCT recipients, but has limitations in monitoring and making clinical decisions due to the persistence of positive PCR over time and manifestations of toxicity caused by the treatment. Copyright © 2014 Asociación Argentina de Microbiología. Publicado por Elsevier España. All rights reserved.

  12. Recent advances in hematopoietic stem cell biology

    DEFF Research Database (Denmark)

    Bonde, Jesper; Hess, David A; Nolta, Jan A

    2004-01-01

    PURPOSE OF REVIEW: Exciting advances have been made in the field of hematopoietic stem cell biology during the past year. This review summarizes recent progress in the identification, culture, and in vivo tracking of hematopoietic stem cells. RECENT FINDINGS: The roles of Wnt and Notch proteins...... made recently in the field of stem cell biology, researchers now have improved tools to define novel populations of stem cells, examine them ex vivo using conditions that promote self-renewal, track them into recipients, and determine whether they can contribute to the repair of damaged tissues...

  13. Molecular regulation of human hematopoietic stem cells

    NARCIS (Netherlands)

    van Galen, P.L.J.

    2014-01-01

    Peter van Galen focuses on understanding the determinants that maintain the stem cell state. Using human hematopoietic stem cells (HSCs) as a model, processes that govern self-renewal and tissue regeneration were investigated. Specifically, a role for microRNAs in balancing the human HSC

  14. Autonomous behavior of hematopoietic stem cells

    NARCIS (Netherlands)

    Kamminga, LM; Akkerman, [No Value; Weersing, E; Ausema, A; Dontje, B; Van Zant, G; de Haan, G

    2000-01-01

    Objective. Mechanisms that affect the function of primitive hematopoietic stem cells with long-term proliferative potential remain largely unknown. Here we assessed whether properties of stem cells are cell-extrinsically or cell-autonomously regulated. Materials and Methods. We developed a model in

  15. Thrombopoietin expands hematopoietic stem cells after transplantation

    OpenAIRE

    Fox, Norma; Priestley, Greg; Papayannopoulou, Thalia; Kaushansky, Kenneth

    2002-01-01

    Multiple lines of evidence indicate that thrombopoietin (TPO) contributes to the development of hematopoietic stem cells (HSC), supporting their survival and proliferation in vitro. To determine whether TPO supports the impressive expansion of HSC observed following transplantation, we transplanted normal marrow cells into lethally irradiated Tpo–/– and Tpo+/+ mice and quantified HSC self-renewal and expansion and hematopoietic progenitor cell homing. Although essentially identical numbers of...

  16. [Hematopoietic reconstitution and prognosis of different types of hematopoietic stem cell transplantation for severe aplastic anemia].

    Science.gov (United States)

    Lu, Jing; Wu, Depei; Hu, Shaoyan; Jin, Song; Wang, Xiuli; Miao, Miao; Chen, Jia; Han, Yue; Tang, Xiaowen; Qiu, Huiying; Sun, Aining; Jin, Zhengming; Fu, Chengcheng; Ma, Xiao; Chen, Feng

    2015-08-01

    To compare the differences between hematopoietic reconstitution and longterm prognosis of patients with severe aplastic anemia (SAA) after HLA- matched sibling donor hematopoietic stem cell transplantation(MSD-HSCT), Haploidentical HSCT(Haplo-HSCT), unrelated donor allogeneic HSCT(UD-HSCT)and umbilical cord blood HSCT(UCB-HSCT). In this retrospective study, 63 patients with SAA who received HSCT in the First Affiliated Hospital of Soochow University between May 2008 and December 2013 were enrolled. The subjects were divided into 4 groups according to the transplantation types. The hematopoietic reconstitution, the incidence of acute graft-versushost disease(aGVHD)and 5- year survival rate after transplantation were compared. All 53 subjects who received MSD-HSCT, Haplo-HSCT and UD-HSCT achieved hematopoietic reconstitution. Of them, the recovery of neutrophil and platelet were not significantly different(P0.05). MSD-HSCT, Haplo-HSCT and UD-HSCT had no statistically significance in terms of hematopoietic reconstitution or prognosis. Although hematopoietic reconstitution of UCB-HSCT was lower than other transplantation types, but no significant difference in overall prognosis. So if HLA-matched sibling donor is not available, SAA patients can choose Haplo- HSCT, UD - HSCT or UCB- HSCT with comparable efficacy to MSD- HSCT, as an alternative therapy.

  17. Ex vivo Expansion of Hematopoietic Stem Cells

    NARCIS (Netherlands)

    E. Farahbakhshian (Elnaz)

    2013-01-01

    textabstractHematopoiesis is a complex cellular differentiation process resulting in the formation of all blood cell types. In this process, hematopoietic stem cells (HSCs) reside at the top of the hematopoiesis hierarchy and have the capacity to differentiate into all blood cell lineages

  18. Cellular memory and, hematopoietic stem cell aging

    NARCIS (Netherlands)

    Kamminga, Leonie M.; de Haan, Gerald

    Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss

  19. Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey.

    Science.gov (United States)

    Yıldıran, Alişan; Çeliksoy, Mehmet Halil; Borte, Stephan; Güner, Şükrü Nail; Elli, Murat; Fışgın, Tunç; Özyürek, Emel; Sancak, Recep; Oğur, Gönül

    2017-12-01

    Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years) with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11), Chediak-Higashi syndrome (n=2), leukocyte adhesion deficiency (n=2), MHC class 2 deficiency (n=2), chronic granulomatous syndrome (n=2), hemophagocytic lymphohistiocytosis (n=1), Wiskott-Aldrich syndrome (n=1), and Omenn syndrome (n=1). Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

  20. Proteomic cornerstones of hematopoietic stem cell differentiation

    DEFF Research Database (Denmark)

    Klimmeck, Daniel; Hansson, Jenny; Raffel, Simon

    2012-01-01

    Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors...... which differentiate into lineage committed progenitors and subsequently mature cells. In this report, we applied an in-depth quantitative proteomic approach to analyze and compare the full proteomes of ex vivo isolated and FACS-sorted populations highly enriched for either multipotent hematopoietic stem...... evaluation, 893 proteins were found differentially expressed between multipotent and myeloid committed cells. The differential protein content in these cell populations points to a distinct structural organization of the cytoskeleton including remodeling activity. In addition, we found a marked difference...

  1. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells

    Science.gov (United States)

    2013-01-01

    Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells. PMID:23796405

  2. Symptoms after hospital discharge following hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Gamze Oguz

    2014-01-01

    Full Text Available Aims: The purposes of this study were to assess the symptoms of hematopoietic stem cell transplant patients after hospital discharge, and to determine the needs of transplant patients for symptom management. Materials and Methods: The study adopted a descriptive design. The study sample comprised of 66 hematopoietic stem cell transplant patients. The study was conducted in Istanbul. Data were collected using Patient Information Form and Memorial Symptom Assessment Scale (MSAS. Results: The frequency of psychological symptoms in hematopoietic stem cell transplant patients after discharge period (PSYCH subscale score 2.11 (standard deviation (SD = 0.69, range: 0.93-3.80 was higher in hematopoietic stem cell transplant patients than frequency of physical symptoms (PHYS subscale score: 1.59 (SD = 0.49, range: 1.00-3.38. Symptom distress caused by psychological and physical symptoms were at moderate level (Mean = 1.91, SD = 0.60, range: 0.95-3.63 and most distressing symptoms were problems with sexual interest or activity, difficulty sleeping, and diarrhea. Patients who did not have an additional chronic disease obtained higher MSAS scores. University graduates obtained higher Global Distress Index (GDI subscale and total MSAS scores with comparison to primary school graduates. Total MSAS, MSAS-PHYS subscale, and MSAS-PSYCH subscale scores were higher in patients with low level of income (P < 0.05. The patients (98.5% reported to receive education about symptom management after hospital discharge. Conclusions: Hematopoietic stem cell transplant patients continue to experience many distressing physical or psychological symptoms after discharge and need to be supported and educated for the symptom management.

  3. Hematopoietic Stem Cell Development and Transcriptional Regulation

    OpenAIRE

    Gekas, Christos

    2008-01-01

    The continuous production of blood cells, a process termed hematopoiesis, is sustained throughout the lifetime of an individual by a relatively small population of cells known as hematopoietic stem cells (HSCs). HSCs are unique cells characterized by their ability to self-renew and give rise to all types of mature blood cells. Given their high proliferative potential, HSCs need to be tightly regulated on the cellular and molecular levels or could otherwise turn malignant. On the other hand, t...

  4. Monitoring of Human Cytomegalovirus and Virus-Specific T-Cell Response in Young Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Lilleri, Daniele; Gerna, Giuseppe; Zelini, Paola; Chiesa, Antonella; Rognoni, Vanina; Mastronuzzi, Angela; Giorgiani, Giovanna; Zecca, Marco; Locatelli, Franco

    2012-01-01

    In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, outcome of human cytomegalovirus (HCMV) infection results from balance between viral load/replication and pathogen-specific T-cell response. Using a cut-off of 30,000 HCMV DNA copies/ml blood for pre-emptive therapy and cut-offs of 1 and 3 virus-specific CD4+ and CD8+ T cells/µl blood for T-cell protection, we conducted in 131 young patients a prospective 3-year study aimed at verifying whether achievement of such immunological cut-offs protects from HCMV disease. In the first three months after transplantation, 55/89 (62%) HCMV-seropositive patients had infection and 36/55 (65%) were treated pre-emptively, whereas only 7/42 (17%) HCMV-seronegative patients developed infection and 3/7 (43%) were treated. After 12 months, 76 HCMV-seropositive and 9 HCMV-seronegative patients (cumulative incidence: 90% and 21%, respectively) displayed protective HCMV-specific immunity. Eighty of these 85 (95%) patients showed spontaneous control of HCMV infection without additional treatment. Five patients after reaching protective T-cell levels needed pre-emptive therapy, because they developed graft-versus-host disease (GvHD). HSCT recipients reconstituting protective levels of HCMV-specific T-cells in the absence of GvHD are no longer at risk for HCMV disease, at least within 3 years after transplantation. The decision to treat HCMV infection in young HSCT recipients may be taken by combining virological and immunological findings. PMID:22848556

  5. Strength Training Following Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Hacker, Eileen Danaher; Larson, Janet; Kujath, Amber; Peace, David; Rondelli, Damiano; Gaston, Lisa

    2010-01-01

    Background Patients receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) experience considerable reductions in physical activity and deterioration of their health status. Objective The purpose of this pilot study was to test the effects of strength training compared to usual activity on physical activity, muscle strength, fatigue, health status perceptions, and quality of life following HSCT. Interventions/Methods Nineteen subjects were randomized to the exercise or control group. Moderate intensity strength training began following discharge from the hospital. Dependent variables included physical activity, muscle strength, fatigue, health status perceptions and quality of life. Variables were measured prior to admission to the hospital for HSCT, day 8 following HSCT, and six weeks following discharge from the hospital. Results Significant time effects were noted for many variables with anticipated declines in physical activity, muscle strength, fatigue, and health status perceptions immediately after HSCT with subsequent improvements six weeks following hospital discharge. One group effect was noted with subjects in the exercise group reporting less fatigue than subjects in the control group. Although no significant interactions were detected, the trends suggest that the exercise group may be more physically active following the intervention compared to the usual activity group. Conclusions This study demonstrates the potential positive effects of strength training on physical activity, fatigue, and quality of life in people receiving high-dose chemotherapy and HSCT. Implications for Practice Preliminary evidence is provided for using strength training to enhance early recovery following HSCT. Elastic resistance bands are easy to use and relatively inexpensive. PMID:21116175

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  9. File list: His.Bld.10.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

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  10. Epigenetic regulation of hematopoietic stem cell aging

    Energy Technology Data Exchange (ETDEWEB)

    Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States); Rossi, Derrick J. [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States)

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  11. Hematopoietic stem cell transplantation in multiple sclerosis

    DEFF Research Database (Denmark)

    Rogojan, C; Frederiksen, J L

    2009-01-01

    Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least...... in restoration of self-tolerance. Relatively young patients with active inflammatory lesions of relatively short duration and rapidly progressive disease, but still low disability scores, unresponsive to conventional therapy seem the best candidates for transplantation. Transplant-related mortality was 6...

  12. Oral changes in individuals undergoing hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Regina Haddad Barrach

    2015-04-01

    Full Text Available INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation receive high doses of chemotherapy and radiotherapy, which cause severe immunosuppression.OBJECTIVE: To report an oral disease management protocol before and after hematopoietic stem cell transplantation.METHODS: A prospective study was carried out with 65 patients aged > 18 years, with hematological diseases, who were allocated into two groups: A (allogeneic transplant, 34 patients; B (autologous transplant, 31 patients. A total of three dental status assessments were performed: in the pre-transplantation period (moment 1, one week after stem cell infusion (moment 2, and 100 days after transplantation (moment 3. In each moment, oral changes were assigned scores and classified as mild, moderate, and severe risks.RESULTS: The most frequent pathological conditions were gingivitis, pericoronitis in the third molar region, and ulcers at the third moment assessments. However, at moments 2 and 3, the most common disease was mucositis associated with toxicity from the drugs used in the immunosuppression.CONCLUSION: Mucositis accounted for the increased score and potential risk of clinical complications. Gingivitis, ulcers, and pericoronitis were other changes identified as potential risk factors for clinical complications.

  13. Oral changes in individuals undergoing hematopoietic stem cell transplantation.

    Science.gov (United States)

    Barrach, Regina Haddad; Souza, Mair Pedro de; Silva, Daniela Polo Camargo da; Lopez, Priscila Suman; Montovani, Jair Cortez

    2015-01-01

    Patients undergoing hematopoietic stem cell transplantation receive high doses of chemotherapy and radiotherapy, which cause severe immunosuppression. To report an oral disease management protocol before and after hematopoietic stem cell transplantation. A prospective study was carried out with 65 patients aged>18 years, with hematological diseases, who were allocated into two groups: A (allogeneic transplant, 34 patients); B (autologous transplant, 31 patients). A total of three dental status assessments were performed: in the pre-transplantation period (moment 1), one week after stem cell infusion (moment 2), and 100 days after transplantation (moment 3). In each moment, oral changes were assigned scores and classified as mild, moderate, and severe risks. The most frequent pathological conditions were gingivitis, pericoronitis in the third molar region, and ulcers at the third moment assessments. However, at moments 2 and 3, the most common disease was mucositis associated with toxicity from the drugs used in the immunosuppression. Mucositis accounted for the increased score and potential risk of clinical complications. Gingivitis, ulcers, and pericoronitis were other changes identified as potential risk factors for clinical complications. Copyright © 2014 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  14. Mobilization of hematopoietic stem and progenitor cells in mice

    NARCIS (Netherlands)

    Robinson, Simon N; van Os, Ronald P; Bunting, Kevin

    2008-01-01

    Animal models have added significantly to our understanding of the mechanism(s) of hematopoietic stem and progenitor cell (HSPC) mobilization. Such models suggest that changes in the interaction between the HSPC and the hematopoietic microenvironmental 'niche' (cellular and extracellular components)

  15. Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia

    Science.gov (United States)

    Lucarelli, Guido; Isgrò, Antonella; Sodani, Pietro; Gaziev, Javid

    2012-01-01

    The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class–based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation. PMID:22553502

  16. Interleukin-7 and hematopoietic stem cell transplantation: beyond the thymus

    NARCIS (Netherlands)

    A.E. Broers (Anna Elisabeth Clasine)

    2007-01-01

    textabstractAllogeneic stem cell transplantation (allo-SCT) has been established as important treatment modality for patients with hematological malignancies, aplastic anemia, and inborn errors of hematopoietic progenitor cells. Nevertheless, major lethal and non-lethal complications

  17. Latexin is a newly discovered regulator of hematopoietic stem cells

    NARCIS (Netherlands)

    de Haan, Gerald

    Deeply hidden in the bone marrow are rare hematopoietic stem cells that produce all types of blood cells in the circulatory system. A new study shows that the latexin gene affects the size of this population of cells.

  18. Hematopoietic stem cells: concepts, definitions, and the new reality

    National Research Council Canada - National Science Library

    Eaves, Connie J

    2015-01-01

    Hematopoietic stem cell (HSC) research took hold in the 1950s with the demonstration that intravenously injected bone marrow cells can rescue irradiated mice from lethality by reestablishing blood cell production...

  19. Hematopoietic stem cell transplantation in Algeria.

    Science.gov (United States)

    Bekadja, Mohamed Amine; Brahimi, Mohamed; Osmani, Soufi; Yafour, Nabil; Krim, Amina; Serradj, Faiza; Talhi, Souad; Amani, Kamila; Bouhass, Rachid Amar

    2017-07-11

    Algeria is a country of 40.4 million inhabitants and half of which is under 30years. In Algeria, Health-care insurance covered, 90% of the population. Health care is free and it is supported by the Ministry of Health. 16 university hospitals exist in Algeria and only two (Algiers and Oran) practicing bone marrow transplant. Adult hematologic malignancies account for 10% (about 4000 new cases/year) of the malignancy affecting in most cases young patients under 65years of age. In 2016, 270 transplants were performed in total (Algiers+Oran), including 149 allografts (related donor transplants: 99%) and 121 autografts. 98% of transplants are done in adults and only 2% in children with cord blood transplants. In summary for the two transplant centers, the predominant types of transplantation performed are allogeneic transplant in 55% and autologous transplant in 45%. The particularity of EHU1st November in Oran, is the use of non-cryopreserved stem cells. Stem cell was mobilized using G-CSF alone and the grafts were kept in a conventional blood bank refrigerator at +4°C until reinfusion on day 0. The outcome with non-cryopreserved stem cells are the same as those with cryopreserved stem cells and we conclude that autologous transplant with non cryopreserved hematopoietic stem cells (HSC) is a simple, effective and safe method and the cryopreservation is not necessary in our work conditions in developing countries. The projects are achieving the autograft in all University Hospitals with non cryopreserved HSC, achieving a center allograft in the east of the country and the development of bone marrow transplantation in children. Currently in Algeria, the number of transplantation is insufficient and the development of new transplant centers is essential. In the future, we hope to implement the National Society of Bone Marrow transplant and also the National recipient registry and Donor registry in Algeria. Copyright © 2017 King Faisal Specialist Hospital & Research

  20. Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development

    Science.gov (United States)

    Robin, Catherine; Bollerot, Karine; Mendes, Sandra; Haak, Esther; Crisan, Mihaela; Cerisoli, Francesco; Lauw, Ivoune; Kaimakis, Polynikis; Jorna, Ruud; Vermeulen, Mark; Kayser, Manfred; van der Linden, Reinier; Imanirad, Parisa; Verstegen, Monique; Nawaz-Yousaf, Humaira; Papazian, Natalie; Steegers, Eric; Cupedo, Tom; Dzierzak, Elaine

    2009-01-01

    Hematopoietic stem cells (HSC) are responsible for the life-long production of the blood system and are pivotal cells in hematologic transplantation therapies. During mouse and human development, the first HSCs are produced in the aorta-gonad-mesonephros region. Subsequent to this emergence, HSCs are found in other anatomical sites of the mouse conceptus. While the mouse placenta contains abundant HSCs at midgestation, little is known concerning whether HSCs or hematopoietic progenitors are present and supported in the human placenta during development. In this study we show, over a range of developmental times including term, that the human placenta contains hematopoietic progenitors and HSCs. Moreover, stromal cell lines generated from human placenta at several developmental time points are pericyte-like cells and support human hematopoiesis. Immunostaining of placenta sections during development localizes hematopoietic cells in close contact with pericytes/perivascular cells. Thus, the human placenta is a potent hematopoietic niche throughout development. PMID:19796619

  1. Major complications following hematopoietic stem cell transplantation.

    Science.gov (United States)

    Afessa, Bekele; Peters, Steve G

    2006-06-01

    Tens of thousands of patients undergo hematopoietic stem cell transplantation (HSCT) annually, 15 to 40% of whom are admitted to the intensive care unit. Pulmonary complications are the most life threatening conditions that develop in HSCT recipients. Both infectious and noninfectious complications occur more frequently in allogeneic HSCT. The management of HSCT recipients requires knowledge of their immune status, appropriate diagnostic evaluation, and early treatment. During the pre-engraftment phase (0 to 30 days after transplant), the most prevalent pathogens causing infection are bacteria and Candida species and, if the neutropenia persists, Aspergillus species. The early post-engraftment phase (30 to 100 days) is characterized by cytomegalovirus (CMV), Pneumocystis jiroveci, and Aspergillus infections. During the late posttransplant phase (> 100 days), allogeneic HSCT recipients are at risk for CMV, community-acquired respiratory virus, and encapsulated bacterial infections. Antigen and polymerase chain reaction assays are important for the diagnosis of CMV and Aspergillus infections. Diffuse alveolar hemorrhage (DAH) and peri-engraftment respiratory distress syndrome occur in both allogeneic and autologous HSCT recipients, usually during the first 30 days. Bronchiolitis obliterans occurs exclusively in allogeneic HSCT recipients with graft versus host disease. Idiopathic pneumonia syndrome occurs at any time following transplant. Bronchoscopy is usually helpful for the diagnosis of the infectious pulmonary complications and DAH.

  2. Polycomb group proteins in hematopoietic stem cell aging and malignancies

    NARCIS (Netherlands)

    Klauke, Karin; de Haan, Gerald

    Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many

  3. Clinical comparison of weight- and age-based strategy of dose administration in children receiving intravenous busulfan for hematopoietic stem cell transplantation.

    Science.gov (United States)

    Gürlek Gökçebay, D; Azik, F; Ozbek, N; Isik, P; Avci, Z; Tavil, B; Kara, A; Tunc, B

    2015-05-01

    Bu, combined with TDM-guided dosing, is associated with fewer graft failures/relapses and lower toxicity in pediatric HSCT. We aimed this retrospective study for comparison of weight- and age-based dosing in terms of clinical outcomes such as time to engraftment, early complications, EFS, OS, and toxicity profiles in children receiving iv Bu. Sixty-one children who underwent HSCT from April 2010 to February 2013 by means of a Bu-based conditioning regimen and completed 100 days after transplantation at Ankara Children?s Hematology and Oncology Hospital Bone Marrow Transplantation Unit were enrolled in this study. SOS and neutropenic fever occurred more frequently in the weight-based dosing group. We found a statistically significant correlation between Bu dose and the incidence of SOS (r = 0.26, p = 0.04). Multivariate analysis showed only weight-based dosing of Bu was a significant predictor of SOS (HR = 9.46; p = 0.009). However, no relationship was found between two groups in terms of hemorrhagic cystitis, engraftment syndrome, acute or chronic GvHD, time to engraftment, chimerism, TRM, OS, and EFS rates. Weight-based dosing of Bu may cause higher incidence of SOS and early infectious complications at the places where TDM of Bu cannot be performed. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. 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.

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  13. Stepwise development of hematopoietic stem cells from embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Kenji Matsumoto

    Full Text Available The cellular ontogeny of hematopoietic stem cells (HSCs remains poorly understood because their isolation from and their identification in early developing small embryos are difficult. We attempted to dissect early developmental stages of HSCs using an in vitro mouse embryonic stem cell (ESC differentiation system combined with inducible HOXB4 expression. Here we report the identification of pre-HSCs and an embryonic type of HSCs (embryonic HSCs as intermediate cells between ESCs and HSCs. Both pre-HSCs and embryonic HSCs were isolated by their c-Kit(+CD41(+CD45(- phenotype. Pre-HSCs did not engraft in irradiated adult mice. After co-culture with OP9 stromal cells and conditional expression of HOXB4, pre-HSCs gave rise to embryonic HSCs capable of engraftment and long-term reconstitution in irradiated adult mice. Blast colony assays revealed that most hemangioblast activity was detected apart from the pre-HSC population, implying the early divergence of pre-HSCs from hemangioblasts. Gene expression profiling suggests that a particular set of transcripts closely associated with adult HSCs is involved in the transition of pre-HSC to embryonic HSCs. We propose an HSC developmental model in which pre-HSCs and embryonic HSCs sequentially give rise to adult types of HSCs in a stepwise manner.

  14. Human Placenta Is a Potent Hematopoietic Niche Containing Hematopoietic Stem and Progenitor Cells throughout Development

    NARCIS (Netherlands)

    C. Robin (Catherine); K. Bollerot (Karine); S.C. Mendes (Sandra); E. Haak (Esther); M. Crisan (Mihaela); F. Cerisoli (Francesco); I. Lauw (Ivoune); P. Kaimakis (Polynikis); R.J.J. Jorna (Ruud); M. Vermeulen (Mark); M.H. Kayser (Manfred); R. van der Linden (Reinier); P. Imanirad (Parisa); M.M.A. Verstegen (Monique); H. Nawaz-Yousaf (Humaira); N. Papazian (Natalie); E.A.P. Steegers (Eric); T. Cupedo (Tom); E.A. Dzierzak (Elaine)

    2009-01-01

    textabstractHematopoietic stem cells (HSCs) are responsible for the life-long production of the blood system and are pivotal cells in hematologic transplantation therapies. During mouse and human development, the first HSCs are produced in the aorta-gonad-mesonephros region. Subsequent to this

  15. Retinoic acid regulates hematopoietic development from human pluripotent stem cells.

    Science.gov (United States)

    Rönn, Roger E; Guibentif, Carolina; Moraghebi, Roksana; Chaves, Patricia; Saxena, Shobhit; Garcia, Bradley; Woods, Niels-Bjarne

    2015-02-10

    The functions of retinoic acid (RA), a potent morphogen with crucial roles in embryogenesis including developmental hematopoiesis, have not been thoroughly investigated in the human setting. Using an in vitro model of human hematopoietic development, we evaluated the effects of RA signaling on the development of blood and on generated hematopoietic progenitors. Decreased RA signaling increases the generation of cells with a hematopoietic stem cell (HSC)-like phenotype, capable of differentiation into myeloid and lymphoid lineages, through two separate mechanisms: by increasing the commitment of pluripotent stem cells toward the hematopoietic lineage during the developmental process and by decreasing the differentiation of generated blood progenitors. Our results demonstrate that controlled low-level RA signaling is a requirement in human blood development, and we propose a new interpretation of RA as a regulatory factor, where appropriate control of RA signaling enables increased generation of hematopoietic progenitor cells from pluripotent stem cells in vitro. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

    Directory of Open Access Journals (Sweden)

    Xiaoying Zhou

    2015-07-01

    Full Text Available Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx. Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.

  17. Transplantation Dose Alters the Differentiation Program of Hematopoietic Stem Cells.

    Science.gov (United States)

    Brewer, Casey; Chu, Elizabeth; Chin, Mike; Lu, Rong

    2016-05-24

    Hematopoietic stem cell (HSC) transplantation is the most prevalent stem cell therapy, but it remains a risky procedure. To improve this treatment, it is important to understand how transplanted stem cells rebuild the blood and immune systems and how this process is impacted by transplantation variables such as the HSC dose. Here, we find that, in the long term following transplantation, 70%-80% of donor-HSC-derived clones do not produce all measured blood cell types. High HSC doses lead to more clones that exhibit balanced lymphocyte production, whereas low doses produce more T-cell-specialized clones. High HSC doses also produce significantly higher proportions of early-differentiating clones compared to low doses. These complex differentiation behaviors uncover the clonal-level regeneration dynamics of hematopoietic regeneration and suggest that transplantation dose can be exploited to improve stem cell therapy. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  18. On signaling pathways: hematopoietic stem cell specification from hemogenic endothelium.

    Science.gov (United States)

    Long, Yan; Huang, He

    2015-12-01

    Hematopoietic stem cells (HSCs) are specified and generated during the embryonic development and have remarkable potential to replenish the full set of blood cell lineages. Researchers have long been interested in clarifying the molecular events involved in HSC specification. Many studies have reported the development of methods for generating functional hematopoietic cells from pluripotent stem cells (PSCs-embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)) for decades. However, the generation of HSCs with robust long-term repopulation potential remains a swingeing challenge, of which a major factor contributing to this failure is the difficulty to define the intraembryonic signals related to the specification of HSCs. Since HSCs directly derive from hemogenic endothelium, in this review, we summarize both in vivo and in vitro studies on conserved signaling pathways that control the specification of HSCs from hemogenic endothelial cells.

  19. Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients

    NARCIS (Netherlands)

    van Hest, Reinier M.; Doorduijn, Jeanette K.; de Winter, Brenda C. M.; Cornelissen, Jan J.; Vulto, Arnold G.; Oellerich, Michael; Löwenberg, Bob; Mathot, Ron A. A.; Armstrong, Victor William; van Gelder, Teun

    2007-01-01

    Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed

  20. Expansion of human cord blood hematopoietic stem cells for transplantation.

    Science.gov (United States)

    Chou, Song; Chu, Pat; Hwang, William; Lodish, Harvey

    2010-10-08

    A recent Science paper reported a purine derivative that expands human cord blood hematopoietic stem cells in culture (Boitano et al., 2010) by antagonizing the aryl hydrocarbon receptor. Major problems need to be overcome before ex vivo HSC expansion can be used clinically. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Longitudinal assessment of hematopoietic stem cell transplantation and hyposalivation

    NARCIS (Netherlands)

    Laaksonen, M.; Ramseier, A. M.; Rovó, A.; Jensen, S. B.; Raber-Durlacher, J. E.; Zitzmann, N. U.; Waltimo, T.

    2011-01-01

    Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study

  2. Lifelong dietary intervention does not affect hematopoietic stem cell function

    NARCIS (Netherlands)

    Lazare, Seka; Ausema, Albertina; Reijne, Aaffien C; van Dijk, Gertjan; van Os, Ronald; de Haan, Gerald

    Hematopoietic stem cells (HSCs) undergo a profound functional decline during normal aging. Because caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we explored the consequences of lifelong caloric restriction, or conversely, lifelong

  3. Primary Immunodeficiency Diseases and Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Ayse Ozkan

    2014-02-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is the only curative therapy for primary immunodeficiency diseases. Early diagnosis, including prenatally, and early transplantation improve HSCT outcomes. Survival rates improve with advances in the methods of preparing hosts and donor cells, and in supportive and conditioning regimes.

  4. 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...

  5. Sexual function 1-year after allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Noerskov, K. H.; Schjødt, I.; Syrjala, K. L.

    2016-01-01

    Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is associated with short and long-term toxicities that can result in alterations in sexual functioning. The aims of this prospective evaluation were to determine: (1) associations between HSCT and increased sexual dysfunction...

  6. Depression and anxiety following hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Kuba, K; Esser, P; Mehnert, A

    2017-01-01

    In this prospective multicenter study, we investigated the course of depression and anxiety during hematopoietic stem cell transplantation (HSCT) until 5 years after transplantation adjusting for medical information. Patients were consulted before HSCT (n=239), at 3 months (n=150), 12 months (n=102...

  7. Hematopoietic stem cell aging and self-renewal

    NARCIS (Netherlands)

    Dykstra, Brad; de Haan, Gerald

    A functional decline of the immune system occurs during organismal aging that is attributable, in large part, to changes in the hematopoietic stem cell (HSC) compartment. In the mouse, several hallmark age-dependent changes in the HSC compartment have been identified, including an increase in HSC

  8. Mom Knows Best: Imprinted Control of Hematopoietic Stem Cell Quiescence.

    Science.gov (United States)

    Serrano-Lopez, Juana; Cancelas, Jose A

    2016-02-04

    The mechanisms by which imprinted loci control activity of hematopoietic stem cells (HSCs) are not known. In this issue of Cell Stem Cell, Qian et al. (2016) demonstrate that non-coding RNAs expressed by the maternal-imprinted locus Dlk1-Gtl2 maintain HSC self-renewal through the inhibition of PI3K-mTOR signaling, mitochondrial biogenesis, and metabolic activity. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Interleukin-1 regulates Hematopoietic progenitor and stem cells in the midgestation mouse fetal liver

    NARCIS (Netherlands)

    C. Orelio (Claudia); M. Peeters (Marian); E. Haak (Esther); K. van der Horn (Karin); E.A. Dzierzak (Elaine)

    2009-01-01

    textabstractBackground Hematopoietic progenitors are generated in the yolk sac and aorta-gonad-mesonephros region during early mouse development. At embryonic day 10.5 the first hematopoietic stem cells emerge in the aorta-gonad-mesonephros. Subsequently, hematopoietic stem cells and progenitors are

  10. File list: Oth.Bld.05.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.05.AllAg.Hematopoietic_Stem_Cells mm9 TFs and others Blood Hematopoietic St...587736,SRX180155 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.05.AllAg.Hematopoietic_Stem_Cells.bed ...

  11. File list: ALL.Bld.50.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.50.AllAg.Hematopoietic_Stem_Cells hg19 All antigens Blood Hematopoietic Ste...38907 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Bld.50.AllAg.Hematopoietic_Stem_Cells.bed ...

  12. File list: ALL.Bld.05.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.05.AllAg.Hematopoietic_Stem_Cells hg19 All antigens Blood Hematopoietic Ste...38918 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Bld.05.AllAg.Hematopoietic_Stem_Cells.bed ...

  13. File list: Oth.Bld.50.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.AllAg.Hematopoietic_Stem_Cells mm9 TFs and others Blood Hematopoietic St...293143,SRX180155 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.50.AllAg.Hematopoietic_Stem_Cells.bed ...

  14. File list: ALL.Bld.10.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.10.AllAg.Hematopoietic_Stem_Cells hg19 All antigens Blood Hematopoietic Ste...38918 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Bld.10.AllAg.Hematopoietic_Stem_Cells.bed ...

  15. File list: Oth.Bld.10.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.AllAg.Hematopoietic_Stem_Cells hg19 TFs and others Blood Hematopoietic S...0347,SRX038912,SRX038913,SRX658606,SRX658607 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.10.AllAg.Hematopoietic_Stem_Cells.bed ...

  16. File list: Oth.Bld.20.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.AllAg.Hematopoietic_Stem_Cells hg19 TFs and others Blood Hematopoietic S...8915,SRX658607,SRX658606,SRX038908,SRX038909 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.20.AllAg.Hematopoietic_Stem_Cells.bed ...

  17. File list: Oth.Bld.20.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.AllAg.Hematopoietic_Stem_Cells mm9 TFs and others Blood Hematopoietic St...293143,SRX180155 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.20.AllAg.Hematopoietic_Stem_Cells.bed ...

  18. File list: Oth.Bld.05.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.05.AllAg.Hematopoietic_Stem_Cells hg19 TFs and others Blood Hematopoietic S...0347,SRX038912,SRX038913,SRX658606,SRX658607 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.05.AllAg.Hematopoietic_Stem_Cells.bed ...

  19. File list: Oth.Bld.50.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.AllAg.Hematopoietic_Stem_Cells hg19 TFs and others Blood Hematopoietic S...8606,SRX038913,SRX038912,SRX038909,SRX038908 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Oth.Bld.50.AllAg.Hematopoietic_Stem_Cells.bed ...

  20. File list: Oth.Bld.10.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.AllAg.Hematopoietic_Stem_Cells mm9 TFs and others Blood Hematopoietic St...293144,SRX180155 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.10.AllAg.Hematopoietic_Stem_Cells.bed ...

  1. File list: ALL.Bld.20.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Bld.20.AllAg.Hematopoietic_Stem_Cells hg19 All antigens Blood Hematopoietic Ste...05150 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Bld.20.AllAg.Hematopoietic_Stem_Cells.bed ...

  2. [Endothelial origin for hematopoietic stem cells: a visual proof].

    Science.gov (United States)

    Boisset, Jean-Charles; Robin, Catherine

    2011-10-01

    Hematopoietic stem cells (HSC) are the source of all blood cell types produced during the entire life of an organism. They appear during embryonic development, where they will transit through different successive hematopoietic organs, before to finally colonize the bone marrow. Nowadays, the precise origin of HSC remains a matter of controversy. Different HSC precursor candidates, located in different anatomical sites, have been proposed. Here, we summarize and discuss the different theories in light of the recent articles, especially those using in vivo confocal microscopy technology. © 2011 médecine/sciences – Inserm / SRMS.

  3. Human hematopoietic stem cell adherence to cytokines and matrix molecules.

    Science.gov (United States)

    Long, M W; Briddell, R; Walter, A W; Bruno, E; Hoffman, R

    1992-07-01

    The hematopoietic microenvironment is a complex structure in which stem cells, progenitor cells, stromal cells, growth factors, and extracellular matrix (ECM) molecules each interact to direct the coordinate regulation of blood cell development. While much is known concerning the individual components of this microenvironment, little is understood of the interactions among these various components or, in particular, the nature of those interactions responsible for the regional localization of specific developmental signals. We hypothesized that cytokines act together with ECM molecules to anchor stem cells within the microenvironment, thus modulating their function. In order to analyze matrix-cytokine-stem cell interactions, we developed an ECM model system in which purified stem cell populations and plastic-immobilized individual proteins are used to assess the role of various matrix molecules and/or cytokines in human hematopoietic cell development. Analysis of these interactions revealed that a single ECM protein, thrombospondin, in conjunction with a single cytokine (e.g., c-kit ligand), constitutes a developmental signal that synergistically modulates hematopoietic stem cell function.

  4. Divisional History and Hematopoietic Stem Cell Function during Homeostasis

    Directory of Open Access Journals (Sweden)

    Jiajing Qiu

    2014-04-01

    Full Text Available We investigated the homeostatic behavior of hematopoietic stem and progenitor cells (HSPCs temporally defined according to their divisional histories using an HSPC-specific GFP label-retaining system. We show that homeostatic hematopoietic stem cells (HSCs lose repopulating potential after limited cell divisions. Once HSCs exit dormancy and accrue divisions, they also progressively lose the ability to return to G0 and functional activities associated with quiescent HSCs. In addition, dormant HSPCs phenotypically defined as multipotent progenitor cells display robust stem cell activity upon transplantation, suggesting that temporal quiescence is a greater indicator of function than cell-surface phenotype. Our studies suggest that once homeostatic HSCs leave dormancy, they are slated for extinction. They self-renew phenotypically, but they lose self-renewal activity. As such, they question self-renewal as a characteristic of homeostatic, nonperturbed HSCs in contrast to self-renewal demonstrated under stress conditions.

  5. Functional assays for hematopoietic stem cell self-renewal.

    Science.gov (United States)

    Perry, John M; Li, Linheng

    2010-01-01

    Stem cells are defined by the ability to self-renew. Specific functional assays have been developed for the rigorous identification and quantification of hematopoietic stem cells (HSCs), making these cells the benchmark in studies of self-renewal. Here, we review the theory behind these functional stem cell tests and discuss important considerations in choosing and designing these assays. Finally, we provide a basic protocol for the serial-dilution assay, a quantitative assay for HSCs, from which individual researchers can construct their own customized protocols utilizing the guidelines discussed.

  6. Characterization of Selectin Ligands on Hematopoietic Stem Cells

    KAUST Repository

    Mahmood, Hanan

    2013-05-18

    Successful bone marrow (BM) transplantation requires the homing of the transplanted hematopoietic stem/progenitor cells (HSPCs) to their bone marrow niche, where they undergo differentiation to form mature cells that are eventually released into the peripheral blood. However, the survival rate of patients receiving BM transplants is poor since many of the transplanted HSPCs do not make it to their BM niches in the recipient’s body. Since the availability of HSPCs from traditional sources is limited, transplanting more number of HSPCs is not a solution to this problem. This study aims to characterize the adhesion molecules mediating cell migration in order to better understand the adhesion mechanisms of HSCs with the bone marrow endothelium. This will aid in developing future tools to improve the clinical transplantation of HSPCs. This study also aims to understand the factors that influence HSPC proliferation in the bone marrow niche. E-selectin plays an important role in the process of homing; however, its ligands on HSPCs are not well characterized. We used western blotting and immunoprecipitation to show that endomucin is expressed on HSPCs and plays a role in the binding of HSPCs to E-selectin. We also studied the effect of recombinant E-selectin on the expression of a newly characterized E-selectin ligand in our lab, CD34, in HSPCs. This will provide us insight into novel roles for endomucin and E-selectin and help us to understand the factors influencing HSPC migration to BM endothelium.

  7. FIFTY YEARS OF MELPHALAN USE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

    Science.gov (United States)

    Bayraktar, Ulas D.; Bashir, Qaiser; Qazilbash, Muzaffar; Champlin, Richard E.; Ciurea, Stefan O.

    2015-01-01

    Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem-cell transplantation. From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantation due to its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas; and has been used successfully in preparative regimens of a variety of other hematological and non-hematological malignancies. The addition of newer agents to conditioning like bortezomib or lenalidomide for myeloma, or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, while in combination with alemtuzumab may represent a backbone for future cellular therapy due to reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic stem-cell transplantation. PMID:22922522

  8. Longitudinal Assessment of Hematopoietic Stem Cell Transplantation and Hyposalivation

    DEFF Research Database (Denmark)

    Laaksonen, Matti; Ramseier, Adrian; Rovó, Alicia

    2011-01-01

    Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study ......-HSCT, respectively. Additionally, conditioning regimen and sex had an impact on saliva flow. In conclusion, hyposalivation was observed to be a common but generally reversible complication among HSCT recipients.......Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study...

  9. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

    DEFF Research Database (Denmark)

    Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

    2009-01-01

    OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed...... wound healing. Allogeneic hematopoietic stem-cell transplantation offers the possibility of curative therapy, and with patient numbers at any individual center being limited, we surveyed the transplant experience at 14 centers worldwide. METHODS: The course of 36 children with a confirmed diagnosis...... of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International...

  10. Imaging of complications from hematopoietic stem cell transplant

    Directory of Open Access Journals (Sweden)

    Tarun Pandey

    2014-01-01

    Full Text Available Stem cell transplant has been the focus of clinical research for a long time given its potential to treat several incurable diseases like hematological malignancies, diabetes mellitus, and neuro-degenerative disorders like Parkinson disease. Hematopoietic stem cell transplantation (HSCT is the oldest and most widely used technique of stem cell transplant. HSCT has not only been used to treat hematological disorders including hematological malignancies, but has also been found useful in treamtent of genetic, immunological, and solid tumors like neuroblastoma, lymphoma, and germ cell tumors. In spite of the rapid advances in stem cell technology, success rate with this technique has not been universal and many complications have also been seen with this form of therapy. The key to a successful HSCT therapy lies in early diagnosis and effective management of complications associated with this treatment. Our article aims to review the role of imaging in diagnosis and management of stem cell transplant complications associated with HSCT.

  11. Self-renewal and differentiation of hematopoietic stem cells.

    Science.gov (United States)

    Arai, Fumio

    2016-01-01

    Hematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate into all blood lineage cells. The fate decisions of HSCs (self-renewal versus differentiation) are made through the process of cell division and are often compared to "birth" and "death". Stem cells give rise to undifferentiated stem cells (birth) or differentiate into progenitor cells (death). This process is regulated by asymmetric/symmetric divisions of HSCs. It has been proposed that fate determination occurs as a stochastic process and that individual stem cell dynamics are randomly regulated. The behavior of HSCs is known to be regulated by the cell intrinsic factor and extrinsic (microenvironmental) stimuli. Therefore, it is possible that the signals from a specific microenvironment (niche) have the potential to control or modulate stem cell dynamics. This review focuses on the functions of the HSC niche and the application of single cell analysis for understanding the mechanisms underlying the HSC decision-making process.

  12. Peripheral blood CD34+ cell count as a predictor of adequacy of hematopoietic stem cell collection for autologous transplantation

    Directory of Open Access Journals (Sweden)

    Combariza, Juan F.

    2016-10-01

    Full Text Available Introduction: In order to carry out an autologous transplantation, hematopoietic stem cells should be mobilized to peripheral blood and later collected by apheresis. The CD34+ cell count is a tool to establish the optimal time to begin the apheresis procedure. Objective: To evaluate the association between peripheral blood CD34+ cell count and the successful collection of hematopoietic stem cells. Materials and methods: A predictive test evaluation study was carried out to establish the usefulness of peripheral blood CD34+ cell count as a predictor of successful stem cell collection in patients that will receive an autologous transplantation. Results: 77 patients were included (median age: 49 years; range: 5-66. The predominant baseline diagnosis was lymphoma (53.2 %. The percentage of patients with successful harvest of hematopoietic stem cells was proportional to the number of CD34+cells in peripheral blood at the end of the mobilization procedure. We propose that more than 15 CD34+cells/μL must be present in order to achieve an adequate collection of hematopoietic stem cells. Conclusion: Peripheral blood CD34+ cell count is a useful tool to predict the successful collection of hematopoietic stem cells.

  13. Hematopoietic Stem Cell Transplantation and History

    Directory of Open Access Journals (Sweden)

    Atila Tanyeli

    2014-02-01

    Full Text Available Attemps to employ marrow stem cell for therapeutic purpose began in 1940’s. Marrow transplantation might be of use not only in irradiation protection, but also with therapeutic aim to marrow aplasia, leukemia and other diseases. The use and defining tissue antigens in humans were crucial to the improving of transplantation. The administration of methotrexate for GVHD improved the long term survival. Conditioning regimens for myeloablation designed according to diseases. Cord blood and peripheral blood stem cells were used for transplantion after 1980’s. Cord blood and bone marrow stem cell banks established to find HLA matched donor.

  14. 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.

  15. Sexuality and Quality of Life after Hematopoietic Stem Cell Transplantation

    OpenAIRE

    Lee, Hong Ghi; Park, Eun Young; Kim, Hyun Mee; Kim, Kihyun; Kim, Won Seog; Yoon, Sung Soo; Kang, Won Ki; Park, Keun Chil; Park, Chan Hyung

    2002-01-01

    Background The quality of sexuality is significantly affected by physical changes following hematopoietic stem cell transplantation (HSCT) and the dissatisfied and/or dysfunctional sexuality may cause deterioration in the quality of life (QOL). Methods With two models of questionnaires, we interviewed thirty-eight patients who remained in the disease-free status after HSCT and had sex partners, to assess: 1) the changes in sexuality, 2) QOL in physical, psychological, social and spiritual dom...

  16. Human hematopoietic stem cell adherence to cytokines and matrix molecules.

    OpenAIRE

    Long, M. W.; Briddell, R.; Walter, A W; Bruno, E; Hoffman, R.

    1992-01-01

    The hematopoietic microenvironment is a complex structure in which stem cells, progenitor cells, stromal cells, growth factors, and extracellular matrix (ECM) molecules each interact to direct the coordinate regulation of blood cell development. While much is known concerning the individual components of this microenvironment, little is understood of the interactions among these various components or, in particular, the nature of those interactions responsible for the regional localization of...

  17. Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

    Science.gov (United States)

    2016-10-01

    Endogenous formalde- hyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Molecular Cell 60(1):177-88. doi: 10.1016/j.molcel...interested in our newly generated data on the role of aldehydes, especially endogenous aldehydes generated as part of normal cellular metabolism , as an...pancytopenia in multiple lineages, including lower platelet counts, lower white and red blood cell counts, and lower hemoglobin levels than their wild-type

  18. Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

    OpenAIRE

    Akunuru, Shailaja; Geiger, Hartmut

    2016-01-01

    Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and increased production of reactive oxygen species have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts such as global ...

  19. Hematopoietic Stem Cell Transplantation and History

    National Research Council Canada - National Science Library

    Atila Tanyeli; Gulcan Aykut; Ahmet Onur Demirel; Tugba Akcaoglu

    2014-01-01

    Attemps to employ marrow stem cell for therapeutic purpose began in 1940's. Marrow transplantation might be of use not only in irradiation protection, but also with therapeutic aim to marrow aplasia, leukemia and other diseases...

  20. Hematopoietic stem cell transplant-related airflow obstruction.

    Science.gov (United States)

    Dudek, Arkadiusz Z; Mahaseth, Hemchandra

    2006-03-01

    Airflow obstruction is a rare but fatal complication following allogeneic hematopoietic stem cell transplantation. It is noninfectious, relatively late, and primarily affects small airways, ultimately leading to their obliteration. If airflow obstruction is consistent with obliteration histologically, the condition is often called bronchiolitis obliterans. This review of literature published recently evaluates progress made in this field. Changes reported in analysis of pulmonary function test results and their follow-up might be helpful to better manage bronchiolitis obliterans and to detect and treat it earlier. Graft-versus-host reaction possibly underlies the development of this fatal disease. Findings from high-resolution computed tomography might aid in the diagnostic process. Anti-inflammatory therapy, azithromycin and lung transplant might be an option to treat bronchiolitis obliterans. The pathomechanism of bronchiolitis obliterans remains unclear and it remains a fatal complication of hematopoietic stem cell transplantation. An appropriate model to study hematopoietic stem cell transplantation-related airflow obstruction, consensus diagnostic criteria, and prospective trials for treatment are necessary to overcome the challenge presented by bronchiolitis obliterans.

  1. Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

    Science.gov (United States)

    Chen, Joey; Seabrook, Jamie; Fulford, Adrienne; Rajakumar, Irina

    2017-03-01

    Background Up to 70% of patients receiving hematopoietic stem cell transplant develop oral mucositis as a side effect of high-dose melphalan conditioning chemotherapy. Oral cryotherapy has been documented to be potentially effective in reducing oral mucositis. The aim of this study was to examine the effectiveness of the cryotherapy protocol implemented within the hematopoietic stem cell transplant program. Methods A retrospective chart review was conducted of adult multiple myeloma patients who received high-dose melphalan conditioning therapy for autologous hematopoietic stem cell transplant. Primary endpoints were incidence and severity of oral mucositis. Secondary endpoints included duration of oral mucositis, duration of hospital stay, parenteral narcotics use and total parenteral nutrition use. Results One hundred and forty patients were included in the study, 70 patients in both no cryotherapy and cryotherapy groups. Both oral mucositis incidence and severity were found to be significantly lower in the cryotherapy group. Fifty (71.4%) experienced mucositis post cryotherapy compared to 67 (95.7%) in the no cryotherapy group (p cryotherapy group (p = 0.03). Oral mucositis duration and use of parenteral narcotics were also significantly reduced. Duration of hospital stay and use of parenteral nutrition were similar between the two groups. Conclusion The cryotherapy protocol resulted in a significantly lower incidence and severity of oral mucositis. These results provide evidence for the continued use of oral cryotherapy, an inexpensive and generally well-tolerated practice.

  2. Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell.

    Science.gov (United States)

    Hoggatt, Jonathan; Singh, Pratibha; Tate, Tiffany A; Chou, Bin-Kuan; Datari, Shruti R; Fukuda, Seiji; Liu, Liqiong; Kharchenko, Peter V; Schajnovitz, Amir; Baryawno, Ninib; Mercier, Francois E; Boyer, Joseph; Gardner, Jason; Morrow, Dwight M; Scadden, David T; Pelus, Louis M

    2018-01-11

    Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Cigarette Smoke Alters the Hematopoietic Stem Cell Niche

    Directory of Open Access Journals (Sweden)

    Robert W. Siggins

    2014-02-01

    Full Text Available Effects of tobacco smoke on hematologic derangements have received little attention. This study employed a mouse model of cigarette smoke exposure to explore the effects on bone marrow niche function. While lung cancer is the most widely studied consequence of tobacco smoke exposure, other malignancies, including leukemia, are associated with tobacco smoke exposure. Animals received cigarette smoke exposure for 6 h/day, 5 days/week for 9 months. Results reveal that the hematopoietic stem and progenitor cell (HSPC pool size is reduced by cigarette smoke exposure. We next examined the effect of cigarette smoke exposure on one supporting cell type of the niche, the mesenchymal stromal cells (MSCs. Smoke exposure decreased the number of MSCs. Transplantation of naïve HSPCs into irradiated mice with cigarette smoke exposure yielded fewer numbers of engrafted HSPCs. This result suggests that smoke-exposed mice possess dysfunctional niches, resulting in abnormal hematopoiesis. Co-culture experiments using MSCs isolated from control or cigarette smoke-exposed mice with naïve HSPCs in vitro showed that MSCs from cigarette smoke-exposed mice generated marked expansion of naïve HSPCs. These data show that cigarette smoke exposure decreases in vivo MSC and HSC number and also increases pro-proliferative gene expression by cigarette smoke-exposed MSCs, which may stimulate HSPC expansion. These results of this investigation are clinically relevant to both bone marrow donors with a history of smoking and bone marrow transplant (BMT recipients with a history of smoking.

  4. Hematopoietic (stem) cell development — how divergent are the roads taken?

    NARCIS (Netherlands)

    M.-L. Kauts (Mari-Liis); C.S. Vink (Chris); E.A. Dzierzak (Elaine)

    2016-01-01

    textabstractThe development of the hematopoietic system during early embryonic stages occurs in spatially and temporally distinct waves. Hematopoietic stem cells (HSC), the most potent and self-renewing cells of this system, are produced in the final ‘definitive’ wave of hematopoietic cell

  5. Cell cycle regulation of hematopoietic stem or progenitor cells.

    Science.gov (United States)

    Hao, Sha; Chen, Chen; Cheng, Tao

    2016-05-01

    The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

  6. DNA Methylation Dynamics of Human Hematopoietic Stem Cell Differentiation.

    Science.gov (United States)

    Farlik, Matthias; Halbritter, Florian; Müller, Fabian; Choudry, Fizzah A; Ebert, Peter; Klughammer, Johanna; Farrow, Samantha; Santoro, Antonella; Ciaurro, Valerio; Mathur, Anthony; Uppal, Rakesh; Stunnenberg, Hendrik G; Ouwehand, Willem H; Laurenti, Elisa; Lengauer, Thomas; Frontini, Mattia; Bock, Christoph

    2016-12-01

    Hematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. Here we present genome-wide reference maps of the associated DNA methylation dynamics. We used a meta-epigenomic approach that combines DNA methylation profiles across many small pools of cells and performed single-cell methylome sequencing to assess cell-to-cell heterogeneity. The resulting dataset identified characteristic differences between HSCs derived from fetal liver, cord blood, bone marrow, and peripheral blood. We also observed lineage-specific DNA methylation between myeloid and lymphoid progenitors, characterized immature multi-lymphoid progenitors, and detected progressive DNA methylation differences in maturing megakaryocytes. We linked these patterns to gene expression, histone modifications, and chromatin accessibility, and we used machine learning to derive a model of human hematopoietic differentiation directly from DNA methylation data. Our results contribute to a better understanding of human hematopoietic stem cell differentiation and provide a framework for studying blood-linked diseases. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  7. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.

    Science.gov (United States)

    Eichler, Florian; Duncan, Christine; Musolino, Patricia L; Orchard, Paul J; De Oliveira, Satiro; Thrasher, Adrian J; Armant, Myriam; Dansereau, Colleen; Lund, Troy C; Miller, Weston P; Raymond, Gerald V; Sankar, Raman; Shah, Ami J; Sevin, Caroline; Gaspar, H Bobby; Gissen, Paul; Amartino, Hernan; Bratkovic, Drago; Smith, Nicholas J C; Paker, Asif M; Shamir, Esther; O'Meara, Tara; Davidson, David; Aubourg, Patrick; Williams, David A

    2017-10-26

    In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to

  8. Maintenance of human embryonic stem cells in mesenchymal stem cell-conditioned media augments hematopoietic specification.

    Science.gov (United States)

    Ramos-Mejía, Verónica; Fernández, Agustín F; Ayllón, Verónica; Real, Pedro J; Bueno, Clara; Anderson, Per; Martín, Francisco; Fraga, Mario F; Menendez, Pablo

    2012-06-10

    The realization of human embryonic stem cells (hESC) as a model for human developmental hematopoiesis and in potential cell replacement strategies relies on an improved understanding of the extrinsic and intrinsic factors regulating hematopoietic-specific hESC differentiation. Human mesenchymal stem cells (hMSCs) are multipotent cells of mesodermal origin that form a part of hematopoietic stem cell niches and have an important role in the regulation of hematopoiesis through production of secreted factors and/or cell-to-cell interactions. We have previously shown that hESCs may be successfully maintained feeder free using hMSC-conditioned media (MSC-CM). Here, we hypothesized that hESCs maintained in MSC-CM may be more prone to differentiation toward hematopoietic lineage than hESCs grown in standard human foreskin fibroblast-conditioned media. We report that specification into hemogenic progenitors and subsequent hematopoietic differentiation and clonogenic progenitor capacity is robustly enhanced in hESC lines maintained in MSC-CM. Interestingly, co-culture of hESCs on hMSCs fully abrogates hematopoietic specification of hESCs, thus suggesting that the improved hematopoietic differentiation is mediated by MSC-secreted factors rather than by MSC-hESC physical interactions. To investigate the molecular mechanism involved in this process, we analyzed global (LINE-1) methylation and genome-wide promoter DNA methylation. hESCs grown in MSC-CM showed a decrease of 17% in global DNA methylation and a promoter DNA methylation signature consisting of 45 genes commonly hypomethylated and 102 genes frequently hypermethylated. Our data indicate that maintenance of hESCs in MSC-CM robustly augments hematopoietic specification and that the process seems mediated by MSC-secreted factors conferring a DNA methylation signature to undifferentiated hESCs which may influence further predisposition toward hematopoietic specification.

  9. The many faces of hematopoietic stem cell heterogeneity.

    Science.gov (United States)

    Crisan, Mihaela; Dzierzak, Elaine

    2016-12-15

    Not all hematopoietic stem cells (HSCs) are alike. They differ in their physical characteristics such as cell cycle status and cell surface marker phenotype, they respond to different extrinsic signals, and they have different lineage outputs following transplantation. The growing body of evidence that supports heterogeneity within HSCs, which constitute the most robust cell fraction at the foundation of the adult hematopoietic system, is currently of great interest and raises questions as to why HSC subtypes exist, how they are generated and whether HSC heterogeneity affects leukemogenesis or treatment options. This Review provides a developmental overview of HSC subtypes during embryonic, fetal and adult stages of hematopoiesis and discusses the possible origins and consequences of HSC heterogeneity. © 2016. Published by The Company of Biologists Ltd.

  10. Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells.

    Science.gov (United States)

    Akunuru, Shailaja; Geiger, Hartmut

    2016-08-01

    Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and the increased production of reactive oxygen species (ROS) have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts, such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as the clonal selection of HSCs upon aging, provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and, potentially, alleviating aging-associated immune remodeling and myeloid malignancies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Uppugunduri, Chakradhara Rao S.; Storelli, Flavia; Mlakar, Vid; Huezo-Diaz Curtis, Patricia; Rezgui, Aziz; Théorêt, Yves; Marino, Denis; Doffey-Lazeyras, Fabienne; Chalandon, Yves; Bader, Peter; Daali, Youssef; Bittencourt, Henrique; Krajinovic, Maja; Ansari, Marc

    2017-01-01

    Hemorrhagic cystitis (HC) is one of the complications of busulfan-cyclophosphamide (BU-CY) conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT) in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU) levels were measured in 39 children following treatment with BU-CY regimen. The cytotoxic effects of Su and acrolein (Ac, water soluble metabolite of CY) were tested on human urothelial cells (HUCs). The effect of Su was also tested on cytochrome P 450 (CYP) function in HepaRG hepatic cells. Cumulative incidences of HC before day 30 post HSCT were estimated using Kaplan–Meier curves and log-rank test was used to compare the difference between groups in a univariate analysis. Multivariate Cox regression was used to estimate hazard ratios with 95% confidence intervals (CIs). Multivariate analysis included co-variables that were significantly associated with HC in a univariate analysis. Cumulative incidence of HC was 15.3%. In the univariate analysis, HC incidence was significantly (p 40 vs. hemorrhagic cystitis following treatment with busulfan and cyclophosphamide based conditioning regimen. (2) Identification of children at high risk for developing hemorrhagic cystitis in an allogeneic HSCT setting will enable us to evaluate and implement optimal strategies for its prevention. Trial registration: This study is a part of the trail “clinicaltrials.gov identifier: NCT01257854.” PMID:28744217

  12. Nicaraven attenuates radiation-induced injury in hematopoietic stem/progenitor cells in mice.

    Directory of Open Access Journals (Sweden)

    Miho Kawakatsu

    Full Text Available Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy, and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2'-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

  13. Characterization, isolation, and differentiation of murine skin cells expressing hematopoietic stem cell markers.

    Science.gov (United States)

    Meindl, Simone; Schmidt, Uwe; Vaculik, Christine; Elbe-Bürger, Adelheid

    2006-10-01

    As the phenotype of adult dermal stem cells is still elusive, and the hematopoietic stem cell is one of the best-characterized stem cells in the body, we tested dermal cell suspensions, sections, and wholemounts in newborn and adult mice for hematopoietic stem cell marker expression. Phenotypic analysis revealed that a small population of CD45(+) cells and a large population of CD45(-) cells expressed CD34, CD117, and stem cell antigen-1 molecules. When cultivated in selected media supplemented with hematopoietic cytokines, total dermal cells, lineage(-), and/or highly enriched phenotypically defined cell subsets produced hematopoietic and nonhematopoietic colonies. When injected into lethally irradiated recipient mice, a small percentage of newborn dermal cells was able to migrate into hematopoietic tissues and the skin and survived through the 11-month monitoring period. Our ability to isolate a candidate autologous stem cell pool will make these cells ideal vehicles for genetic manipulation and gene therapy.

  14. Prophylactic acyclovir and preemptive ganciclovir to prevent cytomegalovirus disease in children after hematopoietic stem cell transplant.

    Science.gov (United States)

    Tavil, Betul; Azik, Fatih Mehmet; Bozkaya, Ikbal; Gokcebay, Dilek Gurlek; Tezer, Hasan; Tunc, Bahattin; Uckan, Duygu

    2014-10-01

    The purpose of this study was to evaluate the effectiveness of acyclovir prophylaxis and preemptive ganciclovir treatment in preventing cytomegalovirus disease in children who underwent hematopoietic stem cell transplant. We reviewed the clinical records of 66 children (36 boys, 30 girls; mean age, 9 ± 5 y; age range, 2-20 y) who underwent hematopoietic stem cell transplant at Ankara Children's Hematology and Oncology Hospital, Bone Marrow Transplantation Unit, between April 2010 and March 2012. In these 66 children, 61 children (92.4%) received allogeneic transplant; 50 children (76.9%) received a myeloablative regimen; and 14 children (21.2%) received anti-thymocyte globulin as part of the conditioning regimen. All children received acyclovir prophylaxis from the beginning of conditioning regimen until 100 days after transplant, and children received preemptive treatment with ganciclovir when cytomegalovirus DNAemia ≥ 400 copies/mL on 2 tests or ≥ 1000 copies/mL on 1 test. There were 19 children (28.8%) who had cytomegalovirus reactivation during median follow-up 381 days (range, 100-720 d). Cytomegalovirus disease was observed in only 2 patients (10.5%); 1 patient had cytomegalovirus hepatitis and 1 patient had cytomegalovirus gastrointestinal disease. Both patients were cured of cytomegalovirus with treatment for 1 month. There was no death attributable to cytomegalovirus reactivation and/or disease. Febrile neutropenia, acute graft-versus-host disease, and steroid use were more frequent in patients who had cytomegalovirus than did not have cytomegalovirus reactivation. The risk of cytomegalovirus reactivation was increased 5-fold in patients who used steroids. Acyclovir prophylaxis and preemptive treatment with ganciclovir may be effective in preventing cytomegalovirus disease in most children who have hematopoietic stem cell transplant.

  15. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Roach, Allana Nicole; Brezo, Jelena

    2002-01-01

    Astronauts experience severe/invasive disorders caused by space environments. These include hematological/cardiac abnormalities, bone and muscle losses, immunodeficiency, neurological disorders and cancer. While the cause of these symptoms are not yet fully delineated, one possible explanation could be the inhibition of hematopoietic stem cell (HSC) growth and hematopoiesis in space. HSCs differentiate into all types of blood cells, and growing evidence indicates that the HSCs also have the ability to transdifferentiate to various tissues, including muscle, skin, liver, neuronal cells and possibly bone. Therefore, a hypothesis was advanced in this laboratory that the hematopoietic stem cell-based therapy, herein called the hematopoietic stem cell therapy (HSCT), could mitigate some of the disorders described above. Due to the magnitude of this project our laboratory has subdivided it into 3 sections: a) HSCT for space anemia; b) HSCT for muscle and bone losses; and c) HSCT for immunodeficiency. Toward developing the HSCT protocol for space anemia, the HSC transplantation procedure was established using a mouse model of beta thalassemia. In addition, the NASA Rotating Wall Vessel (RWV) culture system was used to grow HSCs in space condition. To investigate the HSCT for muscle loss and bone loss, donor HSCs were genetically marked either by transfecting the beta-galactosidase-containing plasmid, pCMV.SPORT-beta-gal or by preparing from b-galactosidase transgenic mice. The transdifferentiation of HSCs to muscle is traced by the reporter gene expression in the hindlimb suspended mice with some positive outcome, as studied by the X-gal staining procedure. The possible structural contribution of HSCs against muscle loss is being investigated histochemically.

  16. Functional evaluation indicates physical losses after hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Clarissa Vasconcellos de Souza

    2012-01-01

    Full Text Available OBJECTIVE: To perform a function evaluation of patients before and after hematopoietic stem cell transplantation. METHODS: From November 2008 to November 2010, 29 female (58% and 21 male patients (42% with median age of 48 years (range: 24-67 were enrolled in this study. Data collection was performed before and after autologous or allogeneic hematopoietic stem cell transplantation. Evaluation instruments included the 2-minute walking test to evaluate gait performance with assessment of the oxygen saturation, heart rate and Borg Scale before and after the test; grip strength for strength evaluation, Schober Test for spine mobility testing and maximum and adapted activity scores of the Human Activity Profile questionnaire to test functionality in daily activities. RESULTS: Fifty patients were evaluated at baseline; six did not undergo hematopoietic stem cell transplantation (three died, one refused and two were excluded. Thus 44/50 (88% - 21 allogeneic and 23 autologous transplantations were performed. Only 33 of the 44 patients (75% performed evaluations after transplantation (nine died and two were excluded. Of the patients who performed both evaluations, significantly lower values were found in the evaluation after transplantation for the 2-minute walking test (p-value = 0.004, grip strength of both right and left hands (p-value = 0.004 and p-value < 0.0001, respectively, the Schober Test, and maximum and adapted activity scores (p-value < 0.0001. The heart rate was higher (p-value = 0.01 before the 2-minute walking test and oxygen saturation was higher (p-value = 0.02 after. CONCLUSION: Statistical differences indicate functional impairment after transplantation showing physical losses in this population.

  17. Autologous hematopoietic stem cell transplantation in classical Hodgkin's lymphoma

    Directory of Open Access Journals (Sweden)

    Afonso José Pereira Cortez

    2011-02-01

    Full Text Available BACKGROUND: Hodgkin's lymphoma has high rates of cure, but in 15% to 20% of general patients and between 35% and 40% of those in advanced stages, the disease will progress or will relapse after initial treatment. For this group, hematopoietic stem cell transplantation is considered one option of salvage therapy. OBJECTIVES: To evaluate a group of 106 patients with Hodgkin's lymphoma, who suffered relapse or who were refractory to treatment, submitted to autologous hematopoietic stem cell transplantation in a single transplant center. METHODS: A retrospective study was performed with data collected from patient charts. The analysis involved 106 classical Hodgkin's lymphoma patients who were consecutively submitted to high-dose chemotherapy followed by autologous transplants in a single institution from April 1993 to December 2006. RESULTS: The overall survival rates of this population at five and ten years were 86% and 70%, respectively. The disease-free survival was approximately 60% at five years. Four patients died of procedure-related causes but relapse of classical Hodgkin's lymphoma after transplant was the most frequent cause of death. Univariate analysis shows that sensitivity to pre-transplant treatment and hemoglobin < 10 g/dL at diagnosis had an impact on patient survival. Unlike other studies, B-type symptoms did not seem to affect overall survival. Lactic dehydrogenase and serum albumin concentrations analyzed at diagnosis did not influence patient survival either. CONCLUSION: Autologous hematopoietic stem cell transplantation is an effective treatment strategy for early and late relapse in classical Hodgkin's lymphoma for cases that were responsive to pre-transplant chemotherapy. Refractory to treatment is a sign of worse prognosis. Additionally, a hemoglobin concentration below 10 g/dL at diagnosis of Hodgkin's lymphoma has a negative impact on the survival of patients after transplant. As far as we know this relationship has not

  18. Hematopoietic stem cell transplantation for Gaucher disease.

    Science.gov (United States)

    Somaraju, Usha R; Tadepalli, Krishna

    2017-10-18

    Gaucher disease is the most common lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice from enzyme replacement therapy, substrate reduction therapy and hemotopoietic stem cell transplantation (HSCT). HSCT is a high risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. This is an update of a previously published Cochrane Review. To determine the role of HSCT in people with Gaucher disease in relation to: mortality risk associated with the procedure; efficacy in modifying the course of the disease; and arrest or regression of neurological manifestations in neuronopathic forms (types 2 and 3). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 19 January 2017.We also searched the websites: www.clinicaltrials.gov; WHO International Clinical Trials Registry Platform portal and www.genzymeclinicalresearch.com. Date of most recent search of these sites: 02 March 2017. All randomised, quasi-randomised and controlled clinical trials comparing stem cell transplantation with enzyme replacement therapy, substrate reduction therapy, symptomatic treatment or no treatment in people with Gaucher disease of all ages. We independently assessed trials for inclusion, however, no relevant trials were identified. Thirty two trials were identified by the searches; however, these were not suitable for inclusion in the review. HSCT is a form of treatment that offers the potential of permanent cure. However, there are no clinical trials that have assessed the safety and efficacy of this treatment in comparison to other

  19. The Hematopoietic Stem Cell Therapy for Exploration of Deep Space

    Science.gov (United States)

    Ohi, Seigo; Roach, Allana-Nicole; Fitzgerald, Wendy; Riley, Danny A.; Gonda, Steven R.

    2003-01-01

    It is hypothesized that the hematopoietic stem cell therapy (HSCT) might countermeasure various space-caused disorders so as to maintain astronauts' homeostasis. If this were achievable, the HSCT could promote human exploration of deep space. Using animal models of disorders (hindlimb suspension unloading system and beta-thalassemia), the HSCT was tested for muscle loss, immunodeficiency and space anemia. The results indicate feasibility of HSCT for these disorders. To facilitate the HSCT in space, growth of HSCs were optimized in the NASA Rotating Wall Vessel (RWV) culture systems, including Hydrodynamic Focusing Bioreactor (HFB).

  20. Pharmacoeconomics of Hematopoietic Stem Cell Mobilization : An Overview of Current Evidence and Gaps in the Literature

    NARCIS (Netherlands)

    Shaughnessy, Paul; Chao, Nelson; Shapiro, Jamie; Walters, Kent; McCarty, John; Abhyankar, Sunil; Shayani, Sepideh; Helmons, Pieter; Leather, Helen; Pazzalia, Amy; Pickard, Simon

    Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have

  1. Isolation and characterization of hematopoietic stem cells in teleost fish.

    Science.gov (United States)

    Kobayashi, Isao; Katakura, Fumihiko; Moritomo, Tadaaki

    2016-05-01

    Despite 400 million years of evolutionary divergence, hematopoiesis is highly conserved between mammals and teleost fish. All types of mature blood cells including the erythroid, myeloid, and lymphoid lineages show a high degree of similarity to their mammalian counterparts at the morphological and molecular level. Hematopoietic stem cells (HSCs) are cells that are capable of self-renewal and differentiating into all hematopoietic lineages over the lifetime of an organism. The study of HSCs has been facilitated through bone marrow transplantation experiments developed in the mouse model. In the last decade, the zebrafish and clonal ginbuna carp (Carassius auratus langsdorfii) have emerged as new models for the study of HSCs. This review highlights the recent progress and future prospects of studying HSCs in teleost fish. Transplantation assays using these teleost models have demonstrated the presence of HSCs in the kidney, which is the major hematopoietic organ in teleost fish. Moreover, it is possible to purify HSCs from the kidney utilizing fluorescent dyes or transgenic animals. These teleost models will provide novel insights into the universal mechanisms of HSC maintenance, homeostasis, and differentiation among vertebrates. Copyright © 2016. Published by Elsevier Ltd.

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  15. The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Chakradhara Rao S. Uppugunduri

    2017-07-01

    Full Text Available Hemorrhagic cystitis (HC is one of the complications of busulfan-cyclophosphamide (BU-CY conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU levels were measured in 39 children following treatment with BU-CY regimen. The cytotoxic effects of Su and acrolein (Ac, water soluble metabolite of CY were tested on human urothelial cells (HUCs. The effect of Su was also tested on cytochrome P 450 (CYP function in HepaRG hepatic cells. Cumulative incidences of HC before day 30 post HSCT were estimated using Kaplan–Meier curves and log-rank test was used to compare the difference between groups in a univariate analysis. Multivariate Cox regression was used to estimate hazard ratios with 95% confidence intervals (CIs. Multivariate analysis included co-variables that were significantly associated with HC in a univariate analysis. Cumulative incidence of HC was 15.3%. In the univariate analysis, HC incidence was significantly (p < 0.05 higher in children older than 10 years (28.6 vs. 6.8% or in children with higher Su levels (>40 vs. <11% or in carriers of both functional GSTM1 and CYP2C9 (33.3 vs. 6.3% compared to the other group. In a multivariate analysis, combined GSTM1 and CYP2C9 genotype status was associated with HC occurrence with a hazards ratio of 4.8 (95% CI: 1.3–18.4; p = 0.02. Ac was found to be toxic to HUC cells at lower concentrations (33 μM, Su was not toxic to HUC cells at concentrations below 1 mM and did not affect CYP function in HepaRG cells. Our observations suggest that pre-emptive genotyping of CYP2C9 and GSTM1 may aid in selection of more effective prophylaxis to

  16. Melanoma Stem Cells and Metastasis: Mimicking Hematopoietic Cell Trafficking?

    Science.gov (United States)

    Lee, Nayoung; Barthel, Steven R.; Schatton, Tobias

    2014-01-01

    Malignant melanoma is a highly metastatic cancer that bears responsibility for the majority of skin cancer-related deaths. Amidst the research efforts to better understand melanoma progression, there has been increasing evidence that hints at a role for a subpopulation of virulent cancer cells, termed malignant melanoma stem or initiating cells (MMICs), in metastasis formation. MMICs are characterized by their preferential ability to initiate and propagate tumor growth and their selective capacity for self-renewal and differentiation into less tumorigenic melanoma cells. The frequency of MMICs has been shown to correlate with poor clinical prognosis in melanoma. Additionally, MMICs are enriched among circulating tumor cells (CTCs) in the peripheral blood of cancer patients, suggesting that MMICs may be a critical player in the metastatic cascade. Although these links exist between MMICs and metastatic disease, the mechanisms by which MMICs may advance metastatic progression are only beginning to be elucidated. Recent studies have shown that MMICs express molecules critical for hematopoietic cell maintenance and trafficking, providing a possible explanation for how circulating MMICs could drive melanoma dissemination. We therefore propose that MMICs might fuel melanoma metastasis by exploiting homing mechanisms commonly utilized by hematopoietic cells. Here we review the biological properties of MMICs and the existing literature on their metastatic potential. We will discuss possible mechanisms by which MMICs might initiate metastases in the context of established knowledge of cancer stem cells (CSCs) in other cancers and of hematopoietic homing molecules, with a particular focus on selectins, integrins, chemokines, and chemokine receptors known to be expressed by melanoma cells. Biological understanding of how these molecules might be utilized by MMICs to propel the metastatic cascade could critically impact the development of more effective therapies for advanced

  17. Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization

    Science.gov (United States)

    Emmons, Russell; Niemiro, Grace M.; De Lisio, Michael

    2016-01-01

    Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers. PMID:27123008

  18. 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.

  19. Mesenchymal stromal cells and hematopoietic stem cell transplantation.

    Science.gov (United States)

    Bernardo, Maria Ester; Fibbe, Willem E

    2015-12-01

    Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent cells that can be isolated from various human tissues and culture-expanded ex vivo for clinical use. Due to their immunoregulatory properties and their ability to secrete growth factors, MSCs play a key role in the regulation of hematopoiesis and in the modulation of immune responses against allo- and autoantigens. In light of these properties, MSCs have been employed in clinical trials in the context of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs) and to prevent graft failure, as well as to treat steroid-resistant acute graft-versus-host disease (GvHD). The available clinical evidence derived from these studies indicates that MSC administration is safe. Moreover, promising preliminary results in terms of efficacy have been reported in some clinical trials, especially in the treatment of acute GvHD. In this review we critically discuss recent advances in MSC therapy by reporting on the most relevant studies in the field of HSCT. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  20. Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization.

    Science.gov (United States)

    Emmons, Russell; Niemiro, Grace M; De Lisio, Michael

    2016-01-01

    Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers.

  1. Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization

    Directory of Open Access Journals (Sweden)

    Russell Emmons

    2016-01-01

    Full Text Available Hematopoietic stem cell transplant (HSCT using mobilized peripheral blood hematopoietic stem cells (HSPCs is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers.

  2. Desensitization for solid organ and hematopoietic stem cell transplantation

    Science.gov (United States)

    Zachary, Andrea A; Leffell, Mary S

    2014-01-01

    Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. PMID:24517434

  3. Eculizumab before and after allogeneic hematopoietic stem cell transplantation in a patient with paroxysmal nocturnal hemoglobinuria

    Directory of Open Access Journals (Sweden)

    Hakan Göker

    2011-09-01

    Full Text Available Paroxysmal nocturnal hemoglobinuria (PNH is characterized by the triad of intravascular hemolysis, venous thrombosis, and cytopenia. Treatment of PNH is generally supportive. Bone marrow transplantation is the only curative therapy for PNH, but is associated with significant morbidity and mortality. Herein, we present a patient with PNH that received eculizumab, a humanized monoclonal antibody that blocks activation of the terminal complement at C5, before and immediately following allogeneic peripheral stem cell transplantation. Prior to hematopoietic stem cell transplantation eculizumab treatment markedly reduced hemolysis and transfusion requirement; however, 1 d post transplantation a hemolytic episode occured, which was successfully stopped with eculizumab re-treatment. Afterwards the patient did not require additional transfusions. The results of this study indicate that early administration of eculizumab may be a safe and effective therapy for hemolytic episodes associated with allogeneic peripheral stem cell transplantation in patients with PNH.

  4. TET2 deficiency inhibits mesoderm and hematopoietic differentiation in human embryonic stem cells

    DEFF Research Database (Denmark)

    Langlois, Thierry; da Costa Reis Monte Mor, Barbara; Lenglet, Gaëlle

    2014-01-01

    . Here, we show that TET2 expression is low in human embryonic stem (ES) cell lines and increases during hematopoietic differentiation. ShRNA-mediated TET2 knockdown had no effect on the pluripotency of various ES cells. However, it skewed their differentiation into neuroectoderm at the expense...... profile, including abnormal expression of neuronal genes. Intriguingly, when TET2 was knockdown in hematopoietic cells, it increased hematopoietic development. In conclusion, our work suggests that TET2 is involved in different stages of human embryonic development, including induction of the mesoderm...... and hematopoietic differentiation. Stem Cells 2014....

  5. Enhancement of committed hematopoietic stem cell colony formation by nandrolone decanoate after sublethal whole body irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Gallicchio, V.S.; Chen, M.G.; Watts, T.D.

    1984-11-01

    The ability of an anabolic steroid, nandrolone decanoate, to increase committed topoietic stem cell (CFU-gm, CFU-e, and BFU-e) colony formation after sublethal irradiation was evaluated. Immediately after receiving whole body irradiation and on the next two days, each mouse was injected intraperitoneally with nandrolone decanoate (1.25 mg) in propylene glycol. Irradiated control mice received only propylene glycol. Compared to controls, drug-treated mice showed marked peripheral blood leukocytosis and more stable packed red cell volume. Drug-treated mice also demonstrated increased erythropoiesis, as CFU-e/BFU-e concentrations from both marrow (9% to 581%) and spleen (15% to 797%) were elevated. Granulopoiesis was increased similarly, as CFU-gm concentrations from marrow (38% to 685%) and spleen (9% to 373%) were elevated. These results demonstrate that nandrolone decanoate enhances hematopoietic stem cell recovery after sublethal whole body irradiation. This suggests that following hematopoietic suppression, nandrolone decanoate may stimulate the recovery of hematopoiesis at the stem cell level and in peripheral blood.

  6. A new chapter: hematopoietic stem cells are direct players in immunity

    Directory of Open Access Journals (Sweden)

    Zheng Junke

    2011-10-01

    Full Text Available Abstract Several lines of evidence support the hypothesis that hematopoietic stem cells (HSCs directly interact with the immune system and have potential for immune privilege. Although the microenvironment or niche provides protection for HSCs from immune attack, HSCs are also capable of interacting with the immune system as signal "providers" and signal "receivers". On the one hand, HSCs display surface immune inhibitory molecules to evade the attack from the innate and adaptive immune systems; on the other hand, HSCs are capable of directly sensing the signals from the immune system through their surface receptors. Thus, HSCs are important direct players in the immune system.

  7. 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...... for underlying malignant diseases was 4% at 5 years (95% CI, 0% to 12%). In summary, this study shows that selected patients receiving SOT after HSCT have a remarkably good overall and organ survival. These data indicate that SOT should be considered in selected patients with single organ failure after HSCT....

  8. Prostaglandin E2 increases hematopoietic stem cell survival and accelerates hematopoietic recovery after radiation injury

    Science.gov (United States)

    Porter, Rebecca L.; Georger, Mary; Bromberg, Olga; McGrath, Kathleen E.; Frisch, Benjamin J.; Becker, Michael W.; Calvi, Laura M.

    2013-01-01

    Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sub-lethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analogue (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-SMA+ subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogues may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression. PMID:23169593

  9. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells.

    Science.gov (United States)

    Guidi, Novella; Sacma, Mehmet; Ständker, Ludger; Soller, Karin; Marka, Gina; Eiwen, Karina; Weiss, Johannes M; Kirchhoff, Frank; Weil, Tanja; Cancelas, Jose A; Florian, Maria Carolina; Geiger, Hartmut

    2017-04-03

    Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging. © 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  10. Validation of a Pediatric Early Warning Score in Hospitalized Pediatric Oncology and Hematopoietic Stem Cell Transplant Patients.

    Science.gov (United States)

    Agulnik, Asya; Forbes, Peter W; Stenquist, Nicole; Rodriguez-Galindo, Carlos; Kleinman, Monica

    2016-04-01

    To evaluate the correlation of a Pediatric Early Warning Score with unplanned transfer to the PICU in hospitalized oncology and hematopoietic stem cell transplant patients. We performed a retrospective matched case-control study, comparing the highest documented Pediatric Early Warning Score within 24 hours prior to unplanned PICU transfers in hospitalized pediatric oncology and hematopoietic stem cell transplant patients between September 2011 and December 2013. Controls were patients who remained on the inpatient unit and were matched 2:1 using age, condition (oncology vs hematopoietic stem cell transplant), and length of hospital stay. Pediatric Early Warning Scores were documented by nursing staff at least every 4 hours as part of routine care. Need for transfer was determined by a PICU physician called to evaluate the patient. A large tertiary/quaternary free-standing academic children's hospital. One hundred ten hospitalized pediatric oncology patients (42 oncology, 68 hematopoietic stem cell transplant) requiring unplanned PICU transfer and 220 matched controls. None. Using the highest score in the 24 hours prior to transfer for cases and a matched time period for controls, the Pediatric Early Warning Score was highly correlated with the need for PICU transfer overall (area under the receiver operating characteristic = 0.96), and in the oncology and hematopoietic stem cell transplant groups individually (area under the receiver operating characteristic = 0.95 and 0.96, respectively). The difference in Pediatric Early Warning Score results between the cases and controls was noted as early as 24 hours prior to PICU admission. Seventeen patients died (15.4%). Patients with higher Pediatric Early Warning Scores prior to transfer had increased PICU mortality (p = 0.028) and length of stay (p = 0.004). We demonstrate that our institution's Pediatric Early Warning Score is highly correlated with the need for unplanned PICU transfer in hospitalized oncology and

  11. Molecular signatures of proliferation and quiescence in hematopoietic stem cells.

    Directory of Open Access Journals (Sweden)

    Teresa A Venezia

    2004-10-01

    Full Text Available Stem cells resident in adult tissues are principally quiescent, yet harbor enormous capacity for proliferation to achieve self renewal and to replenish their tissue constituents. Although a single hematopoietic stem cell (HSC can generate sufficient primitive progeny to repopulate many recipients, little is known about the molecular mechanisms that maintain their potency or regulate their self renewal. Here we have examined the gene expression changes that occur over a time course when HSCs are induced to proliferate and return to quiescence in vivo. These data were compared to data representing differences between naturally proliferating fetal HSCs and their quiescent adult counterparts. Bioinformatic strategies were used to group time-ordered gene expression profiles generated from microarrays into signatures of quiescent and dividing stem cells. A novel method for calculating statistically significant enrichments in Gene Ontology groupings for our gene lists revealed elemental subgroups within the signatures that underlie HSC behavior, and allowed us to build a molecular model of the HSC activation cycle. Initially, quiescent HSCs evince a state of readiness. The proliferative signal induces a preparative state, which is followed by active proliferation divisible into early and late phases. Re-induction of quiescence involves changes in migratory molecule expression, prior to reestablishment of homeostasis. We also identified two genes that increase in both gene and protein expression during activation, and potentially represent new markers for proliferating stem cells. These data will be of use in attempts to recapitulate the HSC self renewal process for therapeutic expansion of stem cells, and our model may correlate with acquisition of self renewal characteristics by cancer stem cells.

  12. Hematopoietic stem cells: concepts, definitions, and the new reality.

    Science.gov (United States)

    Eaves, Connie J

    2015-04-23

    Hematopoietic stem cell (HSC) research took hold in the 1950s with the demonstration that intravenously injected bone marrow cells can rescue irradiated mice from lethality by reestablishing blood cell production. Attempts to quantify the cells responsible led to the discovery of serially transplantable, donor-derived, macroscopic, multilineage colonies detectable on the spleen surface 1 to 2 weeks posttransplant. The concept of self-renewing multipotent HSCs was born, but accompanied by perplexing evidence of great variability in the outcomes of HSC self-renewal divisions. The next 60 years saw an explosion in the development and use of more refined tools for assessing the behavior of prospectively purified subsets of hematopoietic cells with blood cell-producing capacity. These developments have led to the formulation of increasingly complex hierarchical models of hematopoiesis and a growing list of intrinsic and extrinsic elements that regulate HSC cycling status, viability, self-renewal, and lineage outputs. More recent examination of these properties in individual, highly purified HSCs and analyses of their perpetuation in clonally generated progeny HSCs have now provided definitive evidence of linearly transmitted heterogeneity in HSC states. These results anticipate the need and use of emerging new technologies to establish models that will accommodate such pluralistic features of HSCs and their control mechanisms. © 2015 by The American Society of Hematology.

  13. File list: InP.Bld.05.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  16. 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

  17. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Ohi, S.

    Departments of Biochemistry &Molecular Biology, Genetics &Human Genetics, Pediatrics &Child Long-duration space missions require countermeasures against severe/invasive disorders in astronauts that are caused by space environments, such as hematological/cardiac abnormalities, bone/muscle losses, immunodeficiency, neurological disorders, and cancer. Some, if not all, of these disorders may be amenable to hematopoietic stem cell therapy and gene therapy. Growing evidence indicates that hematopoietic stem cells (HSCs) possess extraordinary plasticity to differentiate not only to all types of blood cells but also to various tissues, including bone, muscle, skin, liver and neuronal cells. Therefore, our working hypothesis is that the hematopoietic stem cell-based therapy, herein called as the hematopoietic stem cell therapy (HSCT), might provide countermeasure/prevention for hematological abnormalities, bone and muscle losses in space, thereby maintaining astronauts' homeostasis. Our expertise lies in recombinant adeno-associated virus (rAAV)-mediated gene therapy for the hemoglobinopathies, -thalassemia and sickle cell disease (Ohi S, Kim BC, J Pharm Sci 85: 274-281, 1996; Ohi S, et al. Grav Space Biol Bull 14: 43, 2000). As the requisite steps in this protocol, we established procedures for purification of HSCs from both mouse and human bone marrow in 1 G. Furthermore, we developed an easily harvestable, long-term liquid suspension culture system, which lasts more than one year, for growing/expanding HSCs without stromal cells. Human globin cDNAs/gene were efficiently expressed from the rAAVs in the mouse HSCs in culture. Additionally, the NASA Rotating Wall Vessel (RWV) culture system is being optimized for the HSC growth/expansion. Thus, using these technologies, the above hypothesis is being investigated by the ground-based experiments as follows: 1) -thalassemic mice (C57BL/6-Hbbth/Hbbth, Hbd-minor) are transplanted with normal isologous HSCs to correct the

  18. Iron Overload in Patients Undergoing Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Vinod Pullarkat

    2010-01-01

    Full Text Available Recipients of hematopoietic stem cell transplantation (HSCT frequently have iron overload resulting from chronic transfusion therapy for anemia. In some cases, for example, in patients with myelodysplastic syndromes and thalassemia, this can be further exacerbated by increased absorption of iron from the gut as a result of ineffective erythropoiesis. Accumulating evidence has established the negative impact of elevated pretransplantation serum ferritin, a surrogate marker of iron overload, on overall survival and nonrelapse mortality after HSCT. Complications of HSCT associated with iron overload include increased bacterial and fungal infections as well as sinusoidal obstruction syndrome and possibly other regimen-related toxicities. Based on current evidence, particular attention should be paid to prevention and management of iron overload in allogeneic HSCT candidates, especially in patients with thalassemia and myelodysplastic syndromes. The pathophysiology of iron overload in the HSCT patient and optimum strategies to deal with iron overload during and after HSCT require further study.

  19. Genetic Engineering and Manufacturing of Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Xiuyan Wang

    2017-06-01

    Full Text Available The marketing approval of genetically engineered hematopoietic stem cells (HSCs as the first-line therapy for the treatment of severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID is a tribute to the substantial progress that has been made regarding HSC engineering in the past decade. Reproducible manufacturing of high-quality, clinical-grade, genetically engineered HSCs is the foundation for broadening the application of this technology. Herein, the current state-of-the-art manufacturing platforms to genetically engineer HSCs as well as the challenges pertaining to production standardization and product characterization are addressed in the context of primary immunodeficiency diseases (PIDs and other monogenic disorders.

  20. Bone Marrow Vascular Niche: Home for Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Ningning He

    2014-01-01

    Full Text Available Though discovered later than osteoblastic niche, vascular niche has been regarded as an alternative indispensable niche operating regulation on hematopoietic stem cells (HSCs. As significant progresses gained on this type niche, it is gradually clear that the main work of vascular niche is undertaking to support hematopoiesis. However, compared to what have been defined in the mechanisms through which the osteoblastic niche regulates hematopoiesis, we know less in vascular niche. In this review, based on research data hitherto we will focus on component foundation and various functions of vascular niche that guarantee the normal hematopoiesis process within bone marrow microenvironments. And the possible pathways raised by various research results through which this environment undergoes its function will be discussed as well.

  1. HSC-explorer: a curated database for hematopoietic stem cells.

    Directory of Open Access Journals (Sweden)

    Corinna Montrone

    Full Text Available HSC-Explorer (http://mips.helmholtz-muenchen.de/HSC/ is a publicly available, integrative database containing detailed information about the early steps of hematopoiesis. The resource aims at providing fast and easy access to relevant information, in particular to the complex network of interacting cell types and molecules, from the wealth of publications in the field through visualization interfaces. It provides structured information on more than 7000 experimentally validated interactions between molecules, bioprocesses and environmental factors. Information is manually derived by critical reading of the scientific literature from expert annotators. Hematopoiesis-relevant interactions are accompanied with context information such as model organisms and experimental methods for enabling assessment of reliability and relevance of experimental results. Usage of established vocabularies facilitates downstream bioinformatics applications and to convert the results into complex networks. Several predefined datasets (Selected topics offer insights into stem cell behavior, the stem cell niche and signaling processes supporting hematopoietic stem cell maintenance. HSC-Explorer provides a versatile web-based resource for scientists entering the field of hematopoiesis enabling users to inspect the associated biological processes through interactive graphical presentation.

  2. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues

    NARCIS (Netherlands)

    Jokubaitis, Vanta J.; Sinka, Lidia; Driessen, Rebecca; Whitty, Genevieve; Haylock, David N.; Bertoncello, Ivan; Smith, Ian; Peault, Bruno; Tavian, Manuela; Simmons, Paul J.

    2008-01-01

    Previous studies revealed that mAb BB9 reacts with a subset of CD34(+) human BM cells with hematopoietic stem cell (HSC) characteristics. Here we map B89 expression throughout hernatopoietic development and show that the earliest definitive HSCs that arise at the ventral wall of the aorta and

  3. Collection of peripheral hematopoietic stem/progenitor cells.

    Science.gov (United States)

    Dihenescikova, V Rimajova; Mistrik, M; Martinka, J; Zwiewka, M; Bizikova, I; Batorova, A

    2015-01-01

    Several variables possibly affecting collection of peripheral hematopoietic stem/progenitor cells (PBSC) were evaluated: type of apheresis machine (Amicus version 2.5, Baxter vs Cobe Spectra version 7.0, Terumo BCT), venous access (peripheral vein vs central venous catheter, i.g. CVC), and apheresis regimen (standard vs large volume leukapheresis, i.g. SVL vs LVL) with the objective to increase collection efficacy at the site. Peripheral blood represents the currently preferred source of hematopoietic stem/progenitor cells (HSCs) for transplantation. Data regarding 169 collection procedures performed in healthy donors and patients between January 2008 and December 2011 at the Clinics of Haematology and Transfusiology in St Cyril and Method Hospital in Bratislava (Slovakia) were analysed. With Cobe Spectra apheresis machine it was possible to process larger blood volumes per procedure with higher CD34+ cell collection efficiency (p = 0.0229) and lower RBC contamination of the harvest than with Amicus (p = 0.0116). On the other hand, Amicus helped to limit PLT contamination of the harvest (p < 0.0001), thus minimizing post-procedural decrease in patient´s PLT count. The highest detected advantage of CVC usage was higher flow rate of procedure, thus processing larger blood volumes per unit of time. Interesting finding was the tendency to lower harvest PLT contamination (p = 0.054). When LVL was performed, significantly higher HSCs yields were collected, even in "poor mobilizers" when the pre-run parameters were low. Management of PBSC collection requires a particular approach in each subject. Institutionally and individually optimized collection may help to improve the transplantation outcome and decrease the financial costs (Tab. 8, Ref. 15).

  4. The Hematopoietic Stem Cell Therapy for Exploration of Deep Space

    Science.gov (United States)

    Ohi, Seigo; Roach, Allana-Nicole; Ramsahai, Shweta; Kim, Bak C.; Fitzgerald, Wendy; Riley, Danny A.; Gonda, Steven R.

    2004-02-01

    Astronauts experience severe/invasive disorders caused by space environments. These include hematological and cardiac abnormalities, bone and muscle losses, immunodeficiency, neurological disorders and cancer. Exploiting the extraordinary plasticity of hematopoietic stem cells (HSCs), which differentiate not only to all types of blood cells, but also to various tissues, including muscle, bone, skin, liver, and neuronal cells, we advanced a hypothesis that some of the space-caused disorders might be amenable to hematopoietic stem cell therapy (HSCT) so as to maintain astronauts' homeostasis. If this were achievable, the HSCT could promote human exploration of deep space. Using mouse models of human anemia (β-thalassemia) and spaceflight (hindlimb suspension unloading system), we have obtained feasibility results of HSCT for space anemia, muscle loss, and immunodeficiency. For example, the β-thalassemic mice were successfully transplanted with isologous HSCs, resulting in chimerism of hemoglobin species and alleviation of the hemoglobinopathy. In the case of HSCT for muscle loss, β-galactosidase-marked HSCs, which were prepared from β-galactosidase-transgenic mice, were detected by the X-gal wholemount staining procedure in the hindlimbs of unloaded mice following transplantation. Histochemical and physical analyses indicated structural contribution of HSCs to the muscle. To investigate HSCT for immunodeficiency, β-galactosidase-transformed Escherichia coli was used as the reporter bacteria, and infected to control and the hindlimb suspended mice. Results of the X-gal stained tissues indicated that the HSCT could help eliminate the E. coli infection. In an effort to facilitate the HSCT in space, growth of HSCs has been optimized in the NASA Rotating Wall Vessel (RWV) culture systems, including Hydrodynamic Focusing Bioreactor (HFB).

  5. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

    NARCIS (Netherlands)

    van Pel, M; van Os, R; Velders, GA; Hagoort, H; Heegaard, PMH; Lindley, IJD; Willemze, R; Fibbe, WE

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory

  6. Hes repressors are essential regulators of hematopoietic stem cell development downstream of notch signaling

    NARCIS (Netherlands)

    J. Guiu (Jordi); R. Shimizu (Ritsuko); C. D'Altri; S.T. Fraser (Stuart); S. Hatakeyama (Shingo); E.H. Bresnick (Emery); T. Kageyama (Tsutomu); E.A. Dzierzak (Elaine); M. Yamamoto (Masayuki); L. Espinosa (Lluis); A. Bigas (Anna)

    2013-01-01

    textabstractPrevious studies have identified Notch as a key regulator of hematopoietic stem cell (HSC) development, but the underlying downstream mechanisms remain unknown. The Notch target Hes1 is widely expressed in the aortic endothelium and hematopoietic clusters, though Hes1-deficient mice show

  7. Invasive Mechanical Ventilation and Mortality in Pediatric Hematopoietic Stem Cell Transplantation: A Multicenter Study.

    Science.gov (United States)

    Rowan, Courtney M; Gertz, Shira J; McArthur, Jennifer; Fitzgerald, Julie C; Nitu, Mara E; Loomis, Ashley; Hsing, Deyin D; Duncan, Christine N; Mahadeo, Kris M; Smith, Lincoln S; Moffet, Jerelyn; Hall, Mark W; Pinos, Emily L; Cheifetz, Ira M; Tamburro, Robert F

    2016-04-01

    To establish the current respiratory practice patterns in pediatric hematopoietic stem cell transplant patients and investigate their associations with mortality across multiple centers. Retrospective cohort between 2009 and 2014. Twelve children's hospitals in the United States. Two hundred twenty-two pediatric allogeneic hematopoietic stem cell transplant recipients with acute respiratory failure using invasive mechanical ventilation. None. PICU mortality of our cohort was 60.4%. Mortality at 180 days post PICU discharge was 74%. Length of PICU stay prior to initiation of invasive mechanical ventilation was significantly lower in survivors, and the odds of mortality increased for longer length of PICU stay prior to intubation. A total of 91 patients (41%) received noninvasive ventilation at some point during their PICU stay prior to intubation. Noninvasive ventilation use preintubation was associated with increased mortality (odds ratio, 2.1; 95% CI, 1.2-3.6; p = 0.010). Patients ventilated longer than 15 days had higher odds of death (odds ratio, 2.4; 95% CI, 1.3-4.2; p = 0.004). Almost 40% of patients (n = 85) were placed on high-frequency oscillatory ventilation with a mortality of 76.5% (odds ratio, 3.3; 95% CI, 1.7-6.5; p = 0.0004). Of the 20 patients who survived high-frequency oscillatory ventilation, 18 were placed on high-frequency oscillatory ventilation no later than the third day of invasive mechanical ventilation. In this subset of 85 patients, transition to high-frequency oscillatory ventilation within 2 days of the start of invasive mechanical ventilation resulted in a 76% decrease in the odds of death compared with those who transitioned to high-frequency oscillatory ventilation later in the invasive mechanical ventilation course. This study suggests that perhaps earlier more aggressive critical care interventions in the pediatric hematopoietic stem cell transplant patient with respiratory failure requiring invasive mechanical ventilation may

  8. DNA damage: a sensible mediator of the differentiation decision in hematopoietic stem cells and in leukemia.

    Science.gov (United States)

    Weiss, Cary N; Ito, Keisuke

    2015-03-17

    In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche.

  9. DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia

    Directory of Open Access Journals (Sweden)

    Cary N. Weiss

    2015-03-01

    Full Text Available In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche.

  10. Oral features and dental health in Hurler Syndrome following hematopoietic stem cell transplantation.

    LENUS (Irish Health Repository)

    McGovern, Eleanor

    2010-09-01

    Hurler Syndrome is associated with a deficiency of a specific lysosomal enzyme involved in the degradation of glycosaminoglycans. Hematopoietic stem cell transplantation (HSCT) in early infancy is undertaken to help prevent the accumulation of glycosaminoglycans and improve organ function.

  11. Restricted intra-embryonic origin of bona fide hematopoietic stem cells in the chicken

    NARCIS (Netherlands)

    Yvernogeau, Laurent; Robin, Catherine

    2017-01-01

    Hematopoietic stem cells (HSCs), which are responsible for blood cell production, are generated during embryonic development. Human and chicken embryos share features that position the chicken as a reliable and accessible alternative model to study developmental hematopoiesis. However, the existence

  12. Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation.

    Science.gov (United States)

    Kollek, Matthias; Voigt, Gesina; Molnar, Christian; Murad, Fabronia; Bertele, Daniela; Krombholz, Christopher Felix; Bohler, Sheila; Labi, Verena; Schiller, Stefan; Kunze, Mirjam; Geley, Stephan; Niemeyer, Charlotte M; Garcia-Saez, Ana; Erlacher, Miriam

    2017-10-02

    During hematopoietic stem cell transplantation, a substantial number of donor cells are lost because of apoptotic cell death. Transplantation-associated apoptosis is mediated mainly by the proapoptotic BCL-2 family proteins BIM and BMF, and their proapoptotic function is conserved between mouse and human stem and progenitor cells. Permanent inhibition of apoptosis in donor cells caused by the loss of these BH3-only proteins improves transplantation outcome, but recipients might be exposed to increased risk of lymphomagenesis or autoimmunity. Here, we address whether transient inhibition of apoptosis can serve as a safe but efficient alternative to improve the outcome of stem cell transplantation. We show that transient apoptosis inhibition by short-term overexpression of prosurvival BCL-XL, known to block BIM and BMF, is not only sufficient to increase the viability of hematopoietic stem and progenitor cells during engraftment but also improves transplantation outcome without signs of adverse pathologies. Hence, this strategy represents a promising and novel therapeutic approach, particularly under conditions of limited donor stem cell availability. © 2017 Kollek et al.

  13. The histone demethylase Jarid1b is required for hematopoietic stem cell self-renewal

    DEFF Research Database (Denmark)

    Stewart, Morag H; Albert, Mareike; Sroczynska, Patrycja

    2015-01-01

    Jarid1b/KDM5b is a histone demethylase that regulates self-renewal and differentiation in stem cells and cancer, however its function in hematopoiesis is unclear. Here, we find that Jarid1b is highly expressed in primitive hematopoietic compartments and is overexpressed in acute myeloid leukemias...... compromises hematopoietic stem cell (HSC) self-renewal capacity and suggest that Jarid1b is a positive regulator of HSC potential....

  14. Clonal dominance and transplantation dynamics in hematopoietic stem cell compartments.

    Directory of Open Access Journals (Sweden)

    Peter Ashcroft

    2017-10-01

    Full Text Available Hematopoietic stem cells in mammals are known to reside mostly in the bone marrow, but also transitively passage in small numbers in the blood. Experimental findings have suggested that they exist in a dynamic equilibrium, continuously migrating between these two compartments. Here we construct an individual-based mathematical model of this process, which is parametrised using existing empirical findings from mice. This approach allows us to quantify the amount of migration between the bone marrow niches and the peripheral blood. We use this model to investigate clonal hematopoiesis, which is a significant risk factor for hematologic cancers. We also analyse the engraftment of donor stem cells into non-conditioned and conditioned hosts, quantifying the impact of different treatment scenarios. The simplicity of the model permits a thorough mathematical analysis, providing deeper insights into the dynamics of both the model and of the real-world system. We predict the time taken for mutant clones to expand within a host, as well as chimerism levels that can be expected following transplantation therapy, and the probability that a preconditioned host is reconstituted by donor cells.

  15. Differential bone marrow hematopoietic stem cells mobilization in hepatectomized patients.

    Science.gov (United States)

    Herencia, Carmen; Rodríguez-Ariza, Antonio; Canalejo, Antonio; Naranjo, Alvaro; Briceño, F Javier; López-Cillero, Pedro; De la Mata, Manuel; Muñoz-Castañeda, Juan R

    2011-08-01

    The involvement of bone marrow hematopoietic stem cells (BMHSC) mobilization during liver regeneration from hepatectomized patients is under debate. The main aim of this study was to investigate the role of BMHSC mobilization after hepatic resection in 33 patients with liver disease. Mobilization of CD34(+) BMHSC after 72 h of surgery was found in peripheral blood of some, but not all, of the hepatectomized patients. These CD34(+) cells co-expressed other stem cells markers. The patients without BMHSC mobilization showed high levels of circulating and liver tissue BMHSC (CD34(+) cells) previous to surgery. Therefore, two types of patients: "mobilizers" and "non-mobilizers" were distinguished based on the values of CD34(+) cells before and after surgery. Changes in cytokines involved in the hepatic regeneration (HGF and TGF-β), and in BMHSC mobilization process (SCF, SDF-1, IL-12, or MMP-2), were detected in both groups. In addition, a higher activation previous to surgery of the SDF-1/CXCR4 axis in liver tissue was observed in non mobilizers patients compared to mobilizer patients. BMHSC mobilization seems to be associated with variations in the levels of cytokines and proteolytic enzymes involved in hepatic regeneration and bone marrow matrix degradation. Hepatectomy may be an insufficient stimulus for BMSHC mobilization. The pre-hepatectomy higher levels CD34(+) cells in peripheral blood and liver, associated to the activation of hepatic SDF-1/CXCR4 axis, suggest a BMHSC mobilization process previous to surgery in non mobilizer patients.

  16. Reconstitution of mammary epithelial morphogenesis by murine embryonic stem cells undergoing hematopoietic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Shuxian Jiang

    2010-03-01

    Full Text Available Mammary stem cells are maintained within specific microenvironments and recruited throughout lifetime to reconstitute de novo the mammary gland. Mammary stem cells have been isolated through the identification of specific cell surface markers and in vivo transplantation into cleared mammary fat pads. Accumulating evidence showed that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary epithelial cells may be sequestered and reprogrammed to perform mammary epithelial cell functions and to adopt mammary epithelial characteristics during reconstruction of mammary epithelium in regenerating mammary tissue in vivo.To examine whether other types of progenitor cells are able to contribute to mammary branching morphogenesis, we examined the potential of murine embryonic stem (mES cells, undergoing hematopoietic differentiation, to support mammary reconstitution in vivo. We observed that cells from day 14 embryoid bodies (EBs under hematopoietic differentiation condition, but not supernatants derived from these cells, when transplanted into denuded mammary fat pads, were able to contribute to both the luminal and myoepithelial lineages in branching ductal structures resembling the ductal-alveolar architecture of the mammary tree. No teratomas were observed when these cells were transplanted in vivo.Our data provide evidence for the dominance of the tissue-specific mammary stem cell niche and its role in directing mES cells, undergoing hematopoietic differentiation, to reprogram into mammary epithelial cells and to promote mammary epithelial morphogenesis. These studies should also provide insights into regeneration of damaged mammary gland and the role of the mammary microenvironment in reprogramming cell fate.

  17. Unrelated hematopoietic stem cell transplantation in the pediatric population: single institution experience

    Directory of Open Access Journals (Sweden)

    Daniela Hespanha Marinho

    2015-08-01

    Full Text Available OBJECTIVE: Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution.METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test.RESULTS: This study included 118 patients (46.8% who received bone marrow and 134 (53.2% who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value < 0.001. Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value = 0.653. Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value = 0.007. Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value = 0.117. Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value = 0.4666.CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups.

  18. Sowing the Seeds of a Fruitful Harvest: Hematopoietic Stem Cell Mobilization

    Science.gov (United States)

    Hoggatt, Jonathan; Speth, Jennifer M.; Pelus, Louis M.

    2014-01-01

    Hematopoietic stem cell transplantation is the only curative option for a number of malignant and non-malignant diseases. As the use of hematopoietic transplant has expanded, so too has the source of stem and progenitor cells. The predominate source of stem and progenitors today, particularly in settings of autologous transplantation, is mobilized peripheral blood. This review will highlight the historical advances which lead to the widespread use of peripheral blood stem cells for transplantation, with a look towards future enhancements to mobilization strategies. PMID:24123398

  19. Concise review: Sowing the seeds of a fruitful harvest: hematopoietic stem cell mobilization.

    Science.gov (United States)

    Hoggatt, Jonathan; Speth, Jennifer M; Pelus, Louis M

    2013-12-01

    Hematopoietic stem cell transplantation is the only curative option for a number of malignant and nonmalignant diseases. As the use of hematopoietic transplant has expanded, so too has the source of stem and progenitor cells. The predominate source of stem and progenitors today, particularly in settings of autologous transplantation, is mobilized peripheral blood. This review will highlight the historical advances which led to the widespread use of peripheral blood stem cells for transplantation, with a look toward future enhancements to mobilization strategies. © AlphaMed Press.

  20. Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

    Science.gov (United States)

    Weber, Catherine; Kasberg, Heather; Copelan, Edward

    2012-01-01

    Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

  1. Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

    Directory of Open Access Journals (Sweden)

    Catherine Weber

    2012-01-01

    Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

  2. Fetal hepatic progenitors support long-term expansion of hematopoietic stem cells.

    Science.gov (United States)

    Chou, Song; Flygare, Johan; Lodish, Harvey F

    2013-05-01

    We have developed a coculture system that establishes DLK(+) fetal hepatic progenitors as the authentic supportive cells for expansion of hematopoietic stem (HSCs) and progenitor cells. In 1-week cultures supplemented with serum and supportive cytokines, both cocultured DLK(+) fetal hepatic progenitors and their conditioned medium supported rapid expansion of hematopoietic progenitors and a small increase in HSC numbers. In 2- and 3-week cultures DLK(+) cells, but not their conditioned medium, continuously and significantly (>20-fold) expanded both hematopoietic stem and progenitor cells. Physical contact between HSCs and DLK(+) cells was crucial to maintaining this long-term expansion. Similar HSC expansion (approximately sevenfold) was achieved in cocultures using a serum-free, low cytokine- containing medium. In contrast, DLK(-) cells are incapable of expanding hematopoietic cells, demonstrating that hepatic progenitors are the principle supportive cells for HSC expansion in the fetal liver. Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  3. Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Murase, Kazuyuki; Kim, Haesook T; Bascug, O R Gregory; Kawano, Yutaka; Ryan, Jeremy; Matsuoka, Ken-ichi; Davids, Matthew S; Koreth, John; Ho, Vincent T; Cutler, Corey; Armand, Philippe; Alyea, Edwin P; Blazar, Bruce R; Antin, Joseph H; Soiffer, Robert J; Letai, Anthony; Ritz, Jerome

    2014-09-01

    CD4 regulatory T cells play a critical role in establishment of immune tolerance and prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. The recovery and maintenance of regulatory T cells is dependent on homeostatic factors including the generation of naïve regulatory T cells from hematopoietic precursor cells, the proliferation and expansion of mature regulatory T cells, and the survival of regulatory T cells in vivo. In this study, quantitation of mitochondrial apoptotic priming was used to compare susceptibility of regulatory T cells, conventional CD4 T cells and CD8 T cells to intrinsic pathway apoptosis in 57 patients after allogeneic hematopoietic stem cell transplantation and 25 healthy donors. In healthy donors, regulatory T cells are more susceptible to mitochondrial priming than conventional T cells. Mitochondrial priming is increased after hematopoietic stem cell transplantation in all T-cell subsets and particularly in patients with chronic graft-versus-host disease. Regulatory T cells express high levels of CD95 and are also more susceptible than conventional T cells to apoptosis through the extrinsic pathway. However, CD95 expression and extrinsic pathway apoptosis is not increased after hematopoietic stem cell transplantation. Decreased expression of BCL2 and increased expression of BIM, a mitochondrial cell death activator protein, in regulatory T cells contributes to increased mitochondrial priming in this T-cell subset but additional factors likely contribute to increased mitochondrial priming following hematopoietic stem cell transplantation. Copyright© Ferrata Storti Foundation.

  4. Monitoring the source of mesenchymal stem cells in patients after transplantation of mismatched-sex hematopoietic stem cells plus third-party cells.

    Science.gov (United States)

    Wang, Jing; Huang, Xiao-Jun; Xu, Lan-Ping; Liu, Dai-Hong; Chen, Huan; Chen, Yu-Hong; Lai, Yue-Yun; Hou, Rui-Qin; Qin, Xiao-Ying; Liu, Kai-Yan

    2013-11-01

    In bone marrow transplant patients, the microenvironment in bone marrow is damaged after chemotherapy or radiotherapy. Subsequent to allogenic hematopoietic stem cell transplantation in patients with clinically successful engraftments, the source of mesenchymal stem cells (MSCs) remains controversial. To further verify the stimulatory effect of the simultaneous transplantation of cells from second donors on engraftment success for hematopoietic stem cell transplantation in support of donor MSCs engraftments, the aim of this study is to monitor the dynamics of the engraftment of bone marrow-derived MSCs in patients after transplantation with mismatched-sex hematopoietic stem and third-party cells. In this study, the hematopoietic stem cells from 32 clinical donors of different sexes that resulted in successful engraftments were selected for transplantation and were classified into three groups for research purposes: group A consisted of 14 cases of transplantation with bone marrow and recruited peripheral hematopoietic stem cell transplantation, group B contained 8 cases of simultaneous re-transfusion of MSCs from the second donor, and group C contained 10 cases of simultaneous re-transfusion of umbilical blood from the second donor. The bone marrow from 32 patients with successful engraftments of hematopoietic transplantation were selected and sub-cultured with MSCs. Flow cytometry (FCM) was used to measure the expression of surface antigens on MSCs. Denaturing high-performance liquid chromatography (DHPLC) in combination with polymerase chain reaction amplification of short tandem repeats (STRPCR) was used to measure the engraftment status of fifth-generation MSCs in patients. Fluorescence in situ hybridization (FISH) revealed the sex origin of the fifth-generation MSCs in 32 patients. Dynamic examinations were performed on patients receiving donor transplantations. The progenies of fifth-generation MSCs were successfully cultured in 32 cases. The results of FCM

  5. Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation

    Science.gov (United States)

    Khoury, Hanna J.; Loberiza, Fausto R.; Ringdén, Olle; Barrett, A. John; Bolwell, Brian J.; Cahn, Jean-Yves; Champlin, Richard E.; Gale, Robert Peter; Hale, Gregory A.; Urbano-Ispizua, Alvaro; Martino, Rodrigo; McCarthy, Philip L.; Tiberghien, Pierre; Verdonck, Leo F.; Horowitz, Mary M.

    2006-01-01

    Granulocyte colony-stimulating factor (G-CSF) is often administered after hematopoietic-cell transplantation (HCT) to accelerate neutrophil recovery, but it is unclear what impact G-CSF has on long-term transplantation outcomes. We analyzed within the database of the Center for International Blood and Marrow Transplant Research the impact of giving posttransplantation G-CSF on the outcomes of allogeneic HCT for acute myelogenous leukemia and chronic myelogenous leukemia in 2719 patients who underwent transplantation between 1995 and 2000. These included 1435 recipients of HLA-identical sibling bone marrow (BM), 609 recipients of HLA-identical peripheral-blood stem cells (PBSCs), and 675 recipients of unrelated donor BM transplants. Outcomes were compared between patients receiving or not receiving G-CSF within 7 days of HCT according to graft type. Median follow-up was more than 30 months (range, 2-87 months). G-CSF shortened the posttransplantation neutropenic period, but did not affect days +30 and +100 treatment-related mortality (TRM). Probabilities of acute and chronic graft-versus-host disease (GVHD), leukemia-free survival (LFS), and overall survival were similar whether or not G-CSF was given. Multivariate analyses confirmed that giving G-CSF did not affect the risk of GVHD, TRM, LFS, or survival. In conclusion, results of this study found no long-term benefit or disadvantage of giving G-CSF after transplantation to promote hematopoietic recovery. PMID:16239431

  6. Liver fibrosis alleviation after co-transplantation of hematopoietic stem cells with mesenchymal stem cells in patients with thalassemia major.

    Science.gov (United States)

    Ghavamzadeh, Ardeshir; Sotoudeh, Masoud; Hashemi Taheri, Amir Pejman; Alimoghaddam, Kamran; Pashaiefar, Hossein; Jalili, Mahdi; Shahi, Farhad; Jahani, Mohammad; Yaghmaie, Marjan

    2018-02-01

    The aims of this study are to determine the replacement rate of damaged hepatocytes by donor-derived cells in sex-mismatched recipient patients with thalassemia major and to determine whether co-transplantation of mesenchymal stem cells and hematopoietic stem cells (HSCs) can alleviate liver fibrosis. Ten sex-mismatched donor-recipient pairs who received co-transplantation of HSCs with mesenchymal stem cells were included in our study. Liver biopsy was performed before transplantation. Two other liver biopsies were performed between 2 and 5 years after transplantation. The specimens were studied for the presence of donor-derived epithelial cells or hepatocytes using fluorescence in situ hybridization by X- and Y-centromeric probes and immunohistochemical staining for pancytokeratin, CD45, and a hepatocyte-specific antigen. All sex-mismatched tissue samples demonstrated donor-derived hepatocyte independent of donor gender. XY-positive epithelial cells or hepatocytes accounted for 11 to 25% of the cells in histologic sections of female recipients in the first follow-up. It rose to 47-95% in the second follow-up. Although not statistically significant, four out of ten patients showed signs of improvement in liver fibrosis. Our results showed that co-transplantation of HSC with mesenchymal stem cells increases the rate of replacement of recipient hepatocytes by donor-derived cells and may improve liver fibrosis.

  7. Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Francesco Orio

    2014-01-01

    Full Text Available Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo- and autologous- (auto- stem cell transplant (HSCT. This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma, gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.

  8. [Sirolimus associated pneumonitis in a hematopoietic stem cell transplant patient].

    Science.gov (United States)

    García, Estefanía; Buenasmañanas, Diana; Martín, Carmen; Rojas, Rafael

    2015-07-06

    Sirolimus (SR) is a lipophilic macrocytic lactone with immunosuppressive properties (mTOR inhibitor) commonly used in solid organ transplantation and recently introduced in the prophylaxis and treatment of graft-versus-host disease. Its numerous side effects include: hyperlipidemia, arthralgias, noncardiac peripheral edema, thrombotic microangiopathy and interstitial pneumonitis. SR-associated pneumonitis is a rare but potentially serious complication due to its increasing utilization in transplant patients. We report the case of a patient undergoing hematopoietic stem cell transplantation with severe respiratory distress and SR therapy. Microbiological tests were all negative and other complications related to transplantation were discarded. The chest computed tomography of high-resolution showed pneumonitis. The SR therapy was interrupted and treatment was started with steroids with resolution of symptoms. SR associated pneumonitis is a potentially fatal side effect. In patients treated with SR and respiratory failure, we must suspect this complication because early recognition along with drug discontinuation and steroid treatment is essential to reverse this complication. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  9. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells.

    Science.gov (United States)

    Pellagatti, A; Cazzola, M; Giagounidis, A; Perry, J; Malcovati, L; Della Porta, M G; Jädersten, M; Killick, S; Verma, A; Norbury, C J; Hellström-Lindberg, E; Wainscoat, J S; Boultwood, J

    2010-04-01

    To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or -7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with -7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention.

  10. Features of transfusion therapy in hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    M. A. Kucher

    2016-01-01

    Full Text Available The aim of the research is to identify factors influencing the safety and efficacy of the transfusion therapy with hematopoietic stem cell transplantation (HSCT. From January 1 to December 31, 2015, 329 patients with hematologic diseases and malignancies who had undergone 367 HSCT were included into the study. Transfusion therapy was conducted in 345 HSCT – 94 % of cases. Totally, 9074 cases of transfusion of blood components were recorded: red blood cellcontaining – 2378 (26.2 %, plateletcontaining – 6255 (68.9 %, fresh frozen plasma – 441 (4.9 %. АВ0incompatibility between the donor and recipient was determined in 60.4 % of cases (n=154 in HSCT from allogeneic donor. Acute «graft versus host disease» was observed in 34.9 % of cases (n=89. Hemorrhagic complications were in 46 cases (12.5 %, mainly nasal, gastrointestinal bleeding and hemorrhagic cystitis. Pprevention and treatment of anemic and hemorrhagic complications in HSCT requires longterm and massive transfusion therapy with the availability of АВ0-incompatibility. The use of leukofiltrated, γ - or x-ray irradiated, individually and immunologically compatible blood components can reduce the risk of development of acute and delayed transfusion reactions in HSCT. 

  11. Cytomegalovirus in hematopoietic stem cell transplant recipients - management of infection.

    Science.gov (United States)

    Locatelli, Franco; Bertaina, Alice; Bertaina, Valentina; Merli, Pietro

    2016-11-01

    Cytomegalovirus (CMV) still causes significant morbidity and mortality in patients given allogeneic hematopoietic stem cell transplantation (HSCT). Despite effective pharmacotherapy, potentially life-threatening CMV disease occurs nowadays in up to 10% of HSCT recipients; moreover, routinely used anti-CMV agents have been shown to be associated with morbidity. Areas covered: This review examines different issues related to diagnosis and management of CMV infection in HSCT recipients, paying particular attention to the monitoring of CMV-specific immune recovery, approaches of adoptive cell therapy and new antiviral drugs. Expert commentary: Despite advances in diagnostic tests and treatment, there is still room for refining management of CMV in HSCT recipients. Immunological monitoring should be associated in the future to virological monitoring. The safety profile and efficacy of new anti-CMV agents should be compared with that of standard-of-care drugs. Donor-derived, pathogen-specific T cells adoptively transferred after transplantation could contribute to reduce the impact of CMV infection on patient's outcome.

  12. Replication stress in hematopoietic stem cells in mouse and man.

    Science.gov (United States)

    Flach, Johanna; Milyavsky, Michael

    2017-10-18

    Life-long blood regeneration relies on a rare population of self-renewing hematopoietic stem cells (HSCs). These cells' nearly unlimited self-renewal potential and lifetime persistence in the body signifies the need for tight control of their genome integrity. Their quiescent state, tightly linked with low metabolic activity, is one of the main strategies employed by HSCs to preserve an intact genome. On the other hand, HSCs need to be able to quickly respond to increased blood demands and rapidly increase their cellular output in order to fight infection-associated inflammation or extensive blood loss. This increase in proliferation rate, however, comes at the price of exposing HSCs to DNA damage inevitably associated with the process of DNA replication. Any interference with normal replication fork progression leads to a specialized molecular response termed replication stress (RS). Importantly, increased levels of RS are a hallmark feature of aged HSCs, where an accumulating body of evidence points to causative relationships between RS and the aging-associated impairment of the blood system's functional capacity. In this review, we present an overview of RS in HSCs focusing on its causes and consequences for the blood system of mice and men. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Maffini, Enrico; Giaccone, Luisa; Festuccia, Moreno; Brunello, Lucia; Busca, Alessandro; Bruno, Benedetto

    2016-06-01

    Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.

  14. Longitudinal assessment of hematopoietic stem cell transplantation and hyposalivation.

    Science.gov (United States)

    Laaksonen, M; Ramseier, A M; Rovó, A; Jensen, S B; Raber-Durlacher, J E; Zitzmann, N U; Waltimo, T

    2011-10-01

    Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study determined stimulated whole-saliva flow rates in HSCT recipients in comparison with a healthy control group. Stimulated whole-saliva flow rates of 228 allogeneic HSCT recipients (134 males, 94 females; mean age, 43 yrs) were examined pre-HSCT and 6, 12, and 24 months post-HSCT. Healthy individuals (n = 144; 69 males, 75 females; mean age, 46 yrs) served as the control group. Stimulated saliva flow rates (mL/min) were measured and analyzed statistically, stratifying for hematological diagnoses and conditioning therapy. Hyposalivation (≤ 0.7 mL/min) was found in 40% (p hyposalivation. Severe hyposalivation (≤ 0.3 mL/min) was found in 11%, 18%, 4%, and 4% of the recipients pre-HSCT, and 6, 12, and 24 months post-HSCT, respectively. Additionally, conditioning regimen and sex had an impact on saliva flow. In conclusion, hyposalivation was observed to be a common but generally reversible complication among HSCT recipients.

  15. Early Clostridium difficile infection during allogeneic hematopoietic stem cell transplantation.

    Directory of Open Access Journals (Sweden)

    Melissa A Kinnebrew

    Full Text Available Clostridium difficile infection (CDI is frequently diagnosed in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT. We characterized early-transplant CDI and its associations, and analyzed serially-collected feces to determine intestinal carriage of toxigenic C. difficile. Fecal specimens were collected longitudinally from 94 patients during allo-HSCT hospitalization, from the start of pre-transplant conditioning until up to 35 days after stem cell infusion. Presence of C. difficile 16S rRNA and tcdB genes was determined. Clinical variables and specimen data were analyzed for association with development of CDI. Historical data from an additional 1144 allo-HSCT patients was also used. Fecal specimens from 37 patients (39% were found to harbor C. difficile. Early-transplant CDI was diagnosed in 16 of 94 (17% patients undergoing allo-HSCT; cases were generally mild and resembled non-CDI diarrhea associated with transplant conditioning. CDI was associated with preceding colonization with tcdB-positive C. difficile and conditioning regimen intensity. We found no associations between early-transplant CDI and graft-versus-host disease or CDI later in transplant. CDI occurs with high frequency during the early phase of allo-HSCT, where recipients are pre-colonized with toxigenic C. difficile. During this time, CDI incidence peaks during pre-transplant conditioning, and is correlated to intensity of the treatment. In this unique setting, high rates of CDI may be explained by prior colonization and chemotherapy; however, cases were generally mild and resembled non-infectious diarrhea due to conditioning, raising concerns of misdiagnosis. Further study of this unique population with more discriminating CDI diagnostic tests are warranted.

  16. Successful Large-volume Leukapheresis for Hematopoietic Stem Cell Collection in a Very-low-weight Brain Tumor Infant with Coagulopathy

    Directory of Open Access Journals (Sweden)

    Yu-Mei Liao

    2013-06-01

    Full Text Available Peripheral apheresis has become a safe procedure to collect hematopoietic stem cells, even in pediatric patients and donors. However, the apheresis procedure for small and sick children is more complicated due to difficult venous access, relatively large extracorporeal volume, toxicity of citrate, and unstable hemostasis. We report a small and sick child with refractory medulloblastoma, impaired liver function, and coagulopathy after several major cycles of cisplatin-based chemotherapy. She successfully received large-volume leukapheresis for hematopoietic stem cell collection, although the patient experienced severe coagulopathy during the procedures. Health care providers should be alert to this potential risk.

  17. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures.

    Science.gov (United States)

    Ali, Haytham; Galal, Omima; Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan; Abdelrahim, Eman; Ono, Yusuke; Mostafa, Emtethal; Li, Tao-Sheng

    2014-09-26

    Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30min before exposure to 50mGy γ-ray daily for 30days in sequences (cumulative dose of 1.5Gy). Mice were victimized 24h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit(+) stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60-90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit(+) stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. The polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion

    NARCIS (Netherlands)

    Kamminga, LM; Bystrykh, LV; Boer, AC; Houwer, S; Douma, J; Weersing, E; Dontje, B; de Haan, G

    2006-01-01

    The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of

  19. Persistent seropositivity for yellow fever in a previously vaccinated autologous hematopoietic stem cell transplantation recipient

    Directory of Open Access Journals (Sweden)

    Kayoko Hayakawa

    2015-08-01

    Full Text Available The duration of a protective level of yellow fever antibodies after autologous hematopoietic stem cell transplantation in a previously vaccinated person is unclear. The case of a patient who had previously been vaccinated for yellow fever and who remained seropositive for 22 months after autologous peripheral blood stem cell transplantation for malignant lymphoma is described herein.

  20. The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation

    NARCIS (Netherlands)

    Walasek, Marta A.; Bystrykh, Leonid; van den Boom, Vincent; Olthof, Sandra; Ausema, Albertina; Ritsema, Martha; Huls, Gerwin; de Haan, Gerald; van Os, Ronald

    2012-01-01

    Despite increasing knowledge on the regulation of hematopoietic stem/progenitor cell (HSPC) self-renewal and differentiation, in vitro control of stem cell fate decisions has been difficult. The ability to inhibit HSPC commitment in culture may be of benefit to cell therapy protocols. Small

  1. The combination of valproic acid and lithium delays hematopoietic stem/progenitor cell differentiation.

    NARCIS (Netherlands)

    Walasek, M.A.; Bystrykh, L.; Boom, V. van den; Olthof, S.; Ausema, A.; Ritsema, M.; Huls, G.A.; Haan, G. de; Os, R. van

    2012-01-01

    Despite increasing knowledge on the regulation of hematopoietic stem/progenitor cell (HSPC) self-renewal and differentiation, in vitro control of stem cell fate decisions has been difficult. The ability to inhibit HSPC commitment in culture may be of benefit to cell therapy protocols. Small

  2. 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.

  3. Prospective, comprehensive, and effective viral monitoring in children undergoing allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Schönberger, S; Meisel, R; Adams, O; Pufal, Y; Laws, H J; Enczmann, J; Dilloo, D

    2010-10-01

    Major advances in the monitoring and treatment of viral infections after hematopoietic stem cell transplantation (HSCT) have been achieved over the last decade. The appropriate extent of viral monitoring and antiviral therapy remains controversial, and reports in pediatric patients receiving allogeneic unmanipulated hematopoietic stem cells (HSCs) are sparse. A total of 40 pediatric patients who underwent HSCT with either peripheral blood stem cells (PBSCs, n = 30) or bone marrow (BM; n = 10) were prospectively monitored every week for viral DNAemia (VDNA) by simultaneous detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), human adenovirus (ADV), and polyoma BK virus (BKV) using real-time TaqMan polymerase chain reaction (PCR). All patients received prophylactic acyclovir and preemptive ganciclovir (GCV) when 500 copies/microg DNA (EBV/HHV6) or >1 copy/microg DNA (CMV) were detected on 2 consecutive measurements. VDNA occurred in 25 of 40 recipients (CMV, 11/40 patients [28%]; EBV, 19/40 [48%]; HHV6, 2/40 [5%]; ADV/BKV, 1/40) and was found exclusively after neutrophil engraftment and in most cases up to day +100. Recurrent VDNA (P = .028) and (readily treatable) viral disease (P = .003) were observed predominantly in patients suffering from nonmalignant diseases, a cohort characterized by delayed lymphocyte engraftment. VDNA occurred more frequently in HLA-mismatched HSCT and in the 24 of 40 patients receiving antithymocyte globulin (ATG). The incidence of EBV, but not that of CMV, was increased in the ATG group. Yet, in these patients, viral loads of both EBV and CMV were higher, but with prompt initiation of preemptive GCV, no posttransplantation lymphoproliferative disorder or other life-threatening morbidities occurred. HHV6 was typically detected at low viral loads (stem cell source, but not severe acute graft-versus-host disease were identified as independent risk factors for VDNA. This comprehensive viral monitoring

  4. Deconstructing the Complexity of TGFβ Signaling in Hematopoietic Stem Cells: Quiescence and Beyond.

    Science.gov (United States)

    Hinge, Ashwini; Filippi, Marie-Dominique

    2016-12-01

    The hematopoietic system is highly dynamic and must constantly produce new blood cells every day. Mature blood cells all derive from a pool of rare long-lived hematopoietic stem cells (HSCs) that are mostly quiescent but occasionally divide and self-renew in order to maintain the stem cell pool and continuous replenishment of mature blood cells throughout life. A tight control of HSC self-renewal, commitment to differentiation and maintenance of quiescence states is necessary for lifelong blood supply. Transforming growth factor-β (TGF-β) is a critical regulator hematopoietic cell functions. It is a potent inhibitor of hematopoietic cell growth. However, TGFβ functions are more complex and largely context-dependent. Emerging evidence suggests a role in aging, cell identity and cell fate decisions. Here, we will review the role of TGF-β and downstream signaling in normal HSC functions, in HSC quiescence and beyond.

  5. 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.

  6. Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation

    Science.gov (United States)

    Fernandez-Viña, Marcelo A.; Wang, Tao; Lee, Stephanie J.; Haagenson, Michael; Aljurf, Mahmoud; Askar, Medhat; Battiwalla, Minoo; Baxter-Lowe, Lee-Ann; Gajewski, James; Jakubowski, Ann A.; Marino, Susana; Oudshoorn, Machteld; Marsh, Steven G. E.; Petersdorf, Effie W.; Schultz, Kirk; Turner, E. Victoria; Waller, Edmund K.; Woolfrey, Ann; Umejiego, John; Spellman, Stephen R.; Setterholm, Michelle

    2014-01-01

    In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P HLA mismatches. PMID:24408320

  7. Regulatory Systems in Bone Marrow for Hematopoietic Stem/Progenitor Cells Mobilization and Homing

    Science.gov (United States)

    Alvarez, P.; Carrillo, E.; Vélez, C.; Hita-Contreras, F.; Martínez-Amat, A.; Rodríguez-Serrano, F.; Boulaiz, H.; Ortiz, R.; Melguizo, C.; Prados, J.; Aránega, A.

    2013-01-01

    Regulation of hematopoietic stem cell release, migration, and homing from the bone marrow (BM) and of the mobilization pathway involves a complex interaction among adhesion molecules, cytokines, proteolytic enzymes, stromal cells, and hematopoietic cells. The identification of new mechanisms that regulate the trafficking of hematopoietic stem/progenitor cells (HSPCs) cells has important implications, not only for hematopoietic transplantation but also for cell therapies in regenerative medicine for patients with acute myocardial infarction, spinal cord injury, and stroke, among others. This paper reviews the regulation mechanisms underlying the homing and mobilization of BM hematopoietic stem/progenitor cells, investigating the following issues: (a) the role of different factors, such as stromal cell derived factor-1 (SDF-1), granulocyte colony-stimulating factor (G-CSF), and vascular cell adhesion molecule-1 (VCAM-1), among other ligands; (b) the stem cell count in peripheral blood and BM and influential factors; (c) the therapeutic utilization of this phenomenon in lesions in different tissues, examining the agents involved in HSPCs mobilization, such as the different forms of G-CSF, plerixafor, and natalizumab; and (d) the effects of this mobilization on BM-derived stem/progenitor cells in clinical trials of patients with different diseases. PMID:23844360

  8. Regulatory Systems in Bone Marrow for Hematopoietic Stem/Progenitor Cells Mobilization and Homing

    Directory of Open Access Journals (Sweden)

    P. Alvarez

    2013-01-01

    Full Text Available Regulation of hematopoietic stem cell release, migration, and homing from the bone marrow (BM and of the mobilization pathway involves a complex interaction among adhesion molecules, cytokines, proteolytic enzymes, stromal cells, and hematopoietic cells. The identification of new mechanisms that regulate the trafficking of hematopoietic stem/progenitor cells (HSPCs cells has important implications, not only for hematopoietic transplantation but also for cell therapies in regenerative medicine for patients with acute myocardial infarction, spinal cord injury, and stroke, among others. This paper reviews the regulation mechanisms underlying the homing and mobilization of BM hematopoietic stem/progenitor cells, investigating the following issues: (a the role of different factors, such as stromal cell derived factor-1 (SDF-1, granulocyte colony-stimulating factor (G-CSF, and vascular cell adhesion molecule-1 (VCAM-1, among other ligands; (b the stem cell count in peripheral blood and BM and influential factors; (c the therapeutic utilization of this phenomenon in lesions in different tissues, examining the agents involved in HSPCs mobilization, such as the different forms of G-CSF, plerixafor, and natalizumab; and (d the effects of this mobilization on BM-derived stem/progenitor cells in clinical trials of patients with different diseases.

  9. [Analysis of the risk factors for hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation for beta-thalassemia in children].

    Science.gov (United States)

    Yin, Wen-fang; Pei, Fu-yu; Wu, Xue-dong; Liu, Si-xi; He, Yue-lin; Liao, Jian-yun; Li, Na; Chen, Ge-yu; Feng, Xiao-qing; Li, Chun-fu

    2010-04-01

    To analyze the risk factors of hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation for beta-thalassemia in children. The clinical records of 30 children with beta-thalassemia undergoing allogeneic hematopoietic stem cell transplantation between December, 2008 and November, 2009 were analyzed. Hemorrhagic cystitis occurred in 8 of the 33 patients with an incidence of 24.24%, including 1 with grade I, 6 with grade II and 1 with grade III hemorrhagic cystitis. The median time of hemorrhagic cystitis onset was 22.9 days (range 6-35 days) and the median duration was 11.9 days(range 3-27 days). Univariate analysis indicated that the different types of transplantation and acute graft-versus-host disease affect the occurrence of hemorrhagic cystitis. The children with Allo-PBSCT had higher incidence than those receiving Allo-PBSCT+Allo-UBT and Allo-BMT (Por=6 years had obviously higher incidence of hemorrhagic cystitis than those at younger ages. Age is the major factor that affects the occurrence of hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation for beta-thalassemia.

  10. Predicting clonal self-renewal and extinction of hematopoietic stem cells

    OpenAIRE

    Sieburg, Hans B.; Rezner, Betsy D.; Muller-Sieburg, Christa E.

    2011-01-01

    A single hematopoietic stem cell (HSC) can generate a clone, consisting of daughter HSCs and differentiated progeny, which can sustain the hematopoietic system of multiple hosts for a long time. At the same time, this massive expansion potential must be restrained to prevent abnormal, leukemic proliferation. We used an interdisciplinary approach, combining transplantation assays with mathematical and computational methods, to systematically analyze the proliferative potential of individual HS...

  11. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

    OpenAIRE

    van Pel, Melissa; van Os, Ronald; Velders, Gerjo A.; Hagoort, Henny; Heegaard, Peter M. H.; Lindley, Ivan J. D.; Willemze, Roel; Fibbe, Willem E.

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory mediators in cytokine-induced HSC/HPC mobilization, we considered a possible role for protease inhibitors in the induction of HSC/HPC mobilization. Bone marrow (BM) extracellular extracts that wer...

  12. Donor Dependent Variations in Hematopoietic Differentiation among Embryonic and Induced Pluripotent Stem Cell Lines.

    Directory of Open Access Journals (Sweden)

    Olivier Féraud

    Full Text Available Hematopoiesis generated from human embryonic stem cells (ES and induced pluripotent stem cells (iPS are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non-integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. There is a relatively unpredictable variation in hematopoietic differentiation between ES and iPS cell lines that could not be predicted based on phenotype or gene expression of the undifferentiated cells. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process.

  13. BACTERIAL INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS

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    Elisa Balletto

    2015-07-01

    Full Text Available Bacterial infections are major complications after Hematopoietic Stem Cell Transplant (HSCT. They consist mainly of bloodstream infections (BSI, followed by pneumonia and gastrointestinal infections, including typhlitis and Clostridium difficile infection. Microbiological data come mostly from BSI. Coagulase negative staphylococci and Enterobacteriaceae are the most frequent pathogens causing approximately 25% of BSI each, followed by enterococci, P. aeruginosa and viridans streptococci. Bacterial pneumonia is frequent after HSCT, and Gram-negatives are predominant. Clostridium difficile infection affects approximately 15% of HSCT recipients, being more frequent in case of allogeneic than autologous HSCT. The epidemiology and the prevalence of resistant strains vary significantly between transplant centres. In some regions, multi-drug resistant Gram-negative rods are increasingly frequent. In others, vancomycin-resistant enterococci are predominant. In the era of an increasing resistance to antibiotics, the efficacy of fluoroquinolone prophylaxis and standard treatment of febrile neutropenia have been questioned. Therefore, thorough evaluation of local epidemiology is mandatory in order to decide the need for prophylaxis and the choice of the best regimen for empirical treatment of febrile neutropenia. For the latter, individualised approach has been proposed, consisting of either escalation or de-escalation strategy. De-escalation strategy is recommended is resistant bacteria should be covered upfront, mainly in patients with severe clinical presentation and previous infection or colonisation with a resistant pathogens. Non-pharmacological interventions, such as screening for resistant bacteria, applying isolation and contact precautions should be put in place in order to limit the spread of MDR bacteria. Antimicrobial stewardship program should be implemented in transplant centres.

  14. Bacterial Infections in Hematopoietic Stem Cell Transplant Recipients

    Science.gov (United States)

    Balletto, Elisa; Mikulska, Małgorzata

    2015-01-01

    Bacterial infections are major complications after Hematopoietic Stem Cell Transplant (HSCT). They consist mainly of bloodstream infections (BSI), followed by pneumonia and gastrointestinal infections, including typhlitis and Clostridium difficile infection. Microbiological data come mostly from BSI. Coagulase negative staphylococci and Enterobacteriaceae are the most frequent pathogens causing approximately 25% of BSI each, followed by enterococci, P. aeruginosa and viridans streptococci. Bacterial pneumonia is frequent after HSCT, and Gram-negatives are predominant. Clostridium difficile infection affects approximately 15% of HSCT recipients, being more frequent in case of allogeneic than autologous HSCT. The epidemiology and the prevalence of resistant strains vary significantly between transplant centres. In some regions, multi-drug resistant (MDR) Gram-negative rods are increasingly frequent. In others, vancomycin-resistant enterococci are predominant. In the era of increasing resistance to antibiotics, the efficacy of fluoroquinolone prophylaxis and standard treatment of febrile neutropenia have been questioned. Therefore, a thorough evaluation of local epidemiology is mandatory to decide the need for prophylaxis and the choice of the best regimen for empirical treatment of febrile neutropenia. For the latter, individualised approach has been proposed, consisting of either escalation or de-escalation strategy. De-escalation strategy is recommended since resistant bacteria should be covered upfront, mainly in patients with severe clinical presentation and previous infection or colonisation with a resistant pathogen. Non-pharmacological interventions, such as screening for resistant bacteria, applying isolation and contact precautions should be put in place to limit the spread of MDR bacteria. Antimicrobial stewardship program should be implemented in transplant centres. PMID:26185610

  15. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    Energy Technology Data Exchange (ETDEWEB)

    Ali, Haytham [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Galal, Omima [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Abdelrahim, Eman [Department of Medical Histology, Qena Faculty of Medicine, South Valley University (Egypt); Ono, Yusuke [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Mostafa, Emtethal [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Li, Tao-Sheng, E-mail: litaoshe@nagasaki-u.ac.jp [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

    2014-09-26

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit{sup +} stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit{sup +} stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit{sup +} stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms.

  16. Evaluation of risk for graft-versus-host disease in children who receive less than the full doses of mini-dose methotrexate for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Sook Kyung Yum

    2013-11-01

    Full Text Available Purpose: The use of cyclosporine and mini-dose methotrexate (MTX is a common strategy for graftversus- host disease (GVHD prophylaxis in allogeneic transplants. We investigated whether patients who receive fewer than the planned MTX doses are at increased risk for GVHD. Methods: The study cohort included 103 patients who received allogeneic transplants at the Department of Pediatrics of The Catholic University of Korea College of Medicine, from January 2010 to December 2011. MTX was administered on days 1, 3, 6, and 11 after transplant at a dose of 5 mg/ m2 each. Within the cohort, 76 patients (74% received all 4 doses of MTX [MTX(4 group], while 27 patients (26% received 0&#8211;3 doses [MTX(0–3 group]. Results: Although there was no difference in neutrophil engraftment between the 2 groups, platelet engraftment was significantly faster in the MTX(4 group (median, 15 days, compared to the MTX(0&#8211; 3 group (median, 25 days; P =0.034. The incidence of grades II&#8211;IV acute GVHD was not different between the MTX(4 and MTX(0&#8211;3 groups (P =0.417. In the multivariate study, human leukocyte antigen mismatch was the most significant factor causing grades II&#8211;IV acute GVHD (P =0.002, followed by female donor to male recipient transplant (P =0.034. No difference was found between the MTX(4 and MTX (0&#8211;3 groups regarding grades III&#8211;IV acute GVHD, chronic GVHD, and disease-free survival. Conclusion: Our results indicate that deviations from the full dose schedule of MTX for GVHD prophylaxis do not lead to increased incidence of either acute or chronic GVHD.

  17. Truth-telling and hematopoietic stem cell transplantation: Iranian nurses' experiences.

    Science.gov (United States)

    Valizadeh, Leila; Zamanzadeh, Vahid; Sayadi, Leila; Taleghani, Fariba; Howard, A Fuchsia; Jeddian, Alireza

    2014-08-01

    Hematopoietic stem cell transplantation is a potential cure for a range of life-threatening diseases, but is also associated with a high mortality rate. Nurses encounter a variety of situations wherein they are faced with discussing bad news with hematopoietic stem cell transplantation patients. The aim of this study was to explore the experiences and strategies used by Iranian nurses related to truth-telling and communicating bad news to hematopoietic stem cell transplantation patients. A qualitative approach using content analysis of interview data was conducted. A total of 18 nurses from the main hematopoietic stem cell transplantation center in Iran participated in semi-structured interviews. The Institutional Review Board of the Tabriz University of Medical Sciences and the Hematology-Oncology and Stem Cell Transplantation Research Center affiliated with the Tehran University of Medical Sciences approved the study. In the first main category, not talking about the disease and potential negative outcomes, the nurses described the strategies of not naming the disease, talking about the truth in indirect ways and telling gradually. In the second main category, not disclosing the sad truth, the nurses described the strategies of protecting patients from upsetting information, secrecy, denying the truth and minimizing the importance of the problem. The nurses used these strategies to minimize psychological harm, avoid patient demoralization, and improve the patient's likelihood of a fast and full recovery. The priority for Iranian hematopoietic stem cell transplantation nurses is to first do no harm and to help patients maintain hope. This reflects the Iranian healthcare environment wherein communicating the truth to hematopoietic stem cell transplantation patients is commonly considered inappropriate and avoided. Iranian nurses require education and support to engage in therapeutic, culturally appropriate communication that emphasizes effective techniques for

  18. A problem-solving education intervention in caregivers and patients during allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Bevans, Margaret; Wehrlen, Leslie; Castro, Kathleen; Prince, Patricia; Shelburne, Nonniekaye; Soeken, Karen; Zabora, James; Wallen, Gwenyth R

    2014-05-01

    The aim of this study was to determine the effect of problem-solving education on self-efficacy and distress in informal caregivers of allogeneic hematopoietic stem cell transplantation patients. Patient/caregiver teams attended three 1-hour problem-solving education sessions to help cope with problems during hematopoietic stem cell transplantation. Primary measures included the Cancer Self-Efficacy Scale-transplant and Brief Symptom Inventory-18. Active caregivers reported improvements in self-efficacy (p education; caregiver responders also reported better health outcomes such as fatigue. The effect of problem-solving education on self-efficacy and distress in hematopoietic stem cell transplantation caregivers supports its inclusion in future interventions to meet the multifaceted needs of this population.

  19. Transplantation of mouse fetal liver cells for analyzing the function of hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Gudmundsson, Kristbjorn Orri; Stull, Steven W; Keller, Jonathan R

    2012-01-01

    Hematopoietic stem cells are defined by their ability to self-renew and differentiate through progenitor cell stages into all types of mature blood cells. Gene-targeting studies in mice have demonstrated that many genes are essential for the generation and function of hematopoietic stem and progenitor cells. For definitively analyzing the function of these cells, transplantation studies have to be performed. In this chapter, we describe methods to isolate and transplant fetal liver cells as well as how to analyze donor cell reconstitution. This protocol is tailored toward mouse models where embryonic lethality precludes analysis of adult hematopoiesis or where it is suspected that the function of fetal liver hematopoietic stem and progenitor cells is compromised.

  20. Engineering antigen-specific T cells from genetically modified human hematopoietic stem cells in immunodeficient mice.

    Directory of Open Access Journals (Sweden)

    Scott G Kitchen

    Full Text Available There is a desperate need for effective therapies to fight chronic viral infections. The immune response is normally fastidious at controlling the majority of viral infections and a therapeutic strategy aimed at reestablishing immune control represents a potentially powerful approach towards treating persistent viral infections. We examined the potential of genetically programming human hematopoietic stem cells to generate mature CD8+ cytotoxic T lymphocytes that express a molecularly cloned, "transgenic" human anti-HIV T cell receptor (TCR. Anti-HIV TCR transduction of human hematopoietic stem cells directed the maturation of a large population of polyfunctional, HIV-specific CD8+ cells capable of recognizing and killing viral antigen-presenting cells. Thus, through this proof-of-concept we propose that genetic engineering of human hematopoietic stem cells will allow the tailoring of effector T cell responses to fight HIV infection or other diseases that are characterized by the loss of immune control.

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  8. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    Directory of Open Access Journals (Sweden)

    Cécile eCoste

    2015-06-01

    Full Text Available Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL12-abundant reticular (CAR cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs, which have been recently identified as neural crest-derived cells (NCSCs. Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-to-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  9. Acquisition and Cure of Autoimmune Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Hsin-An Hou

    2007-09-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT can either cause or eliminate autoimmune disease. Here, we report two cases. One was a 33-year-old woman with myelodysplastic syndrome (refractory anemia who received bone marrow transplantation from her human leukocyte antigen (HLA-identical sister who had a history of Graves' disease. Antithyroid antibodies, including antimicrosomal antibody and antithy-roglobulin antibody, appeared 4 months after transplantation. Clinical hyperthyroidism appeared 7 months after transplantation, and a hypothyroid state was noted 2 months later. The other case was a 50-year-old woman with Sjögren's syndrome and hypothyroidism who was diagnosed with peripheral T cell non-Hodgkin's lymphoma. She received allogeneic peripheral blood stem cell transplantation (PBSCT from her histocompatible sister owing to only partial response to traditional chemotherapy. Cure of lymphoma and remission of Sjögren's syndrome was noted 4 years after PBSCT. These two illustrative cases, one of acquisition of hyperthyroidism and the other of remission of Sjögren's syndrome after transplantation, highlights that HSCT can induce adoptive autoimmune disease or cure coincidental autoimmune disease. Donor selection and attentive monitoring is required in such circumstances.

  10. An Analysis of MicroRNA Expression in the Myelodysplastic Syndromes Using Hematopoietic Stem Cells

    Science.gov (United States)

    2015-10-01

    predisposition for the development of MDS. 15. SUBJECT TERMS MicroRNAs, the myelodysplastic syndromes, hematopoietic stem cells...hematopoietic  stem  cells  (HSCs),  demonstrating   the  presence  of  disease  associated  cytogenetic  and  molecular   genetic ...hematopoiesis   in   the   context   of   aging   and   its   likely   implication   in   the   age-­‐related   predisposition

  11. PRDM11 is dispensable for the maintenance and function of hematopoietic stem and progenitor cells

    DEFF Research Database (Denmark)

    Thoren, Lina A; Fog, Cathrine K; Jensen, Klaus T

    2013-01-01

    Hematopoietic stem cells (HSC)(1) supply organisms with life-long output of mature blood cells. To do so, the HSC pool size has to be maintained by HSC self-renewing divisions. PRDM3 and PRDM16 have been documented to regulate HSC self-renewal, maintenance and function. We found Prdm11 to have...... similar expression patterns in the hematopoietic stem and progenitor cell (HSPC) compartments as Prdm3 and Prdm16. Therefore, we undertook experiments to test if PRDM11 regulates HSC self-renewal, maintenance and function by investigating the Prdm11(-/-) mice. Our data shows that phenotypic HSPCs...

  12. 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

    2014-01-01

    Objective To study the factors affecting the time to onset of ocular GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A retrospective chart review of 200 patients with ocular GVHD was performed to evaluate the association between various donor-recipient characteristics on the time to onset of ocular GVHD after allo-HSCT. Results The median time to onset of chronic ocular GVHD after allo-HSCT was 293 days (range 26 to 2308). Patients receiving fully HLA-matched transplants had a delayed onset of ocular GVHD (median 294 days) compared to mismatched transplants (219 days; P=0.029). HLA-matched transplants from related donors had delayed onset of ocular GVHD (307 days) compared to 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). Conclusion The onset of ocular GVHD after allogeneic hematopoietic stem cell transplantation is variable and is influenced by the 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. Regular ophthalmic follow-up is recommended after allo-HSCT regardless the concurrent systemic GVHD status. PMID:25603230

  13. Hematopoietic stem cell-specific GFP-expressing transgenic mice generated by genetic excision of a pan-hematopoietic reporter gene.

    Science.gov (United States)

    Perez-Cunningham, Jessica; Boyer, Scott W; Landon, Mark; Forsberg, E Camilla

    2016-08-01

    Selective labeling of specific cell types by expression of green fluorescent protein (GFP) within the hematopoietic system would have great utility in identifying, localizing, and tracking different cell populations in flow cytometry, microscopy, lineage tracing, and transplantation assays. In this report, we describe the generation and characterization of a new transgenic mouse line with specific GFP labeling of all nucleated hematopoietic cells and platelets. This new "Vav-GFP" mouse line labels the vast majority of hematopoietic cells with GFP during both embryonic development and adulthood, with particularly high expression in hematopoietic stem and progenitor cells (HSPCs). With the exception of transient labeling of fetal endothelial cells, GFP expression is highly selective for hematopoietic cells and persists in donor-derived progeny after transplantation of HSPCs. Finally, we also demonstrate that the loxP-flanked reporter allows for specific GFP labeling of different hematopoietic cell subsets when crossed to various Cre reporter lines. By crossing Vav-GFP mice to Flk2-Cre mice, we obtained robust and highly selective GFP expression in hematopoietic stem cells (HSCs). These data describe a new mouse model capable of directing GFP labeling exclusively of hematopoietic cells or exclusively of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  14. Successfully-treated advanced bile duct cancer of donor origin after hematopoietic stem cell transplantation by pancreaticoduodenectomy: a case report.

    Science.gov (United States)

    Haruki, Koichiro; Shiba, Hiroaki; Futagawa, Yasuro; Wakiyama, Shigeki; Misawa, Takeyuki; Yanaga, Katsuhiko

    2014-07-01

    Secondary malignancies are one of the late complications observed in long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). However, reports on secondary non-hematopoietic solid tumors derived from donor cells is extremely rare. We herein report a successfully-treated case of advanced bile duct cancer of donor-origin after allogeneic HSCT. A 44-year-old man was diagnosed with acute myeloid leukemia. When he achieved the third complete response, allogeneic hematopoietic stem cells of one-mismatch female donor were transplanted at the age of 50 years. Post-transplant acute and chronic graft-versus-host disease was treated by increased immunosuppression. At the age of 59, the patient was diagnosed with lower bile duct cancer and underwent pancreaticoduodenectomy with lymph node dissection. Pathological findings revealed a well-differentiated adenocarcinoma of the bile duct. Additional fluorescence in situ hybridization analysis revealed female patterns of the tumor cells, which suggested that the tumor cells originated from the donor. The patient had a satisfactory recovery, and received adjuvant chemotherapy with S-1. He remains well with no evidence of tumor recurrence as of one year after resection. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Hematopoietic Support Capacity of Mesenchymal Stem Cells: Biology and Clinical Potential.

    Science.gov (United States)

    Fajardo-Orduña, Guadalupe R; Mayani, Héctor; Montesinos, Juan J

    2015-11-01

    Mesenchymal stem cells (MSCs) play an important role in the physiology and homeostasis of the hematopoietic system. Because MSCs generate most of the stromal cells present in the bone marrow (BM), form part of the hematopoietic stem cell (HSC) niche, and produce various molecules regulating hematopoiesis, their hematopoiesis-supporting capacity has been demonstrated. In the last decade, BM-MSCs have been proposed to be useful in some ex vivo protocols for HSC expansion, with the aim of expanding their numbers for transplant purposes (HSC transplant, HSCT). Furthermore, application of MSCs has been proposed as an adjuvant cellular therapy for promoting rapid hematopoietic recovery in HSCT patients. Although the MSCs used in preliminary clinical trials have come from the BM, isolation of MSCs from far more accessible sources such as neonatal tissues has now been achieved, and these cells have been found to possess similar biological characteristics to those isolated from the BM. Therefore, such tissues are now considered as a potential alternative source of MSCs for clinical applications. In this review, we discuss current knowledge regarding the biological characteristics of MSCs as related to their capacity to support the formation of hematopoietic stem and progenitor cells. We also describe MSC manipulation for ex vivo HSC expansion protocols used for transplants and their clinical relevance for hematopoietic recovery in HSCT patients. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  16. Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation.

    Science.gov (United States)

    Tarafdar, Anuradha; Dobbin, Edwina; Corrigan, Pamela; Freeburn, Robin; Wheadon, Helen

    2013-01-01

    The generation of hematopoietic stem cells (HSCs) during development is a complex process linked to morphogenic signals. Understanding this process is important for regenerative medicine applications that require in vitro production of HSC. In this study we investigated the effects of canonical Wnt/β-catenin signaling during early embryonic differentiation and hematopoietic specification using an embryonic stem cell system. Our data clearly demonstrates that following early differentiation induction, canonical Wnt signaling induces a strong mesodermal program whilst maintaining a degree of stemness potential. This involved a complex interplay between β-catenin/TCF/LEF/Brachyury/Nanog. β-catenin mediated up-regulation of TCF/LEF resulted in enhanced brachyury levels, which in-turn lead to Nanog up-regulation. During differentiation, active canonical Wnt signaling also up-regulated key transcription factors and cell specific markers essential for hematopoietic specification, in particular genes involved in establishing primitive erythropoiesis. This led to a significant increase in primitive erythroid colony formation. β-catenin signaling also augmented early hematopoietic and multipotent progenitor (MPP) formation. Following culture in a MPP specific cytokine cocktail, activation of β-catenin suppressed differentiation of the early hematopoietic progenitor population, with cells displaying a higher replating capacity and a propensity to form megakaryocytic erythroid progenitors. This bias towards erythroid lineage commitment was also observed when hematopoietic progenitors were directed to undergo myeloid colony formation. Overall this study underscores the importance of canonical Wnt/β-catenin signaling in mesodermal specification, primitive erythropoiesis and early hematopietic progenitor formation during hematopoietic induction.

  17. Canonical Wnt signaling promotes early hematopoietic progenitor formation and erythroid specification during embryonic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Anuradha Tarafdar

    Full Text Available The generation of hematopoietic stem cells (HSCs during development is a complex process linked to morphogenic signals. Understanding this process is important for regenerative medicine applications that require in vitro production of HSC. In this study we investigated the effects of canonical Wnt/β-catenin signaling during early embryonic differentiation and hematopoietic specification using an embryonic stem cell system. Our data clearly demonstrates that following early differentiation induction, canonical Wnt signaling induces a strong mesodermal program whilst maintaining a degree of stemness potential. This involved a complex interplay between β-catenin/TCF/LEF/Brachyury/Nanog. β-catenin mediated up-regulation of TCF/LEF resulted in enhanced brachyury levels, which in-turn lead to Nanog up-regulation. During differentiation, active canonical Wnt signaling also up-regulated key transcription factors and cell specific markers essential for hematopoietic specification, in particular genes involved in establishing primitive erythropoiesis. This led to a significant increase in primitive erythroid colony formation. β-catenin signaling also augmented early hematopoietic and multipotent progenitor (MPP formation. Following culture in a MPP specific cytokine cocktail, activation of β-catenin suppressed differentiation of the early hematopoietic progenitor population, with cells displaying a higher replating capacity and a propensity to form megakaryocytic erythroid progenitors. This bias towards erythroid lineage commitment was also observed when hematopoietic progenitors were directed to undergo myeloid colony formation. Overall this study underscores the importance of canonical Wnt/β-catenin signaling in mesodermal specification, primitive erythropoiesis and early hematopietic progenitor formation during hematopoietic induction.

  18. Mobilization of Hematopoietic Stem and Progenitor Cells Using Inhibitors of CXCR4 and VLA-4

    Science.gov (United States)

    Rettig, Michael P.; Ansstas, George; DiPersio, John F.

    2012-01-01

    Successful hematopoietic stem cell transplant (HSCT) requires the infusion of a sufficient number of hematopoietic stem/progenitor cells (HSPCs) that are capable of homing to the bone marrow cavity and regenerating durable trilineage hematopoiesis in a timely fashion. Stem cells harvested from peripheral blood are the most commonly used graft source in HSCT. While granulocyte colony-stimulating factor (G-CSF) is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients. Both the chemokine receptor CXCR4 and the integrin α4β1 (VLA-4) play important roles in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of CXCR4 or VLA-4 with their ligands results in the rapid and reversible mobilization of hematopoietic stem cells into the peripheral circulation and is synergistic when combined with G-CSF. In this review we discuss the development of small molecule CXCR4 and VLA-4 inhibitors and how they may improve the utility and convenience of peripheral blood stem cell transplantation. PMID:21886173

  19. Signaling pathways in self-renewing hematopoietic and leukemic stem cells : do all stem cells need a niche?

    NARCIS (Netherlands)

    Rizo, Aleksandra; Vellenga, Edo; de Haan, Gerald; Schuringa, Jan Jacob

    2006-01-01

    Many adult tissue stem cells, such as the cells of the hematopoietic system, gastrointestinal epithelium, brain, epidermis, mammary gland and lung have now been identified, all of them fulfilling a crucial role in supplying organisms with mature cells during normal homeostasis as well as in times of

  20. Mobilization of Hematopoietic Stem/Progenitor Cells: General Principles and Molecular Mechanisms

    Science.gov (United States)

    Bonig, Halvard; Papayannopoulou, Thalla

    2013-01-01

    Hematopoietic stem/progenitor cell mobilization can be achieved by a variety of bone marrow niche modifications, although efficient mobilization requires simultaneous expansion of the stem/progenitor cell pool and niche modification. Many of the mechanisms involved in G-CSF-induced mobilization have been described. With regard to mobilization of hematopoietic stem/progenitor cells, challenges for the future include the analysis of genetic factors responsible for the great variability in mobilization responses, and the identification of predictors of mobilization efficiency, as well as the development of mobilizing schemes for poor mobilizers. Moreover, improved regimens for enhanced or even preferential mobilization of nonhematopoietic stem/progenitor cell types, and their therapeutic potential for endogenous tissue repair will be questions to be vigorously pursued in the near future. PMID:22890918

  1. 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.

  2. Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yun Hee; Kim, Ji Yoon; Choi, Byung Ock; Ryu, Mi Ryeong; Chung, Su Mi [Dept. of Radiation Oncology, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of)

    2012-12-15

    To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused. Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate. With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT. In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.

  3. Long-term adverse effects of hematopoietic stem cell transplantation on dental development in children

    NARCIS (Netherlands)

    van der Pas-Voskuilen, I.G.M.; Veerkamp, J.S.J.; Raber-Durlacher, J.E.; Bresters, D.; van Wijk, A.J.; Barasch, A.; McNeal, S.; Gortzak, R.A.T.

    2009-01-01

    Purpose: The purpose of this study was to assess late effects of cytotoxic therapy with hematopoietic stem cell transplantation (HCT) on dental development in survivors of childhood cancer. Materials and methods: Forty children who underwent allogeneic HCT for a variety of hematological malignancies

  4. Long-term adverse effects of hematopoietic stem cell transplantation on dental development in children

    NARCIS (Netherlands)

    van der Pas-van Voskuilen, I. G. M.; Veerkamp, J. S. J.; Raber-Durlacher, J. E.; Bresters, D.; van Wijk, A. J.; Barasch, A.; McNeal, S.; Gortzak, R. A. Th

    2009-01-01

    The purpose of this study was to assess late effects of cytotoxic therapy with hematopoietic stem cell transplantation (HCT) on dental development in survivors of childhood cancer. Forty children who underwent allogeneic HCT for a variety of hematological malignancies were evaluated at a minimum of

  5. Routine Surveillance for Bloodstream Infections in a Pediatric Hematopoietic Stem Cell Transplant Cohort: Do Patients Benefit?

    Directory of Open Access Journals (Sweden)

    Heather Rigby

    2007-01-01

    Full Text Available BACKGROUND: Hematopoietic stem cell transplant (HSCT recipients are at a high risk for late bloodstream infection (BSI. Controversy exists regarding the benefit of surveillance blood cultures in this immunosuppressed population. Despite the common use of this practice, the practical value is not well established in non-neutropenic children following HSCT.

  6. CD133-targeted Gene Transfer Into Long-term Repopulating Hematopoietic Stem Cells

    NARCIS (Netherlands)

    Brendel, Christian; Goebel, Benjamin; Daniela, Abriss; Brugman, Martijn; Kneissl, Sabrina; Schwaeble, Joachim; Kaufmann, Kerstin B.; Mueller-Kuller, Uta; Kunkel, Hana; Chen-Wichmann, Linping; Abel, Tobias; Serve, Hubert; Bystrykh, Leonid; Buchholz, Christian J.; Grez, Manuel

    Gene therapy for hematological disorders relies on the genetic modification of CD34(+) cells, a heterogeneous cell population containing about 0.01% long-term repopulating cells. Here, we show that the lentiviral vector CD133-LV, which uses a surface marker on human primitive hematopoietic stem

  7. Pericarditis mediated by respiratory syncytial virus in a hematopoietic stem cell transplant patient.

    Science.gov (United States)

    Rubach, M P; Pavlisko, E N; Perfect, J R

    2013-08-01

    We describe a case of pericarditis and large pericardial effusion in a 63-year-old African-American man undergoing autologous hematopoietic stem cell transplant for multiple myeloma. Pericardial tissue biopsy demonstrated fibrinous pericarditis, and immunohistochemistry stains were positive for respiratory syncytial virus. The patient improved with oral ribavirin and intravenous immune globulin infusions. © 2013 John Wiley & Sons A/S.

  8. Hematopoietic stem cell development requires transient Wnt/β-catenin activity

    NARCIS (Netherlands)

    C. Ruiz-Herguido (Cristina); J. Guiu (Jordi); C. D'Altri; J. Inglés-Esteve (Julia); E.A. Dzierzak (Elaine); L. Espinosa (Lluis); A. Bigas (Anna)

    2012-01-01

    textabstractUnderstanding how hematopoietic stem cells (HSCs) are generated and the signals that control this process is a crucial issue for regenerative medicine applications that require in vitro production of HSC. HSCs emerge during embryonic life from an endothelial-like cell population that

  9. Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients

    DEFF Research Database (Denmark)

    Averbuch, Diana; Tridello, Gloria; Hoek, Jennifer

    2017-01-01

    Background: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). Methods: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors ...

  10. Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation

    NARCIS (Netherlands)

    Langereis, Eveline J.; den Os, Matthijs M.; Breen, Catherine; Jones, Simon A.; Knaven, Olga C.; Mercer, Jean; Miller, Weston P.; Kelly, Paula M.; Kennedy, Jim; Ketterl, Tyler G.; O'Meara, Anne; Orchard, Paul J.; Lund, Troy C.; van Rijn, Rick R.; Sakkers, Ralph J.; White, Klane K.; Wijburg, Frits A.

    2016-01-01

    Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia,

  11. Differential role for very late antigen-5 in mobilization and homing of hematopoietic stem cells

    NARCIS (Netherlands)

    Wierenga, P. K.; Weersing, E.; Dontje, B.; de Haan, G.; van Os, R.

    2006-01-01

    The role of very late antigen-5 (VLA-5) in homing and mobilization of hematopoietic stem cells from normal bone marrow (NBM) and bone marrow (MBM) and peripheral blood (MPB) from mobilized mice was investigated. We found a decreased number of VLA-5-expressing cells in the lineage-negative fraction

  12. YOUTUBE videos on oral care of the organ or hematopoietic stem cell transplant patients.

    Science.gov (United States)

    López-Jornet, Pia; Pons-Fuster, Eduardo; Ruiz-Roca, Juan Antonio

    2017-04-01

    Video-sharing websites can be a useful platform for disseminating information. The aim of this study was to evaluate information about the oral health care of the organ transplant and hematopoietic stem cell transplant patients available on YouTube™. The transversal study evaluated the content of YouTube™ videos. The videos were located by entering key search terms in the YouTube™ search engine-oral care/dental management/organ transplant/hematopoietic stem cell transplant patients. The videos were then classified as useful, misleading, or as personal experiences reported by patients. The following information was registered: the source of the video, content, interaction, and overall quality. A total of 50 videos were reviewed; 16 (33.14%) were classed as useful, 22 (44%) were misleading, and 12 (24%) reported patients' personal experiences. Significant differences were found in overall quality (p = 0.012). When interaction variables were analyzed statistically significant differences were found for the following: "I did not like this video" (p ≤ 0.05) and comments (p ≤ 0.05). Several videos reviewed information on oral care of organ transplant and hematopoietic stem cell transplant patients but were sometimes difficult to interpret. Nevertheless, YouTube™ is a tool that can help supply information and promote oral health care education among of organ transplant and hematopoietic stem cell transplant patients.

  13. Bacterial meningitis in hematopoietic stem cell transplant recipients: a population-based prospective study

    NARCIS (Netherlands)

    van Veen, K. E. B.; Brouwer, M. C.; van der Ende, A.; van de Beek, D.

    2016-01-01

    We performed a nationwide prospective cohort study on the epidemiology and clinical features of community-acquired bacterial meningitis. Patients with a medical history of autologous or allogeneic hematopoietic stem cell transplantation (HSCT) were identified from the cohort performed from March

  14. 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...

  15. 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...

  16. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Fagius, J.; Lundgren, J.; Oberg, G.

    2009-01-01

    BACKGROUND: During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been...

  17. Effectiveness of Partner Social Support Predicts Enduring Psychological Distress after Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Rini, Christine; Redd, William H.; Austin, Jane; Mosher, Catherine E.; Meschian, Yeraz Markarian; Isola, Luis; Scigliano, Eileen; Moskowitz, Craig H.; Papadopoulos, Esperanza; Labay, Larissa E.; Rowley, Scott; Burkhalter, Jack E.; Schetter, Christine Dunkel; DuHamel, Katherine N.

    2011-01-01

    Objective: Hematopoietic stem cell transplant (HSCT) survivors who are 1 to 3 years posttransplant are challenged by the need to resume valued social roles and activities--a task that may be complicated by enduring transplant-related psychological distress common in this patient population. The present study investigated whether transplant…

  18. Placenta as a source of hematopoietic stem cells

    NARCIS (Netherlands)

    E.A. Dzierzak (Elaine); C. Robin (Catherine)

    2010-01-01

    textabstractThe placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother,

  19. Automated Identification and Localization of Hematopoietic Stem Cells in 3D Intravital Microscopy Data

    OpenAIRE

    Khorshed, Reema?A.; Hawkins, Edwin?D.; Duarte, Delfim; Scott, Mark?K.; Akinduro, Olufolake?A.; Rashidi, Narges?M.; Spitaler, Martin; Lo?Celso, Cristina

    2015-01-01

    Summary Measuring three-dimensional (3D) localization of hematopoietic stem cells (HSCs) within the bone marrow microenvironment using intravital microscopy is a rapidly expanding research theme. This approach holds the key to understanding the detail of HSC-niche interactions, which are critical for appropriate stem cell function. Due to the complex tissue architecture of the bone marrow and to the progressive introduction of scattering and signal loss at increasing imaging depths, there is ...

  20. Persistent seropositivity for yellow fever in a previously vaccinated autologous hematopoietic stem cell transplantation recipient.

    Science.gov (United States)

    Hayakawa, Kayoko; Takasaki, Tomohiko; Tsunemine, Hiroko; Kanagawa, Shuzo; Kutsuna, Satoshi; Takeshita, Nozomi; Mawatari, Momoko; Fujiya, Yoshihiro; Yamamoto, Kei; Ohmagari, Norio; Kato, Yasuyuki

    2015-08-01

    The duration of a protective level of yellow fever antibodies after autologous hematopoietic stem cell transplantation in a previously vaccinated person is unclear. The case of a patient who had previously been vaccinated for yellow fever and who remained seropositive for 22 months after autologous peripheral blood stem cell transplantation for malignant lymphoma is described herein. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Co-transplantation of Hematopoietic Stem Cells and Cxcr4 Gene-Transduced Mesenchymal Stem Cells Promotes Hematopoiesis.

    Science.gov (United States)

    Chen, Wei; Li, Miao; Su, Guizhen; Zang, Yu; Yan, Zhiling; Cheng, Hai; Pan, Bin; Cao, Jiang; Wu, Qingyun; Zhao, Kai; Zhu, Feng; Zeng, Lingyu; Li, Zhenyu; Xu, Kailin

    2015-04-01

    Mesenchymal stem cells (MSCs) are a promising candidate for cellular therapies. Co-transplantation of MSCs and hematopoietic stem cells (HSCs) promotes successful engraftment and improves hematopoietic recovery. In this study, the effects of co-transplantation of HSCs and mouse bone marrow (BM)-derived MSCs overexpressing CXCR4 (CXCR4-MSC) on CXCR4-MSC homing capacity and the reconstitution potential in lethally irradiated mice were evaluated. Recovery of donor-derived peripheral blood leukocytes and platelets was accelerated when CXCR4-MSCs were co-transplanted with BM cells. The frequency of c-kit(+)Sca(+)Lin(-) HSCs was higher in recipient BM following co-transplantation of CXCR4-MSCs compared with the EGFP-MSC control and the BMT only groups. Surprisingly, the rate of early engraftment of donor-derived BM cells in recipients co-transplanted with CXCR4-MSCs was slightly lower than in the absence of MSCs on day 7. Moreover, co-transplantation of CXCR4-MSCs regulated the balance of T helper cells subsets. Hematopoietic tissue reconstitution was evaluated by histopathological analysis of BM and spleen. Co-transplantation of CXCR4-MSCs was shown to promote the recovery of hematopoietic organs. These findings indicate that co-transplantation of CXCR4-MSCs promotes the early phase of hematopoietic recovery and sustained hematopoiesis.

  2. Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

    Science.gov (United States)

    Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-10-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

  3. In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.

    Science.gov (United States)

    Derderian, S Christopher; Togarrati, P Priya; King, Charmin; Moradi, Patriss W; Reynaud, Damien; Czechowicz, Agnieszka; Weissman, Irving L; MacKenzie, Tippi C

    2014-08-07

    Although in utero hematopoietic cell transplantation is a promising strategy to treat congenital hematopoietic disorders, levels of engraftment have not been therapeutic for diseases in which donor cells have no survival advantage. We used an antibody against the murine c-Kit receptor (ACK2) to deplete fetal host hematopoietic stem cells (HSCs) and increase space within the hematopoietic niche for donor cell engraftment. Fetal mice were injected with ACK2 on embryonic days 13.5 to 14.5 and surviving pups were transplanted with congenic hematopoietic cells on day of life 1. Low-dose ACK2 treatment effectively depleted HSCs within the bone marrow with minimal toxicity and the antibody was cleared from the serum before the neonatal transplantation. Chimerism levels were significantly higher in treated pups than in controls; both myeloid and lymphoid cell chimerism increased because of higher engraftment of HSCs in the bone marrow. To test the strategy of repeated HSC depletion and transplantation, some mice were treated with ACK2 postnatally, but the increase in engraftment was lower than that seen with prenatal treatment. We demonstrate a successful fetal conditioning strategy associated with minimal toxicity. Such strategies could be used to achieve clinically relevant levels of engraftment to treat congenital stem cell disorders. © 2014 by The American Society of Hematology.

  4. 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

  5. Umbilical cord bloods hematopoietic stem cells ex vivo expansion (the literature review

    Directory of Open Access Journals (Sweden)

    T. V. Shamanskaya

    2012-01-01

    Full Text Available Umbilical cord blood (CB is now an attractive source of hematopoietic stem cells (HSCs for transplantation in pediatric and adult patients with various malignant and non-malignant diseases. However, its clinical application is limited by low cells numbers in graft, which correlates with delayed engraftment, an extension of time to platelets and neutrophils recovery and increasing risk of infectious complications. Several strategies have been suggested to overcome this limitation, one of which is obtaining a sufficient number of hematopoietic progenitor cells by ex vivo expansion. Literature review about CB HSCs expansion in given article is presented.

  6. Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation

    OpenAIRE

    Nemeth, Michael J.; Kirby, Martha R.; Bodine, David M

    2006-01-01

    Hmgb3 is an X-linked member of a family of sequence-independent chromatin-binding proteins that is preferentially expressed in hematopoietic stem cells (HSC). Hmgb3-deficient mice (Hmgb3−/Y) contain normal numbers of HSCs, capable of self-renewal and hematopoietic repopulation, but fewer common lymphoid (CLP) and common myeloid progenitors (CMP). In this study, we tested the hypothesis that Hmgb3−/Y HSCs are biased toward self-renewal at the expense of progenitor production. Wild-type and Hmg...

  7. Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment.

    Science.gov (United States)

    Speth, Jennifer M; Hoggatt, Jonathan; Singh, Pratibha; Pelus, Louis M

    2014-01-09

    Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E2 (dmPGE2). While exploring regulatory molecules involved in dmPGE2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-α (HIF1α) is required for dmPGE2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1α is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1α in enhancement of hematopoietic transplantation.

  8. Hematopoietic stem cells : Self-renewing or aging?

    NARCIS (Netherlands)

    de Haan, G

    2002-01-01

    Stem cells are defined by their extensive self-renewal properties, and yet there is abundant evidence of erosion of stem cell functioning during aging. Whereas intracellular repair and protection mechanisms determine the lifespan of an individual cell, here an argument is made that somatic stem

  9. Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Döring Michaela

    2012-07-01

    Full Text Available Abstract Background Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT often receive intravenous liposomal amphotericin B (L-AmB as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS, a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB. Methods We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day and another 60 patients received CAS (50 mg/m2/day as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively. Results No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT. Conclusion Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.

  10. Teriparatide (PTH 1-34) treatment increases peripheral hematopoietic stem cells in postmenopausal women.

    Science.gov (United States)

    Yu, Elaine W; Kumbhani, Ruchit; Siwila-Sackman, Erica; DeLelys, Michelle; Preffer, Frederic I; Leder, Benjamin Z; Wu, Joy Y

    2014-06-01

    Cells of the osteoblast lineage play an important role in regulating the hematopoietic stem cell (HSC) niche and early B-cell development in animal models, perhaps via parathyroid hormone (PTH)-dependent mechanisms. There are few human clinical studies investigating this phenomenon. We studied the impact of long-term daily teriparatide (PTH 1-34) treatment on cells of the hematopoietic lineage in postmenopausal women. Twenty-three postmenopausal women at high risk of fracture received teriparatide 20 mcg sc daily for 24 months as part of a prospective longitudinal trial. Whole blood measurements were obtained at baseline, 3, 6, 12, and 18 months. Flow cytometry was performed to identify hematopoietic subpopulations, including HSCs (CD34+/CD45(moderate); ISHAGE protocol) and early transitional B cells (CD19+, CD27-, IgD+, CD24[hi], CD38[hi]). Serial measurements of spine and hip bone mineral density (BMD) as well as serum P1NP, osteocalcin, and CTX were also performed. The average age of study subjects was 64 ± 5 years. We found that teriparatide treatment led to an early increase in circulating HSC number of 40% ± 14% (p = 0.004) by month 3, which persisted to month 18 before returning to near baseline by 24 months. There were no significant changes in transitional B cells or total B cells over the course of the study period. In addition, there were no differences in complete blood count profiles as quantified by standard automated flow cytometry. Interestingly, the peak increase in HSC number was inversely associated with increases in bone markers and spine BMD. Daily teriparatide treatment for osteoporosis increases circulating HSCs by 3 to 6 months in postmenopausal women. This may represent a proliferation of marrow HSCs or increased peripheral HSC mobilization. This clinical study establishes the importance of PTH in the regulation of the HSC niche within humans. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for

  11. Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.

    Science.gov (United States)

    Li, Qian; Luo, Changying; Luo, Chengjuan; Wang, Jianmin; Li, Benshang; Ding, Lixia; Chen, Jing

    2017-08-01

    Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 108/kg and 4.3 × 106/kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.

  12. Clostridium difficile infection in Chilean patients submitted to hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Javier Pilcante

    2015-12-01

    Full Text Available ABSTRACT Introduction: Patients submitted to hematopoietic stem cell transplantation have an increased risk of Clostridium difficile infection and multiple risk factors have been identi- fied. Published reports have indicated an incidence from 9% to 30% of transplant patients however to date there is no information about infection in these patients in Chile. Methods: A retrospective analysis was performed of patients who developed C. difficile infection after hematopoietic stem cell transplantations from 2000 to 2013. Statistical analysis used the Statistical Package for the Social Sciences software. Results: Two hundred and fifty patients were studied (mean age: 39 years; range: 17-69, with 147 (59% receiving allogeneic transplants and 103 (41% receiving autologous trans- plants. One hundred and ninety-two (77% patients had diarrhea, with 25 (10% cases of C. difficile infection being confirmed. Twenty infected patients had undergone allogeneic trans- plants, of which ten had acute lymphoblastic leukemia, three had acute myeloid leukemia and seven had other diseases (myelodysplastic syndrome, chronic myeloid leukemia, severe aplastic anemia. In the autologous transplant group, five patients had C. difficile infection; two had multiple myeloma, one had amyloidosis, one had acute myeloid leukemia and one had germinal carcinoma. The overall incidence of C. difficile infection was 4% within the first week, 6.4% in the first month and 10% in one year, with no difference in overall survival between infected and non-infected groups (72.0% vs. 67.6%, respectively; p-value = 0.56. Patients infected after allogeneic transplants had a slower time to neutrophil engraftment compared to non-infected patients (17.5 vs. 14.9 days, respectively; p-value = 0.008. In the autologous transplant group there was no significant difference in the neutrophil engraftment time between infected and non-infected patients (12.5 days vs. 11.8 days, respectively; p

  13. Role of reactive oxygen species in the radiation response of human hematopoietic stem/progenitor cells.

    Directory of Open Access Journals (Sweden)

    Masaru Yamaguchi

    Full Text Available Hematopoietic stem/progenitor cells (HSPCs, which are present in small numbers in hematopoietic tissues, can differentiate into all hematopoietic lineages and self-renew to maintain their undifferentiated phenotype. HSPCs are extremely sensitive to oxidative stressors such as anti-cancer agents, radiation, and the extensive accumulation of reactive oxygen species (ROS. The quiescence and stemness of HSPCs are maintained by the regulation of mitochondrial biogenesis, ROS, and energy homeostasis in a special microenvironment called the stem cell niche. The present study evaluated the relationship between the production of intracellular ROS and mitochondrial function during the proliferation and differentiation of X-irradiated CD34(+ cells prepared from human placental/umbilical cord blood HSPCs. Highly purified CD34(+ HSPCs exposed to X-rays were cultured in liquid and semi-solid medium supplemented with hematopoietic cytokines. X-irradiated CD34(+ HSPCs treated with hematopoietic cytokines, which promote their proliferation and differentiation, exhibited dramatically suppressed cell growth and clonogenic potential. The amount of intracellular ROS in X-irradiated CD34(+ HSPCs was significantly higher than that in non-irradiated cells during the culture period. However, neither the intracellular mitochondrial content nor the mitochondrial superoxide production was elevated in X-irradiated CD34(+ HSPCs compared with non-irradiated cells. Radiation-induced gamma-H2AX expression was observed immediately following exposure to 4 Gy of X-rays and gradually decreased during the culture period. This study reveals that X-irradiation can increase persistent intracellular ROS in human CD34(+ HSPCs, which may not result from mitochondrial ROS due to mitochondrial dysfunction, and indicates that substantial DNA double-strand breakage can critically reduce the stem cell function.

  14. [Dose adaptation of the drugs used for hematopoietic stem-cell transplantation in patients with comorbidity: Obesity, chronic renal disease or hepatopathy: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    Science.gov (United States)

    Simon, Nicolas; Coiteux, Valérie; Bruno, Bénédicte; Taque, Sophie; Charbonnier, Amandine; Souchet, Laetitia; Vincent, Laure; Yakoub-Agha, Ibrahim; Chalandon, Yves

    2017-12-01

    In September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th Allogeneic Stem Cell Transplantation Clinical Practices Harmonization Workshop Series. Our work group focused on chemotherapy drug dose adaptation for hematopoietic stem cell transplantation patients presenting a comorbidity. The purpose of this workshop was to provide recommendations on chemotherapy drug dose adaptation for patient populations receiving hematopoietic stem cell transplantation who also had the following comorbidities: obesity, chronic kidney disease and hepatopathy. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  15. Cartography of hematopoietic stem cell commitment dependent upon a reporter for transcription factor activation.

    Science.gov (United States)

    Akashi, Koichi

    2007-06-01

    A hierarchical hematopoietic developmental tree has been proposed based on the result of prospective purification of lineage-restricted progenitors. For more detailed mapping for hematopoietic stem cell (HSC) commitment, we tracked the expression of PU.1, a major granulocyte/monocyte (GM)- and lymphoid-related transcription factor, from the HSC to the myelolymphoid progenitor stages by using a mouse line harboring a knockin reporter for PU.1. This approach enabled us to find a new progenitor population committed to GM and lymphoid lineages within the HSC fraction. This result suggests that there should be another developmental pathway independent of the conventional one with myeloid versus lymphoid bifurcation, represented by common myeloid progenitors and common lymphoid progenitors, respectively. The utilization of the transcription factor expression as a functional marker might be useful to obtain cartography of the hematopoietic development at a higher resolution.

  16. Transcriptional Regulation of Hhex in Hematopoiesis and Hematopoietic Stem Cell Ontogeny

    DEFF Research Database (Denmark)

    Portero Migueles, Rosa; Shaw, Louise; Rodrigues, Neil P

    2017-01-01

    Hematopoietic stem cells (HSCs) emerge during development via an endothelial-to-hematopoietic transition from hemogenic endothelium of the dorsal aorta (DA). Using in situ hybridization and analysis of a knock-in RedStar reporter, we show that the transcriptional regulator Hhex is expressed...... in endothelium of the dorsal aorta (DA) and in clusters of putative HSCs as they are specified during murine development. We exploited this observation, using the Hhex locus to define cis regulatory elements, enhancers and interacting transcription factors that are both necessary and sufficient to support gene...... expression in the emerging HSC. We identify an evolutionarily conserved non-coding region (ECR) in the Hhex locus with the capacity to bind the hematopoietic-affiliated transcriptional regulators Gata2, SCL, Fli1, Pu.1 and Ets1/2. This region is sufficient to drive the expression of a transgenic GFP reporter...

  17. The Involvment of Hematopoietic-Specific PLC -β2 in Homing and Engraftment of Hematopoietic Stem/Progenitor Cells.

    Science.gov (United States)

    Adamiak, Mateusz; Suszynska, Malwina; Abdel-Latif, Ahmed; Abdelbaset-Ismail, Ahmed; Ratajczak, Janina; Ratajczak, Mariusz Z

    2016-12-01

    Migration and bone marrow (BM) homing of hematopoietic stem progenitor cells (HSPCs) is regulated by several signaling pathways, and here we provide evidence for the involvement in this process of hematopoietic-specific phospholipase C-β2 (PLC-β2). This enzyme is involved in release of intracellular calcium and activation of protein kinase C (PKC). Recently we reported that PLC-β2 promotes mobilization of HSPCs from BM into peripheral blood (PB), and this effect is mediated by the involvement of PLC-β2 in the release of proteolytic enzymes from granulocytes and its role in disintegration of membrane lipid rafts. Here we report that, besides the role of PLC-β2 in the release of HSPCs from BM niches, PLC-β2 regulates the migration of HSPCs in response to chemotactic gradients of BM homing factors, including SDF-1, S1P, C1P, and ATP. Specifically, HSPCs from PLC-β2-KO mice show impaired homing and engraftment in vivo after transplantation into lethally irradiated mice. This decrease in migration of HSPCs can be explained by impaired calcium release in PLC-β2-KO mice and a high baseline level of heme oxygenase 1 (HO-1), an enzyme that negatively regulates cell migration.

  18. The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Myelofibrosis: a Retrospective Study in a Single Center

    Directory of Open Access Journals (Sweden)

    Mei-Fang Hou

    2015-03-01

    Conclusions: Allogeneic hematopoietic stem cell transplantation is effective in treating myelofibrosis and is associated with modest toxicity and post-transplantation complications. In order to improve the treatment outcome, we have to manage GVHD and infection more carefully.

  19. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation : A multicenter study

    NARCIS (Netherlands)

    Ansari, Marc; Curtis, Patricia Huezo Diaz; Uppugunduri, Chakradhara Rao S.; Rezgui, Mohammed Aziz; Nava, Tiago; Mlakar, Vid; Lesne, Laurence; Théoret, Yves; Chalandon, Yves; Dupuis, Lee L.; Schechter, Tao; Bartelink, Imke H.; Boelens, Jaap J.|info:eu-repo/dai/nl/189880783; Bredius, Robbert; Dalle, Jean-Hugues; Azarnoush, Saba; Sedlacek, Petr; Lewis, Victor A.; Champagne, Martin A.; Peters, Christina; Bittencourt, Henrique; Krajinovic, Maja

    2017-01-01

    Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S

  20. Total body irradiation in hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Fundagul Andic

    2014-06-01

    Full Text Available Total body irradiation is used in conjunction with chemotherapy as a conditioning regimen in the treatment of many disease such as leukemia, myelodysplastic syndrome, aplastic anemia, multiple myeloma and lymphoma prior to the hematopoetic stem cell transplantation. The main purposes of the hematopoetic stem cell transplantation are eradication of the recipient bone marrow and any residual cancer cells, creation of space in the receipient bone marrow for donor hematopoetic stem cells, and immunosuppression to prevent rejection of donor stem cells in the case of an allotransplant. [Archives Medical Review Journal 2014; 23(3.000: 398-410

  1. Effective treatment of severe BK virus-associated hemorrhagic cystitis with leflunomide in children after hematopoietic stem cell transplantation: a pilot study.

    Science.gov (United States)

    Wu, Kang-Hsi; Weng, Tefu; Wu, Han-Ping; Peng, Ching-Tien; Sheu, Ji-Nan; Chao, Yu-Hua

    2014-11-01

    Leflunomide, an immunosuppressant with antiviral activity, was used to treat 5 children with severe BK virus-associated hemorrhagic cystitis after hematopoietic stem cell transplantation. Without severe side effects, BK viral loads in blood and urine decreased significantly after leflunomide treatment. Compared with 7 historical controls, duration of BK virus-associated hemorrhagic cystitis was significantly shorter in patients receiving leflunomide therapy (P < 0.01).

  2. Kinetics of hematopoietic stem cells and supportive activities of stromal cells in a three-dimensional bone marrow culture system.

    Science.gov (United States)

    Harada, Tomonori; Hirabayashi, Yukio; Hatta, Yoshihiro; Tsuboi, Isao; Glomm, Wilhelm Robert; Yasuda, Masahiro; Aizawa, Shin

    2015-01-01

    In the bone marrow, hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment. Previously, we established a 3D bone marrow culture system. In this study, we analyzed the kinetics of hematopoietic cells, and more than 50% of hematopoietic progenitor cells, including CFU-Mix, CFU-GM and BFU-E in 3D culture were in a resting (non-S) phase. Furthermore, we examined the hematopoietic supportive ability of stromal cells by measuring the expression of various mRNAs relevant to hematopoietic regulation. Over the 4 weeks of culture, the stromal cells in the 3D culture are not needlessly activated and "quietly" regulate hematopoietic cell proliferation and differentiation during the culture, resulting in the presence of resting hematopoietic stem cells in the 3D culture for a long time. Thus, the 3D culture system may be a new tool for investigating hematopoietic stem cell-stromal cell interactions in vitro.

  3. Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype

    Directory of Open Access Journals (Sweden)

    Sidinh Luc

    2016-09-01

    Full Text Available B cell CLL/lymphoma 11A (BCL11A is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6, and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A.

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

    Directory of Open Access Journals (Sweden)

    Shigeo eFuji

    2013-09-01

    Full Text Available 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 (GVHD. 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.

  5. Music Therapy for Patients Who Have Undergone Hematopoietic Stem Cell Transplant

    Directory of Open Access Journals (Sweden)

    Chelsea G. Ratcliff

    2014-01-01

    Full Text Available Objectives. This study examines the short- and long-term QOL benefits of a music therapy intervention for patients recovering from hematopoietic stem cell transplantation (HSCT. Methods. Ninety allogeneic HSCT patients, after transplant, were randomized to receive ISO-principle (i.e., mood matching based music therapy (MT; n=29, unstructured music (UM; n=30, or usual care (UC; n=31 for four weeks. The ISO principle posits that patients may shift their mood from one state to another by listening to music that is “equal to” the individual’s initial mood state and subsequently listening to music selections that gradually shift in tempo and mood to match the patient’s desired disposition. Participants in MT and UM groups developed two audio CDs to help them feel more relaxed and energized and were instructed to use the CDs to improve their mood as needed. Short-term effects on mood and long-term effects on QOL were examined. Results. MT and UM participants reported improved mood immediately after listening to CDs; the within-group effect was greater for UM participants compared to MT participants. Participant group was not associated with long-term QOL outcomes. Conclusions. Music listening improves mood acutely but was not associated with long-term benefits in this study.

  6. Music therapy improves the mood of patients undergoing hematopoietic stem cells transplantation (controlled randomized study).

    Science.gov (United States)

    Dóro, Carlos Antonio; Neto, José Zanis; Cunha, Rosemyriam; Dóro, Maribel Pelaez

    2017-03-01

    The allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a therapeutic medical treatment for various neoplastic hematologic, congenital, genetic, or acquired disorders. In this procedure which combines high-dose chemotherapy and/or radiotherapy and has a high degree of cytotoxicity, the patient experiences solitary confinement, which causes psychological distress, pain, anxiety, mood disorders and can lead him/her to depression. Music therapy was applied with the purpose of decreasing this social confinement. This is a randomized controlled trial. Patients (n = 100) were selected randomly. Patients (n = 50) were selected for the Experimental Music Therapy Group (EMG) and n = 50 for the control group (CG) who received the standard treatment. The intervention of live music was applied using music therapy techniques. Assessment and quantification were made using the visual analog scale (VAS). The dependent variables were pain, anxiety, and mood of patients. The Mann-Whitney test (p Music therapy proved to be a strong ally in the treatment of patients undergoing allo-HSCT, providing bio-psychosocial welfare.

  7. Hyperbaric oxygen: an important treatment modality in severe hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

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    Deniz Sargın

    2009-12-01

    Full Text Available Objective: Hemorrhagic cystitis (HC is a generally self-limited complication of hematopoietic stem cell transplantation (HSCT. It may occur in the early or late posttransplant period and can promote sometimes severe morbidity. We analyzed our data regarding HC in allogeneic HSCT patients in order to establish the efficacy of hyperbaric oxygen (HBO therapy in severe HC and to document the main problems during its use. Material and Methods: Between March 1993 and August 2006, 161 patients received allogeneic HSCT. Mesna, hyperhydration and forced diuresis were used as early HC prophylaxis of cyclophosphamide-induced HC. However, HC was diagnosed in 49 of the 161 recipients and 17 of them were considered as severe HC. We analyzed their data retrospectively.Results: Forced diuresis with hyperhydration (up to 8 L/day and transfusion support to maintain a platelet count above 30x109/L were sufficient in 10 of the 17 patients with severe HC. Alternative therapies used included intravesical irrigation with formalin and prostaglandin (PGF2 alpha and HBO, and HBO appeared to be the most useful among them. Conclusion: We conclude that HBO offers a noninvasive therapeutic alternative in the management of intractable HC in the HSCT setting.

  8. Choreito formula for BK virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Kawashima, Nozomu; Ito, Yoshinori; Sekiya, Yuko; Narita, Atsushi; Okuno, Yusuke; Muramatsu, Hideki; Irie, Masahiro; Hama, Asahito; Takahashi, Yoshiyuki; Kojima, Seiji

    2015-02-01

    Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Cytomegalovirus disease in hematopoietic stem cell transplant patients: current and future therapeutic options.

    Science.gov (United States)

    Fuji, Shigeo; Einsele, Hermann; Kapp, Markus

    2017-08-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become one of the standard treatment for hematological diseases. Although the clinical outcome has improved significantly during the last decades, the morbidity and mortality after allo-HSCT are still obstacles to cure. Out of major morbidities, opportunistic virus infections such as cytomegalovirus (CMV) infection are important complications, in particular in patients who received human leukocyte antigen-mismatched HSCT. Here, we aim to summarize information about current and future therapeutic options in CMV disease after allo-HSCT. Recently, not only new drugs but also adoptive T-cell therapy are tested in the setting of clinical trials. CMV prophylaxis using letermovir significantly reduced the incidence of CMV disease in comparison to placebo in a phase III clinical trial. Meanwhile, adoptive T-cell therapies which are fully adapted to good manufacturing practice (GMP) conditions are now available. A recent multicenter study in Germany showed a promising result using Streptamer-isolated T-cell therapy. With the recent development of CMV-targeted therapy, treatment strategies of CMV infection would be further sophisticated in the near future. VIDEO ABSTRACT: http://links.lww.com/COID/A19.

  10. Nephrotoxicity of concomitant use of tacrolimus and teicoplanin in allogeneic hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Mori, T; Shimizu, T; Kato, J; Kikuchi, T; Kohashi, S; Koda, Y; Toyama, T; Saburi, M; Iketani, O; Okamoto, S

    2014-04-01

    Both tacrolimus and glycopeptide antibiotics are known to be nephrotoxic, and are often concomitantly given after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. The aim of this study is to evaluate the nephrotoxicity of concomitant use of tacrolimus and glycopeptide antibiotics in HSCT recipients. We retrospectively evaluated 67 patients who received intravenous tacrolimus and teicoplanin concomitantly for >4 days after allogeneic HSCT for hematologic diseases. Therapeutic drug monitoring (TDM) was performed in all patients for both tacrolimus and teicoplanin. The median age of the patients was 48 years (range: 16-62), and the median duration of the co-administration of tacrolimus and teicoplanin was 11 days (range: 4-40). The mean serum creatinine (sCr) level tended to be elevated after the co-administration (from 0.69 ± 0.26 to 0.75 ± 0.30 mg/dL; P = 0.08); however, a 2-fold or greater increase in sCr was observed only in 2 (3.0%) patients. Increased sCr was reversible, and no patient required hemodialysis. These results suggest that the incidence of clinically significant nephrotoxicity can be minimized if the TDM of each drug is properly applied. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Selenium supplementation in patients undergoing hematopoietic stem cell transplantation: effects on pro-inflammatory cytokines levels.

    Science.gov (United States)

    Daeian, Nesa; Radfar, Mania; Jahangard-Rafsanjani, Zahra; Hadjibabaie, Molouk; Ghavamzadeh, Ardeshir

    2014-06-17

    Pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) play an important role in the development of hematopoietic stem cell transplantation (HSCT) complications. We explored the effect of Selenium as an antioxidant and anti-inflammatory agent on pro-inflammatory cytokines levels in HSCT candidates. Plasma concentrations of TNF-α, IL-1β and IL-6 were measured in 74 patients from a double-blind, randomized, placebo-controlled study. In both groups, there were 37 patients with median age of 32 years. Patients received oral Se tablets (200 mcg) or placebo twice daily beginning from the first day of high dose chemotherapy (HDC) through 14 days after HSCT. Cytokine levels were determined before starting HDC (prior to first dose of Se), 7 and 14 days after HSCT. Plasma levels of TNF-α were not significantly different between Se and control group (P = 0.13). IL-1 levels were similar between two groups (P = 0.88). No significant differences were detected in IL-6 levels between Se and control group (P = 0.96). Selenium had no effect on pro-inflammatory cytokines levels in patients undergoing HSCT. It is likely that earlier initiation and/or larger doses of Se are required to affect inflammatory cytokines significantly.

  12. Music Therapy for Patients Who Have Undergone Hematopoietic Stem Cell Transplant

    Science.gov (United States)

    Ratcliff, Chelsea G.; Richardson, Michael; Baynham-Fletcher, Laura; Cohen, Marlene Z.; de Lima, Marcos; Cohen, Lorenzo

    2014-01-01

    Objectives. This study examines the short- and long-term QOL benefits of a music therapy intervention for patients recovering from hematopoietic stem cell transplantation (HSCT). Methods. Ninety allogeneic HSCT patients, after transplant, were randomized to receive ISO-principle (i.e., mood matching) based music therapy (MT; n = 29), unstructured music (UM; n = 30), or usual care (UC; n = 31) for four weeks. The ISO principle posits that patients may shift their mood from one state to another by listening to music that is “equal to” the individual's initial mood state and subsequently listening to music selections that gradually shift in tempo and mood to match the patient's desired disposition. Participants in MT and UM groups developed two audio CDs to help them feel more relaxed and energized and were instructed to use the CDs to improve their mood as needed. Short-term effects on mood and long-term effects on QOL were examined. Results. MT and UM participants reported improved mood immediately after listening to CDs; the within-group effect was greater for UM participants compared to MT participants. Participant group was not associated with long-term QOL outcomes. Conclusions. Music listening improves mood acutely but was not associated with long-term benefits in this study. PMID:24527052

  13. [Mycobacterium tuberculosis infection in a pediatric patient who underwent a hematopoietic stem cell transplant].

    Science.gov (United States)

    Palma, Julia; Catalán, Paula; Mardones, Patricia; Santolaya, M Elena

    2013-04-01

    We report the case of a 10 year old girl with a relapsed acute lymphoblastic leukemia, who underwent a haploidentical hematopoietic stem cell transplant (HSCT), with grade II skin and digestive graft versus host disease, treated with corticosteroids and cyclosporine. On day + 54, she presented fever, with no other remarkable clinical findings. Imaging study showed the presence of lung and liver nodules, liver biopsy was performed. The study included histology, staining and culture for bacteria and fungi, and the preservation of a piece of tissue at -20°C for future prospective studies. Ziehl Nielsen stain was positive, and study for Mycobacterium infection was performed. Microbiological smears of tracheal and gastric aspirate, and bronchial fluid obtained by bronchoalveolar lavage (BAL) were positive. The final report confirmed Mycobacterium tuberculosis in gastric content, sputum, BAL and liver tissue, susceptible to rifampin, isoniazid, streptomycin and ethambutol, with determination of mutations for genes rpoβ and kat G (-). Tuberculosis (TB) diagnosis was confirmed. The girl received daily therapy for two months and then she continued on three times per week therapy for 9 months. Controlled by the transplant, infectious diseases and respiratory teams, the patient remained in good general condition, with radiologic resolution of pulmonary and liver involvement and negative smears. We conclude that Mycobacterium tuberculosis infection should be part of differential diagnosis of febrile illness in patients undergoing HSCT, and biopsy should be a standard practice of early diagnosis in these patients.

  14. Different Motile Behaviors of Human Hematopoietic Stem versus Progenitor Cells at the Osteoblastic Niche

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    Katie Foster

    2015-11-01

    Full Text Available Despite advances in our understanding of interactions between mouse hematopoietic stem cells (HSCs and their niche, little is known about communication between human HSCs and the microenvironment. Using a xenotransplantation model and intravital imaging, we demonstrate that human HSCs display distinct motile behaviors to their hematopoietic progenitor cell (HPC counterparts, and the same pattern can be found between mouse HSCs and HPCs. HSCs become significantly less motile after transplantation, while progenitor cells remain motile. We show that human HSCs take longer to find their niche than previously expected and suggest that the niche be defined as the position where HSCs stop moving. Intravital imaging is the only technique to determine where in the bone marrow stem cells stop moving, and future analyses should focus on the environment surrounding the HSC at this point.

  15. Sirt1 Protects Stressed Adult Hematopoietic Stem Cells | Center for Cancer Research

    Science.gov (United States)

    The immune system relies on a stable pool of hematopoietic stem and progenitor cells (HSPCs) to respond properly to injury or stress. Maintaining genomic integrity and appropriate gene expression is essential for HSPC homeostasis, and dysregulation can result in myeloproliferative disorders or loss of immune function. Sirt1 is a histone deacetylase that can protect embryonic stem (ES) cells from accumulating DNA damage and has been linked to hematopoietic differentiation of ES cells. Satyendra Singh, Ph.D., a postdoctoral fellow working with Philipp Oberdoerffer, Ph.D., in CCR’s Laboratory of Receptor Biology and Gene Expression, and their colleagues set out to determine whether Sirt1 could play a similar protective role in adult HSPCs.

  16. Hematopoietic stem cell transplantation monitoring in childhood. Hematological diseases in Serbia: STR-PCR techniques

    Directory of Open Access Journals (Sweden)

    Krstić Aleksandra D.

    2007-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is a very successful method of treatment for children with different aquired or inborn diseases. The main goal of post-transplantation chimerism monitoring in HSCT is to predict negative events (such as disease relapse and graft rejection, in order to intervene with appropriate therapy and improve the probability of long-term DFS (disease free survival. In this context, by quantifying the relative amounts of donor and recipient cells present in the peripheral blood sample, it can be determined if engraftment has taken place at all, or if full or mixed chimerism exists. In a group of patients who underwent hematopoietic stem cell transplantation at the Mother and Child Health Care Institute, we decided to use standard human identfication tests based on multiplex PCR analyses of short tandem repeats (STRs, as they are highly informative, sensitive, and fast and therefore represent an optimal methodological approach to engraftment analysis.

  17. Stomatitis-Related Pain in Women with Breast Cancer Undergoing Autologous Hematopoietic Stem Cell Transplant

    OpenAIRE

    Fall-Dickson, Jane M.; Mock, Victoria; Berk, Ronald A.; Grimm, Patricia M.; Davidson, Nancy; Gaston-Johansson, Fannie

    2008-01-01

    The purpose of this cross-sectional, correlational study was to describe stomatitis-related pain in women with breast cancer undergoing autologous hematopoietic stem cell transplant. Hypotheses tested were that significant, positive relationships would exist between oral pain and stomatitis, state anxiety, depression, and alteration in swallowing. Stomatitis, sensory dimension of oral pain, and state anxiety were hypothesized to most accurately predict oral pain overall intensity. Thirty-two ...

  18. The role of hematopoietic stem cell transplantation for type 1 diabetes mellitus

    OpenAIRE

    Voltarelli,Júlio C; Couri,Carlos Eduardo B.; RODRIGUES, Maria Carolina; Ana Beatriz P. L. Stracieri; Moraes,Daniela A.; Pieroni,Fabiano; Navarro,George; MADEIRA, Maria Isabel A.; Belinda P. Simões

    2008-01-01

    In this review, we present 1) scientific basis for the use of high dose immunosuppression followed by autologous peripheral blood hematopoietic stem cell transplantation for newly diagnosed type 1 diabetes mellitus, 2) an update of clinical and laboratory outcomes in 21 patients transplanted at the University Hospital of the Ribeirão Preto Medical School, University of São Paulo, Brazil, including 6 relapses in patients without previous ketoacidosis and 3) a discussion of future prospectives ...

  19. Basic oral care for hematology–oncology patients and hematopoietic stem cell transplantation recipients

    DEFF Research Database (Denmark)

    Elad, Sharon; Raber-Durlacher, Judith E; Brennan, Michael T

    2015-01-01

    PURPOSE: Hematology-oncology patients undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT) recipients are at risk for oral complications which may cause significant morbidity and a potential risk of mortality. This emphasizes the importance of basic oral care prior to, durin...... a protocol to assist the health care provider and present a practical approach for basic oral care. Research is warranted to provide robust scientific evidence and to enhance this clinical protocol....

  20. Synergistic actions of hematopoietic and mesenchymal stem/progenitor cells in vascularizing bioengineered tissues.

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    Eduardo K Moioli

    Full Text Available Poor angiogenesis is a major road block for tissue repair. The regeneration of virtually all tissues is limited by angiogenesis, given the diffusion of nutrients, oxygen, and waste products is limited to a few hundred micrometers. We postulated that co-transplantation of hematopoietic and mesenchymal stem/progenitor cells improves angiogenesis of tissue repair and hence the outcome of regeneration. In this study, we tested this hypothesis by using bone as a model whose regeneration is impaired unless it is vascularized. Hematopoietic stem/progenitor cells (HSCs and mesenchymal stem/progenitor cells (MSCs were isolated from each of three healthy human bone marrow samples and reconstituted in a porous scaffold. MSCs were seeded in micropores of 3D calcium phosphate (CP scaffolds, followed by infusion of gel-suspended CD34(+ hematopoietic cells. Co-transplantation of CD34(+ HSCs and CD34(- MSCs in microporous CP scaffolds subcutaneously in the dorsum of immunocompromised mice yielded vascularized tissue. The average vascular number of co-transplanted CD34(+ and MSC scaffolds was substantially greater than MSC transplantation alone. Human osteocalcin was expressed in the micropores of CP scaffolds and was significantly increased upon co-transplantation of MSCs and CD34(+ cells. Human nuclear staining revealed the engraftment of transplanted human cells in vascular endothelium upon co-transplantation of MSCs and CD34(+ cells. Based on additional in vitro results of endothelial differentiation of CD34(+ cells by vascular endothelial growth factor (VEGF, we adsorbed VEGF with co-transplanted CD34(+ and MSCs in the microporous CP scaffolds in vivo, and discovered that vascular number and diameter further increased, likely owing to the promotion of endothelial differentiation of CD34(+ cells by VEGF. Together, co-transplantation of hematopoietic and mesenchymal stem/progenitor cells may improve the regeneration of vascular dependent tissues such as bone

  1. An Analysis of microRNA Expression in the Myelodysplastic Syndromes Using Hematopoietic Stem Cells

    Science.gov (United States)

    2015-10-01

    disease  associated  cytogenetic  and  molecular   genetic ...the age-related predisposition for the development of MDS. 15. SUBJECT TERMS MicroRNAs, the myelodysplastic syndromes, hematopoietic stem cells...hematopoiesis   in   the   context   of   aging   and   its   likely   implication   in   the   age-­‐related   predisposition

  2. Evaluation of Quality of Life and Care Needs of Turkish Patients Undergoing Hematopoietic Stem Cell Transplantation

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    Neslisah Yasar

    2016-01-01

    Full Text Available This descriptive study explored the quality of life and care needs of Turkish patients who underwent hematopoietic stem cell transplantation. The study sample consisted of 100 hematopoietic stem cell transplant patients. Their quality of life was assessed using Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale. The mean patient age was 44.99 ± 13.92 years. Changes in sexual functions, loss of hair, loss of taste, loss of appetite, and sleep disturbances were the most common symptoms. The quality of life of transplant patients was moderately affected; the functional well-being and social/family well-being subscales were the most adversely and least negatively affected (12.13 ± 6.88 dimensions, respectively. Being female, being between 50 and 59 years of age, being single, having a chronic disease, and having a history of hospitalization were associated with lower quality of life scores. Interventions to improve functional status, physical well-being, and emotional status of patients during the transplantation process may help patients cope with treatment-related impairments more effectively. Frequent screening and management of patient symptoms in order to help patients adapt to life following allogeneic hematopoietic stem cell transplantation are crucial for meeting care needs and developing strategies to improve their quality of life.

  3. Umbilical cord blood banking in the worldwide hematopoietic stem cell transplantation system: perspectives for Ukraine.

    Science.gov (United States)

    Kalynychenko, T O

    2017-09-01

    Significant progress in the promotion of procedural technologies associated with the transplantation of hematopoietic stem cells caused a rapid increase in activity. The exchange of hematopoietic stem cells for unrelated donor transplantations is now much easier due to the relevant international professional structures and organizations established to support cooperation and standard setting, as well as rules for the functioning of both national donor registries and cord blood banks. These processes are increasing every year and are contributing to the outpacing rates of development in this area. Products within their country should be regulated by the competent government authorities. This study analyzes the work of international and national levels of support for transplantation activity in the field of unrelated hematopoietic stem cell transplantation, the standardization order of technologies, as well as data that justify the need to create a network of donated umbilical cord blood banks in Ukraine as a factor in the development of allogeneic transplantation. This will promote the accessibility of international standards for the treatment of serious diseases for Ukrainian citizens.

  4. Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

    Science.gov (United States)

    Yan, Xiao; Himburg, Heather A; Pohl, Katherine; Quarmyne, Mamle; Tran, Evelyn; Zhang, Yurun; Fang, Tiancheng; Kan, Jenny; Chao, Nelson J; Zhao, Liman; Doan, Phuong L; Chute, John P

    2016-11-01

    Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10+/+ mice. After total body irradiation (TBI), Grb10m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10+/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance.

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    Granados, Jose M M; Benichou, Gilles; Kawai, Tatsuo

    2015-02-01

    The present review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, and to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications.

  6. Fhit-deficient hematopoietic stem cells survive hydroquinone exposure carrying precancerous changes.

    Science.gov (United States)

    Ishii, Hideshi; Mimori, Koshi; Ishikawa, Kazuhiro; Okumura, Hiroshi; Pichiorri, Flavia; Druck, Teresa; Inoue, Hiroshi; Vecchione, Andrea; Saito, Toshiyuki; Mori, Masaki; Huebner, Kay

    2008-05-15

    The fragile FHIT gene is among the first targets of DNA damage in preneoplastic lesions, and recent studies have shown that Fhit protein is involved in surveillance of genome integrity and checkpoint response after genotoxin exposure. We now find that Fhit-deficient hematopoietic cells, exposed to the genotoxin hydroquinone, are resistant to the suppression of stem cell in vitro colony formation observed with wild-type (Wt) hematopoietic cells. In vivo-transplanted, hydroquinone-exposed, Fhit-deficient bone marrow cells also escaped the bone marrow suppression exhibited by Wt-transplanted bone marrow. Comparative immunohistochemical analyses of bone marrow transplants showed relative absence of Bax in Fhit-deficient bone marrow, suggesting insensitivity to apoptosis; assessment of DNA damage showed that occurrence of the oxidized base 8-hydroxyguanosine, a marker of DNA damage, was also reduced in Fhit-deficient bone marrow, as was production of intracellular reactive oxygen species. Treatment with the antioxidant N-acetyl-l-cysteine relieved hydroquinone-induced suppression of colony formation by Wt hematopoietic cells, suggesting that the decreased oxidative damage to Fhit-deficient cells, relative to Wt hematopoietic cells, accounts for the survival advantage of Fhit-deficient bone marrow. Homology-dependent recombination repair predominated in Fhit-deficient cells, although not error-free repair, as indicated by a higher incidence of 6-thioguanine-resistant colonies. Tissues of hydroquinone-exposed Fhit-deficient bone marrow-transplanted mice exhibited preneoplastic alterations, including accumulation of histone H2AX-positive DNA damage. The results indicate that reduced oxidative stress, coupled with efficient but not error-free DNA damage repair, allows unscheduled long-term survival of genotoxin-exposed Fhit-deficient hematopoietic stem cells carrying deleterious mutations.

  7. Functional analysis of human hematopoietic stem cell gene expression using zebrafish.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Although several reports have characterized the hematopoietic stem cell (HSC transcriptome, the roles of HSC-specific genes in hematopoiesis remain elusive. To identify candidate regulators of HSC fate decisions, we compared the transcriptome of human umbilical cord blood and bone marrow (CD34+(CD33-(CD38-Rho(lo(c-kit+ cells, enriched for hematopoietic stem/progenitor cells with (CD34+(CD33-(CD38-Rho(hi cells, enriched in committed progenitors. We identified 277 differentially expressed transcripts conserved in these ontogenically distinct cell sources. We next performed a morpholino antisense oligonucleotide (MO-based functional screen in zebrafish to determine the hematopoietic function of 61 genes that had no previously known function in HSC biology and for which a likely zebrafish ortholog could be identified. MO knock down of 14/61 (23% of the differentially expressed transcripts resulted in hematopoietic defects in developing zebrafish embryos, as demonstrated by altered levels of circulating blood cells at 30 and 48 h postfertilization and subsequently confirmed by quantitative RT-PCR for erythroid-specific hbae1 and myeloid-specific lcp1 transcripts. Recapitulating the knockdown phenotype using a second MO of independent sequence, absence of the phenotype using a mismatched MO sequence, and rescue of the phenotype by cDNA-based overexpression of the targeted transcript for zebrafish spry4 confirmed the specificity of MO targeting in this system. Further characterization of the spry4-deficient zebrafish embryos demonstrated that hematopoietic defects were not due to more widespread defects in the mesodermal development, and therefore represented primary defects in HSC specification, proliferation, and/or differentiation. Overall, this high-throughput screen for the functional validation of differentially expressed genes using a zebrafish model of hematopoiesis represents a major step toward obtaining meaningful information from global

  8. Efficient hematopoietic redifferentiation of induced pluripotent stem cells derived from primitive murine bone marrow cells.

    Science.gov (United States)

    Pfaff, Nils; Lachmann, Nico; Kohlscheen, Saskia; Sgodda, Malte; Araúzo-Bravo, Marcos J; Greber, Boris; Kues, Wilfried; Glage, Silke; Baum, Christopher; Niemann, Heiner; Schambach, Axel; Cantz, Tobias; Moritz, Thomas

    2012-03-20

    Heterogeneity among induced pluripotent stem cell (iPSC) lines with regard to their gene expression profile and differentiation potential has been described and at least partly linked to the tissue of origin. Here, we generated iPSCs from primitive [lineage negative (Lin(neg))] and nonadherent differentiated [lineage positive (Lin(pos))] bone marrow cells (BM-iPSC), and compared their differentiation potential to that of fibroblast-derived iPSCs (Fib-iPSC) and embryonic stem cells (ESC). In the undifferentiated state, individual iPSC clones but also ESCs proved remarkably similar when analyzed for alkaline phosphatase and SSEA-1 staining, endogenous expression of the pluripotency genes Nanog, Oct4, and Sox2, or global gene expression profiles. However, substantial differences between iPSC clones were observed after induction of differentiation, which became most obvious upon cytokine-mediated instruction toward the hematopoietic lineage. All 3 BM-iPSC lines derived from undifferentiated Lin(neg) cells yielded high proportions of cells expressing the hematopoietic differentiation marker CD41 and in 2 of these lines high proportions of CD41+/ CD45+ cells were detected. In contrast, little hematopoiesis-specific surface marker expression was detected in 4 Lin(pos) BM-iPSC and 3 Fib-iPSC lines. These results were corroborated by functional studies demonstrating robust colony outgrowth from hematopoietic progenitors in 2 of the Lin(neg) BM-iPSCs only. Thus, in conclusion, our data demonstrate efficient generation of iPSCs from primitive hematopoietic tissue as well as efficient hematopoietic redifferentiation for Lin(neg) BM-iPSC lines, thereby supporting the notion of an epigenetic memory in iPSCs.

  9. [Fusarium solani infection in a patient after allogeneic hematopoietic stem cell transplantation: case report and literature review].

    Science.gov (United States)

    Hu, Jiang-Wei; Shu, Xiang-Rong; Ren, Jing; Yin, Xiu-Yun; Jiang, Min; Hu, Liang-Ding; Zhang, Bo; Chen, Hu

    2010-10-01

    To study Fusarium solani infection as a complication in patients after allogeneic hematopoietic stem cell transplantation and to discuss the diagnosis and appropriate therapy. Symptoms, physical examination, laboratory tests, computed tomographic (CT) scans, treatments and outcomes of Fusarium solani infection in a patient with acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation were retrospectively analyzed, and related literatures reviewed. The patient developed pulmonary infiltration and systemic multiple subcutaneous masses after allogeneic hematopoietic stem cell transplantation. Tissue biopsy smear showed a large number of hyphae and spores, and fungal culture grew Fusarium solani. The subcutaneous masses were incised and drained, while amphotericin B and voriconazole were administered, with granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) for hematopoietic recovery. The patient was discharge after full recovery. Fusarium solani infection is a rare but fatal complication after allogeneic hematopoietic stem cell transplantation. Once the skin lesions or subcutaneous masses developed, tissue smear and culture should be done as soon as possible. Early diagnosis and effective treatment to recovery of the patient after allogeneic hematopoietic stem cell transplant. Moreover, the recovery of adequate neutrophil levels is the most important factor in the resolution of fusarial infection.

  10. A synthetic three-dimensional niche system facilitates generation of functional hematopoietic cells from human-induced pluripotent stem cells

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    Yulin Xu

    2016-09-01

    Full Text Available Abstract Background The efficient generation of hematopoietic stem cells (HSCs from human-induced pluripotent stem cells (iPSCs holds great promise in personalized transplantation therapies. However, the derivation of functional and transplantable HSCs from iPSCs has had very limited success thus far. Methods We developed a synthetic 3D hematopoietic niche system comprising nanofibers seeded with bone marrow (BM-derived stromal cells and growth factors to induce functional hematopoietic cells from human iPSCs in vitro. Results Approximately 70 % of human CD34+ hematopoietic cells accompanied with CD43+ progenitor cells could be derived from this 3D induction system. Colony-forming-unit (CFU assay showed that iPSC-derived CD34+ cells formed all types of hematopoietic colonies including CFU-GEMM. TAL-1 and MIXL1, critical transcription factors associated with hematopoietic development, were expressed during the differentiation process. Furthermore, iPSC-derived hematopoietic cells gave rise to both lymphoid and myeloid lineages in the recipient NOD/SCID mice after transplantation. Conclusions Our study underscores the importance of a synthetic 3D niche system for the derivation of transplantable hematopoietic cells from human iPSCs in vitro thereby establishing a foundation towards utilization of human iPSC-derived HSCs for transplantation therapies in the clinic.

  11. Mitigation of Late Renal and Pulmonary Injury After Hematopoietic Stem Cell Transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Cohen, Eric P., E-mail: Eric.Cohen2@va.gov [Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Bedi, Manpreet; Irving, Amy A. [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Jacobs, Elizabeth; Tomic, Rade [Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Klein, John [Department of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Lawton, Colleen A.; Moulder, John E. [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States)

    2012-05-01

    Purpose: To update the results of a clinical trial that assessed whether the angiotensin-converting enzyme inhibitor captopril was effective in mitigating chronic renal failure and pulmonary-related mortality in subjects undergoing total body irradiation (TBI) in preparation for hematopoietic stem cell transplantation (HSCT). Methods and Materials: Updated records of the 55 subjects who were enrolled in this randomized controlled trial were analyzed. Twenty-eight patients received captopril, and 27 patients received placebo. Definitions of TBI-HSCT-related chronic renal failure (and relapse) were the same as those in the 2007 analysis. Pulmonary-related mortality was based on clinical or autopsy findings of pulmonary failure or infection as the primary cause of death. Follow-up data for overall and pulmonary-related mortality were supplemented by use of the National Death Index. Results: The risk of TBI-HSCT-related chronic renal failure was lower in the captopril group (11% at 4 years) than in the placebo group (17% at 4 years), but this was not statistically significant (p > 0.2). Analysis of mortality was greatly extended by use of the National Death Index, and no patients were lost to follow-up for reasons other than death prior to 67 months. Patient survival was higher in the captopril group than in the placebo group, but this was not statistically significant (p > 0.2). The improvement in survival was influenced more by a decrease in pulmonary mortality (11% risk at 4 years in the captopril group vs. 26% in the placebo group, p = 0.15) than by a decrease in chronic renal failure. There was no adverse effect on relapse risk (p = 0.4). Conclusions: Captopril therapy produces no detectable adverse effects when given after TBI. Captopril therapy reduces overall and pulmonary-related mortality after radiation-based HSCT, and there is a trend toward mitigation of chronic renal failure.

  12. [Drug interaction of voriconazole-cyclosporine in children undergoing hematopoietic stem cell transplantation (2013-2014)].

    Science.gov (United States)

    Valenzuela, Romina; Torres, Juan P; Salas, Carolina; Gajardo, Iván; Palma, Julia; Catalán, Paula; Santolaya, M Elena; Morales, Jorge

    2017-02-01

    Drug interactions (DI) in patients receiving hematopoietic stem cell transplantation (HSCT) are common and clinically significant, highlighting: anticonvulsants, voriconazole (VCZ) and cyclosporine (CsA), which require monitoring. To describe the interactions between CsA-VCZ in children undergoing HSCT. Retrospective, descriptive study in immunocompromised children hospitalized since January 2013 to December 2014 at Bone Marrow Transplant Unit, Hospital Dr. Luis Calvo Mackenna, who received CsA and VCZ. The median age was 5 years (3-6) and the median weight was 20 kg (17-30). Sixtythree baseline drug levels were analyzed, of those, 27 were CsA drug levels obtained previous to using VCZ and 36 were CsA drug levels collected concomitantly with VCZ. In the group CsA previous to VCZ, the CsA dose was 4.6 ± 2.6 (mg/ kg/ day) and the CsA average level was 188.8 ± 84.1 (μg/ml). In the group of CsA concomitantly with VCZ, the dose of CsA was 5.5 ± 3.0 (mg/ kg/day) (p = 0.07) and CsA average level was significantly higher: 232.5 ± 106.7 (μg/ml) (p = 0.04). This study shows an increased level of CsA when it is used together with VCZ. Therapeutic drug monitoring could improve the management of the DI and optimize the co-administration of CsA and VCZ.

  13. Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation

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    Aurélie Tormo

    2017-06-01

    Full Text Available Abstract Background Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM transplantation (BMT due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo-stimulatory property of interleukin (IL-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development. Methods To evaluate the effect of IL-21 on de novo T cell development in vivo, BM derived from RAG2p-GFP mice was transplanted into LP/J mice. Lymphocyte reconstitution was first assessed using a hematological analyzer and a flow cytometer on collected blood samples. Detailed flow cytometry analysis was then performed on the BM, thymus, and spleen of transplanted animals. Finally, the effect of human IL-21 on thymopoiesis was validated in humanized mice. Results Using a major histocompatibility complex (MHC-matched allogeneic BMT model, we found that IL-21 administration improves immune reconstitution by triggering the proliferation of BM Lin−Sca1+c-kit+ (LSK subsets. The pharmacological effect of IL-21 also culminates in the recovery of both hematopoietic (thymocytes and non-hematopoietic (stromal cells within the thymi of IL-21-treated recipient animals. Although T cells derived from all transplanted groups proliferate, secrete various cytokines, and express granzyme B similarly in response to T cell receptor (TCR stimulation, full regeneration of peripheral naïve CD4+ and CD8+ T cells and normal TCRvβ distribution could only be detected in IL-21-treated recipient mice. Astonishingly, none of the recipient mice who underwent IL-21 treatment developed graft-versus-host disease (GVHD in the MHC-matched allogeneic setting while the graft-versus-tumor (GVT effect was strongly retained. Inhibition of GVHD onset could also be attributed to the enhanced generation of regulatory B cells (B10 observed in the IL-21, but not PBS, recipient mice. We also tested the

  14. Frozen cord blood hematopoietic stem cells differentiate into higher numbers of functional natural killer cells in vitro than mobilized hematopoietic stem cells or freshly isolated cord blood hematopoietic stem cells.

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    Martha Luevano

    Full Text Available Adoptive natural killer (NK cell therapy relies on the acquisition of large numbers of NK cells that are cytotoxic but not exhausted. NK cell differentiation from hematopoietic stem cells (HSC has become an alluring option for NK cell therapy, with umbilical cord blood (UCB and mobilized peripheral blood (PBCD34(+ being the most accessible HSC sources as collection procedures are less invasive. In this study we compared the capacity of frozen or freshly isolated UCB hematopoietic stem cells (CBCD34(+ and frozen PBCD34(+ to generate NK cells in vitro. By modifying a previously published protocol, we showed that frozen CBCD34(+ cultures generated higher NK cell numbers without loss of function compared to fresh CBCD34(+ cultures. NK cells generated from CBCD34(+ and PBCD34(+ expressed low levels of killer-cell immunoglobulin-like receptors but high levels of activating receptors and of the myeloid marker CD33. However, blocking studies showed that CD33 expression did not impact on the functions of the generated cells. CBCD34(+-NK cells exhibited increased capacity to secrete IFN-γ and kill K562 in vitro and in vivo as compared to PBCD34(+-NK cells. Moreover, K562 killing by the generated NK cells could be further enhanced by IL-12 stimulation. Our data indicate that the use of frozen CBCD34(+ for the production of NK cells in vitro results in higher cell numbers than PBCD34(+, without jeopardizing their functionality, rendering them suitable for NK cell immunotherapy. The results presented here provide an optimal strategy to generate NK cells in vitro for immunotherapy that exhibit enhanced effector function when compared to alternate sources of HSC.

  15. Ex vivo virotherapy with myxoma virus does not impair hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Villa, Nancy Y; Bais, Swarna; Chan, Winnie M; Meacham, Amy M; Wise, Elizabeth; Rahman, Masmudur M; Moreb, Jan S; Rosenau, Emma H; Wingard, John R; McFadden, Grant; Cogle, Christopher R

    2016-03-01

    Relapsing disease is a major challenge after hematopoietic cell transplantation for hematological malignancies. Myxoma virus (MYXV) is an oncolytic virus that can target and eliminate contaminating cancer cells from auto-transplant grafts. The aims of this study were to examine the impact of MYXV on normal hematopoietic stem and progenitor cells and define the optimal treatment conditions for ex vivo virotherapy. Bone marrow (BM) and mobilized peripheral blood stem cells (mPBSCs) from patients with hematologic malignancies were treated with MYXV at various time, temperature and incubation media conditions. Treated BM cells from healthy normal donors were evaluated using flow cytometry for MYXV infection, long-term culture-initiating cell (LTC-IC) assay and colony-forming cell (CFC) assay. MYXV initiated infection in up to 45% of antigen-presenting monocytes, B cells and natural killer cells; however, these infections were uniformly aborted in >95% of all cells. Fresh graft sources showed higher levels of MYXV infection initiation than cryopreserved specimens, but in all cases less than 10% of CD34(+) cells could be infected after ex vivo MYXV treatment. MYXV did not impair LTC-IC colony numbers compared with mock treatment. CFC colony types and numbers were also not impaired by MYXV treatment. MYXV incubation time, temperature or culture media did not significantly change the percentage of infected cells, LTC-IC colony formation or CFC colony formation. Human hematopoietic cells are non-permissive for MYXV. Human hematopoietic stem and progenitor cells were not infected and thus unaffected by MYXV ex vivo treatment. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  16. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells.

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    Yu, Vionnie W C; Yusuf, Rushdia Z; Oki, Toshihiko; Wu, Juwell; Saez, Borja; Wang, Xin; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J; Lee, Eunjung; Gu, Hongcang; Meissner, Alexander; Lin, Charles P; Kharchenko, Peter V; Scadden, David T

    2016-11-17

    Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Identification of the Niche and Phenotype of the First Human Hematopoietic Stem Cells

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    Andrejs Ivanovs

    2014-04-01

    Full Text Available In various vertebrate species, the dorsal aorta (Ao is the site of specification of adult hematopoietic stem cells (HSCs. It has been observed that the upregulation of essential hematopoietic transcription factors and the formation of specific intra-aortic hematopoietic cell clusters occur predominantly in the ventral domain of the Ao (AoV. In the mouse, the first HSCs emerge in the AoV. Here, we demonstrate that in the human embryo the first definitive HSCs also emerge asymmetrically and are localized to the AoV, which thus identifies a functional niche for developing human HSCs. Using magnetic cell separation and xenotransplantations, we show that the first human HSCs are CD34+VE-cadherin+CD45+C-KIT+THY-1+Endoglin+RUNX1+CD38−/loCD45RA−. This population harbors practically all committed hematopoietic progenitors and is underrepresented in the dorsal domain of the Ao (AoD and urogenital ridges (UGRs. The present study provides a foundation for analysis of molecular mechanisms underpinning embryonic specification of human HSCs.

  18. Individualization of drug exposure in pediatric hematopoietic stem cell transplantation

    NARCIS (Netherlands)

    Bartelink, I.H.

    2012-01-01

    Allogeneic haematopoeitic stem cell transplantation is a potentially curative treatment for a variety of diseases. Its use is limited by 1) the risk of graft failures and relapse of malignant diseases, 2) transplantation-associated complications, and 3) late effects. There is a large and largely

  19. Collection of hematopoietic stem cells from patients with autoimmune diseases

    NARCIS (Netherlands)

    Burt, RK; Fassas, A; Snowden, JA; Kozak, T; Wulffraat, NM; Nash, RA; Dunbar, CE; Arnold, R; Prentice, G; Bingham, S; Marmont, AM; McSweeney, PA; van Laar, J.M.

    We reviewed data from 24 transplant centers in Asia, Australia, Europe, and North America to determine the outcomes of stem cell collection including methods used, cell yields, effects on disease activity, and complications in patients with autoimmune diseases. Twenty-one unprimed bone marrow

  20. [Hematopoietic reconstitution after transplantation of uncontrolled-rate cryopreservation autologous peripheral blood hematopoietic stem cells using -80 °C mechanical freezer].

    Science.gov (United States)

    Liu, Mo; Zhao, Yu; Sun, Jing-Fen; Zhao, Wei; Wang, Li-Li; Yu, Li

    2015-02-01

    This study was to identify the efficacy of -80°C cryopreservated peripheral blood hemato-poietic stem cell (PBHSC) transplantation for hematopoietic reanstitution in patients. The efficacy of 104 patients underwent autologous peripheral blood hematopoietic stem cell transplantation using uncontrolled-rate freezing and storage at -80°C was evaluated. This cryopreservation method could effectively cryopreserve peripheral blood stem cells. Out of 104 patients only 2 patients died, other patients got hematologic reconstition satisfactorily, the median engrafement times of neutrophils and platelet were 12 and 14 days respectively, the activity of cells after rehabilitation was 94%, the mean recovery rates of CD34(+) cells and mononuclear cells (MNC) were 86% and 80.3% respectively. There were no significant influences on engrafement time in sex, chemotherapy circles and radiotherapy. The engrafement of leukocytes associated with amount of CD34(+) cells. This simple uncontrolled-rate freezing PBHSC at -80°C is safe, effective and economic, and can meet clinical needs. As compared with the classical cryopreservation, there were no significant differences in hematopoietic reconstitution. Therefore, this method worth to popularize and apply in clinic.

  1. Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression.

    Science.gov (United States)

    Ali, Mohamed A E; Fuse, Kyoko; Tadokoro, Yuko; Hoshii, Takayuki; Ueno, Masaya; Kobayashi, Masahiko; Nomura, Naho; Vu, Ha Thi; Peng, Hui; Hegazy, Ahmed M; Masuko, Masayoshi; Sone, Hirohito; Arai, Fumio; Tajima, Atsushi; Hirao, Atsushi

    2017-09-12

    Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFPhigh cells exhibited significantly higher repopulating capacity than NS-GFPlow cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFPhigh cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34+ cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs.

  2. Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

    Science.gov (United States)

    Rissone, Alberto; Weinacht, Katja Gabriele; la Marca, Giancarlo; Bishop, Kevin; Giocaliere, Elisa; Jagadeesh, Jayashree; Felgentreff, Kerstin; Dobbs, Kerry; Al-Herz, Waleed; Jones, Marypat; Chandrasekharappa, Settara; Kirby, Martha; Wincovitch, Stephen; Simon, Karen Lyn; Itan, Yuval; DeVine, Alex; Schlaeger, Thorsten; Schambach, Axel; Sood, Raman

    2015-01-01

    Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD. PMID:26150473

  3. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

    Science.gov (United States)

    Guitart, Amelie V; Panagopoulou, Theano I; Villacreces, Arnaud; Vukovic, Milica; Sepulveda, Catarina; Allen, Lewis; Carter, Roderick N; van de Lagemaat, Louie N; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; Gonzalez, Marta Vila; Lawson, Hannah; Paris, Jasmin; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O'Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P; Pollard, Patrick J; Morton, Nicholas M; Finch, Andrew; Kranc, Kamil R

    2017-03-06

    Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1/Hoxa9-driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation. © 2017 Guitart et al.

  4. Distinct Functions of Different scl Isoforms in Zebrafish Definitive Hematopoietic Stem Cell Initiation and Maintenance

    Science.gov (United States)

    Lan, Yahui

    2011-07-01

    The establishment of entire blood system relies on the multi-potent hematopoietic stem cells (HSCs), thus identifying the molecular mechanism in HSC generation is of importance for not only complementing the fundamental knowledge in stem cell biology, but also providing insights to the regenerative therapies. Recent researches have documented the formation of nascent HSCs through a direct transition from ventral aortic endothelium, named as endothelial hematopoietic transition (EHT) process. However, the precise genetic program engaged in this process remains largely elusive. The transcription factor scl plays pivotal and conserved roles in embryonic and adult hematopoiesis from teleosts to mammals. Our lab have previously identified a new truncated scl isoform, scl-beta, which is indispensible for the specification of HSCs in the ventral wall of dorsal aorta (VDA), the zebrafish equivalent of mammalian fetal hematopoietic organ. Here we observe that, by combining time-lapse confocal imaging of transgenic zebrafish and genetic epistasis analysis, scl-beta is expressed in a subset of ventral aortic endothelial cells and critical for their forthcoming transformation to hemogenic endothelium; in contrast, runx1 is required downstream to govern the successful egress of the hemogenic endothelial cells to become naive HSCs. In addition, the traditional known full-length scl-alpha isoform is firstly evidenced to be required for the maintenance or survival of newly formed HSCs in VDA. Collectively our data has established the genetic hierarchy controlling discrete steps in the consecutive process of HSC formation from endothelial cells and further development in VDA.

  5. Why are hematopoietic stem cells so 'sexy'? on a search for developmental explanation.

    Science.gov (United States)

    Ratajczak, M Z

    2017-08-01

    Evidence has accumulated that normal human and murine hematopoietic stem cells express several functional pituitary and gonadal sex hormones, and that, in fact, some sex hormones, such as androgens, have been employed for many years to stimulate hematopoiesis in patients with bone marrow aplasia. Interestingly, sex hormone receptors are also expressed by leukemic cell lines and blasts. In this review, I will discuss the emerging question of why hematopoietic cells express these receptors. A tempting hypothetical explanation for this phenomenon is that hematopoietic stem cells are related to subpopulation of migrating primordial germ cells. To support of this notion, the anatomical sites of origin of primitive and definitive hematopoiesis during embryonic development are tightly connected with the migratory route of primordial germ cells: from the proximal epiblast to the extraembryonic endoderm at the bottom of the yolk sac and then back to the embryo proper via the primitive streak to the aorta-gonado-mesonephros (AGM) region on the way to the genital ridges. The migration of these cells overlaps with the emergence of primitive hematopoiesis in the blood islands at the bottom of the yolk sac, and definitive hematopoiesis that occurs in hemogenic endothelium in the embryonic dorsal aorta in AGM region.

  6. Why are hematopoietic stem cells so “sexy”? – on a search for developmental explanation

    Science.gov (United States)

    Ratajczak, Mariusz Z.

    2017-01-01

    Evidence has accumulated that normal human and murine hematopoietic stem cells express several functional pituitary and gonadal sex hormones and that, in fact, some sex hormones, such as androgens, have been employed for many years to stimulate hematopoiesis in patients with bone marrow aplasia. Interestingly, sex hormone receptors are also expressed by leukemic cell lines and blasts. In this review I will discuss the emerging question of why hematopoietic cells express these receptors. A tempting hypothetical explanation for this phenomenon is that precursors of hematopoietic stem cells are related to subpopulation of migrating primordial germ cells. To support of this notion, the anatomical sites of origin of primitive and definitive hematopoiesis during embryonic development are tightly connected with the migratory route of primordial germ cells: from the proximal epiblast to the extraembryonic endoderm at the bottom of the yolk sac and then back to the embryo proper via the primitive streak to the aorta-gonado-mesonephros (AGM) region on the way to the genital ridges. The migration of these cells overlaps with the emergence of primitive hematopoiesis in the blood islands at the bottom of the yolk sac, and definitive hematopoiesis that occurs in hemogenic endothelium in the embryonic dorsal aorta in AGM region. PMID:28502982

  7. Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition

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    Aimin Yang

    2015-01-01

    Full Text Available Abnormal activation of the mammalian target of rapamycin (mTOR signaling pathway has been observed in a variety of human cancers. Therefore, targeting of the mTOR pathway is an attractive strategy for cancer treatment and several mTOR inhibitors, including AZD8055 (AZD, a novel dual mTORC1/2 inhibitor, are currently in clinical trials. Although bone marrow (BM suppression is one of the primary side effects of anticancer drugs, it is not known if pharmacological inhibition of dual mTORC1/2 affects BM hematopoietic stem and progenitor cells (HSPCs function and plasticity. Here we report that dual inhibition of mTORC1/2 by AZD or its analogue (KU-63794 depletes mouse BM Lin−Sca-1+c-Kit+ cells in cultures via the induction of apoptotic cell death. Subsequent colony-forming unit (CFU assays revealed that inhibition of mTORC1/2 suppresses the clonogenic function of hematopoietic progenitor cells (HPCs in a dose-dependent manner. Surprisingly, we found that dual inhibition of mTORC1/2 markedly inhibits the growth of day-14 cobblestone area-forming cells (CAFCs but enhances the generation of day-35 CAFCs. Given the fact that day-14 and day-35 CAFCs are functional surrogates of HPCs and hematopoietic stem cells (HSCs, respectively, these results suggest that dual inhibition of mTORC1/2 may have distinct effects on HPCs versus HSCs.

  8. The current status in hematopoietic stem cell mobilization.

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    Civriz Bozdag, Sinem; Tekgunduz, Emre; Altuntas, Fevzi

    2015-10-01

    Hemotopoietic stem cell mobilization with cytokines alone, has still been widely accepted as the initial attempt for stem cell mobilization. Chemotherapy based mobilization can be preferred as first choice in high risk patients or for remobilization. But mobilization failure still remains to be a problem in one third of patients. Salvage mobilization strategies have been composed to give one more chance to 'poor mobilizers'. Synergistic effect of a reversible inhibitor of CXCR4, plerixafor, with G-CSF has opened a new era for these patients. Preemptive approach in predicted poor mobilizers, immediate salvage approach for patients with suboptimal mobilization or remobilization approach of plerixafor in failed mobilizers have all been demonstrated convincing results in various studies. Alternative CXCR4 inhibitors, VLA4 inhibitors, bortezomib, parathormone have also been emerged as novel agents for mobilization failure. © 2015 Wiley Periodicals, Inc.

  9. Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells

    NARCIS (Netherlands)

    Moore, Malcolm A. S.; Dorn, David C.; Schuringa, Jan Jacob; Chung, Ki Young; Morrone, Giovanni

    Objective. To model human leukemogenesis by transduction of human hematopoietic stem cells (HSC) with genes associated with leukemia and expressed in leukemic stem cells. Methods. Constitutive activation of Flt3 (Flt3-ITD) has been reported in 25 to 30% of patients with acute myeloid leukemia (AML).

  10. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.

    Science.gov (United States)

    Chang, Jianhui; Wang, Yingying; Shao, Lijian; Laberge, Remi-Martin; Demaria, Marco; Campisi, Judith; Janakiraman, Krishnamurthy; Sharpless, Norman E; Ding, Sheng; Feng, Wei; Luo, Yi; Wang, Xiaoyan; Aykin-Burns, Nukhet; Krager, Kimberly; Ponnappan, Usha; Hauer-Jensen, Martin; Meng, Aimin; Zhou, Daohong

    2016-01-01

    Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.

  11. Regulation of hematopoietic stem cell behavior by the nanostructured presentation of extracellular matrix components.

    Directory of Open Access Journals (Sweden)

    Christine Anna Muth

    Full Text Available Hematopoietic stem cells (HSCs are maintained in stem cell niches, which regulate stem cell fate. Extracellular matrix (ECM molecules, which are an essential part of these niches, can actively modulate cell functions. However, only little is known on the impact of ECM ligands on HSCs in a biomimetic environment defined on the nanometer-scale level. Here, we show that human hematopoietic stem and progenitor cell (HSPC adhesion depends on the type of ligand, i.e., the type of ECM molecule, and the lateral, nanometer-scaled distance between the ligands (while the ligand type influenced the dependency on the latter. For small fibronectin (FN-derived peptide ligands such as RGD and LDV the critical adhesive interligand distance for HSPCs was below 45 nm. FN-derived (FN type III 7-10 and osteopontin-derived protein domains also supported cell adhesion at greater distances. We found that the expression of the ECM protein thrombospondin-2 (THBS2 in HSPCs depends on the presence of the ligand type and its nanostructured presentation. Functionally, THBS2 proved to mediate adhesion of HSPCs. In conclusion, the present study shows that HSPCs are sensitive to the nanostructure of their microenvironment and that they are able to actively modulate their environment by secreting ECM factors.

  12. [Clinical risks analysis of EBV infection in patients with allogeneic hematopoietic stem cell transplantation].

    Science.gov (United States)

    Bao, Xiebing; Zhu, Qian; Qiu, Huiying; Chen, Feng; Xue, Shengli; Ma, Xiao; Sun, Aining; Wu, Depei

    2016-02-01

    To analyze the prevalence of Epstein Barr Virus (EBV) infection in patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The occurrence of EBV viremia, EBV disease and post-transplant lymphoproliferative disease (PTLD) were retrospectively analyzed in 736 patients received allo-HSCT in single-center from 1st January 2012 through July 31th, 2014. Of 736 patients (302 male and 434 females) with a median age of 31 (2 to 62) years old, EBV infection occurred in 181 patients, the total incidence of EBV infection was 27.6%, with a median time of 57 (16 to 829) days. The cumulative incidences of probable EBV disease and PTLD were 7.2% (13/181) and 2.8% (5/181). Viral load higher than 1.0×10(4) copies/ml occurs in 130 patients, of which 67 patients received rituximab as pre-empty prophylaxis and significantly reduced the incidences of probable EBV disease and PTLD (6.0% vs 22.2%, P=0.009). The mortality was 27.6% in all patients with EBV infection: 24.5% in EBV viremia, 53.8% in probable EBV disease, and 60.6% in PTLD. By univariate and multivariate analysis, the use of anti-thymocyte globulin (ATG), HLA-mismatch HSCT, cGVHD and CMV reactivation were independent risk factors for EBV infection. The time of first EBV reactivation was closely related with cGVHD(OR=0.620, 95%CI 0.453-0.849, P=0.003) and bone marrow or cord blood (OR=1.156, 95%CI 1.022-2.250, P=0.039) as source of stem cells for transplantation. EBV reactivation is a common complication in patients with allo-HSCT, especially high mortality in PTLD and probable EBV disease. The use of ATG, HLA-mismatch HSCT, cGVHD and CMV reactivation were independent risk factors for EBV infection. The usage of rituximab as pre-empty prophylaxis may reduce the incidences of probable EBV disease and PTLD.

  13. Roles of p53 in Various Biological Aspects of Hematopoietic Stem Cells

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    Takenobu Nii

    2012-01-01

    Full Text Available Hematopoietic stem cells (HSCs have the capacity to self-renew as well as to differentiate into all blood cell types, and they can reconstitute hematopoiesis in recipients with bone marrow ablation. In addition, transplantation therapy using HSCs is widely performed for the treatment of various incurable diseases such as hematopoietic malignancies and congenital immunodeficiency disorders. For the safe and successful transplantation of HSCs, their genetic and epigenetic integrities need to be maintained properly. Therefore, understanding the molecular mechanisms that respond to various cellular stresses in HSCs is important. The tumor suppressor protein, p53, has been shown to play critical roles in maintenance of “cell integrity” under stress conditions by controlling its target genes that regulate cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In this paper, we summarize recent reports that describe various biological functions of HSCs and discuss the roles of p53 associated with them.

  14. Genetic modification of hematopoietic stem cells as a therapy for HIV/AIDS.

    Science.gov (United States)

    Younan, Patrick; Kowalski, John; Kiem, Hans-Peter

    2013-11-28

    The combination of genetic modification and hematopoietic stem cell (HSC) transplantation may provide the necessary means to develop an alternative treatment option to conventional antiretroviral therapy. As HSCs give rise to all hematopoietic cell types susceptible to HIV infection, modification of HSCs is an ideal strategy for the development of infection-resistant immune cell populations. Although promising results have been obtained in multiple animal models, additional evidence is needed to convincingly demonstrate the feasibility of this approach as a treatment of HIV-1 infected patients. Here, we review the potential of HSC transplantation and the recently identified limitations of this approach. Using the Berlin Patient as a model for a functional cure, we contrast the confines of autologous versus allogeneic transplantation. Finally, we suggest that although autologous, gene-modified HSC-transplantation may significantly reduce plasma viremia, reaching the lower detection limits currently obtainable through daily HAART will remain a challenging endeavor that will require innovative combinatorial therapies.

  15. Cellular and humoral immunity elicited by influenza vaccines in pediatric hematopoietic-stem cell transplantation.

    Science.gov (United States)

    Guérin-El Khourouj, Valérie; Duchamp, Marie; Krivine, Anne; Pédron, Béatrice; Ouachée-Chardin, Marie; Yakouben, Karima; Frémond, Marie-Louise; Baruchel, André; Dalle, Jean-Hugues; Sterkers, Ghislaine

    2012-09-01

    Immunity induced by influenza vaccines following hematopoietic stem-cell transplantation (HSCT) is poorly understood. Here, 14 pediatric recipients (mean age: 6 years) received H1N1 (n=9) or H1N1/H3N2 (n=5) vaccines at a median of 5.7 months post-HSCT (HLA-identical related bone-marrow graft: 10/14). Fourteen clinically-matched non-vaccinated recipients were included as controls. Cellular response to vaccination was assessed by a T-cell proliferation assay. Humoral response was assessed by H1N1-specific antibody titration. IL2 and IFNγ responses to influenza were also evaluated by an intracellular cytokine accumulation method for some of the recipients. Higher proliferative responses to H1N1 (p=0.0001) and higher H1N1-specific antibody titers (p<0.02) were observed in vaccines opposed to non-vaccinated recipients. In some cases, proliferative responses to H1N1 developed while at the same time antibody titers did not reach protective (≥1:40) levels. Most recipients vaccinated with only the H1N1 strain had proliferative responses to both H1N1 and H3N2 (median stimulation index H1N1: 96, H3N2: 126 in responders). Finally, IL2 responses predominated over IFNγ responses (p<0.02) to influenza viruses in responders. In conclusion, H1N1 vaccination induced substantial cell-mediated immunity, and to a lesser extent, humoral immunity at early times post-HSCT. H1N1/H3N2 T-cell cross-reactivity and protective (IL2) rather than effector (IFNγ) cytokinic profiles were elicited. Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  16. [A retrospective study of kidney insufficiency in adult patients after myeloablative allogeneic hematopoietic stem cell transplantation].

    Science.gov (United States)

    Luo, Cheng-Wei; DU, Xin; Weng, Jiang-Yu; Wu, Sui-Jing; Guo, Rong; Lu, Ze-Sheng; Ling, Wei

    2012-06-01

    The aim of this study was to investigate the renal function in 149 patients receiving myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) from June 2005 to June 2010 in our hospital, and analyze the risk factors resulting in kidney insufficiency and experience in diagnose and therapy. The creatinine clearance (CrCL) and serial creatinine level were evaluated before and after allo-HSCT within 100 days and 1 year. Non-radiation conditioning regimens were used for any patients. The acute kidney insufficiency (AKI) was defined as at least a 1.5-fold rise in serum creatinine level after allo-HSCT within the first 100 days. The chronic kidney insufficiency (CKI) was defined as the creatinine clearance kidney insufficiency was found in 41 patients, in which the incidence of AKI was 32/149 (21.5%). CsA, amphotericin B (P = 0.025) and ES (P = 0.022) were defined as risk factors for AKI. The incidence of CKI was 18/138 (13%). cGVHD (P = 0.013) and TA-TMA (P = 0.012) were associated with the development of CKI. The 2-year survival was lower in patients with kidney dysfunction than that in patients without kidney dysfunction (39% vs 74.1%, P kidney insufficiency were defined as infection (52%), GVHD (20%), TA-TMA (12%) and tumor relapse (12%). It is concluded that kidney insufficiency is an important complication of allo-HSCT. Careful monitoring kidney function, minimizing the use of amphotericin B, prophylaxis and effective treatment of fungal infection, GVHD and TA-TMA may be effective preventive measures to decrease the incidence of kidney insufficiency.

  17. Hepatitis B-related events in autologous hematopoietic stem cell transplantation recipients

    Science.gov (United States)

    Çeneli, Özcan; Özkurt, Zübeyde Nur; Acar, Kadir; Rota, Seyyal; Akı, Şahika Zeynep; Yeğin, Zeynep Arzu; Yağcı, Münci; Özenirler, Seren; Sucak, Gülsan Türköz

    2010-01-01

    AIM: To investigate the frequency of occult hepatitis B, the clinical course of hepatitis B virus (HBV) reactivation and reverse seroconversion and associated risk factors in autologous hematopoietic stem cell transplantation (HSCT) recipients. METHODS: This study was conducted in 90 patients undergoing autologous HSCT. Occult HBV infection was investigated by HBV-DNA analysis prior to transplantation, while HBV serology and liver function tests were screened prior to and serially after transplantation. HBV-related events including reverse seroconversion and reactivation were recorded in all patients. RESULTS: None of the patients had occult HBV prior to transplantation. Six (6.7%) patients were positive for HBV surface antigen (HBsAg) prior to transplantation and received lamivudine prophylaxis; they did not develop HBV reactivation after transplantation. Clinical HBV infection emerged in three patients after transplantation who had negative HBV-DNA prior to HSCT. Two of these three patients had HBV reactivation while one patient developed acute hepatitis B. Three patients had anti-HBc as the sole hepatitis B-related antibody prior to transplantation, two of whom developed hepatitis B reactivation while none of the patients with antibody to HBV surface antigen (anti-HBs) did so. The 14 anti-HBs- and/or anti-HBc-positive patients among the 90 HSCT recipients experienced either persistent (8 patients) or transient (6 patients) disappearance of anti-HBs and/or anti-HBc. HBsAg seroconversion and clinical hepatitis did not develop in these patients. Female gender and multiple myeloma emerged as risk factors for loss of antibody in regression analysis (P < 0.05). CONCLUSION: Anti-HBc as the sole HBV marker seems to be a risk factor for reactivation after autologous HSCT. Lamivudine prophylaxis in HbsAg-positive patients continues to be effective. PMID:20380010

  18. Vitamin D deficiency and outcomes in pediatric hematopoietic stem cell transplantation.

    Science.gov (United States)

    Beebe, Kristen; Magee, Kyrie; McNulty, Annmarie; Stahlecker, Jennifer; Salzberg, Dana; Miller, Holly; Mirea, Lucia; Adams, Roberta; Ngwube, Alexander

    2018-02-01

    Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are frequently diagnosed with vitamin D deficiency, which may impact outcomes. To estimate the prevalence of vitamin D deficiency and examine its association with short-term survival in pediatric HSCT patients. Patients undergoing HSCT at Phoenix Children's Hospital were retrospectively identified. Routine serum 25-hydroxyvitamin D measurements were described prior to transplant and at 100 days and 1-year post-HSCT. Associations of pre-HSCT vitamin D groups (i.e., normal ≥30 ng/ml, insufficient 20-29 ng/ml, and deficient <30 ng/ml) with demographics, clinical factors, and outcomes were examined using nonparametric tests and Cox proportional hazards analyses. Among 72 study subjects, the median vitamin D pre-HSCT was 26 ng/ml (range: 19-34 ng/ml). Levels were insufficient and deficient in 25 (35%) and 20 (28%) patients, respectively, with only two (3%) patients on supplemental therapy pre-HSCT. Despite supplemental therapy provided to 46 (74%) subjects, insufficient/deficient rates did not significantly change between pre-HSCT and 100 days post-HSCT, but mean vitamin D levels significantly increased by 1-year post-HSCT (P = 0.01).Vitamin D pre-HSCT was not associated with the development of acute or chronic graft-versus-host disease (GVHD) or delayed engraftment. Overall 1-year survival was significantly lower for patients with deficient (65%) compared to normal (93%) pre-HSCT vitamin D (P = 0.001). Suboptimal vitamin D levels are common in pediatric patients scheduled to receive HSCT and are associated with lower overall 1-year survival. Further study is warranted to delineate the mechanisms underlying the role of vitamin D in successful HSCT. © 2017 Wiley Periodicals, Inc.

  19. Employment Status as an Indicator of Recovery and Function One Year after Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Morrison, Eleshia J; Ehlers, Shawna L; Bronars, Carrie A; Patten, Christi A; Brockman, Tabetha A; Cerhan, James R; Hogan, William J; Hashmi, Shahrukh K; Gastineau, Dennis A

    2016-09-01

    Employment after hematopoietic stem cell transplantation (HSCT) is an indicator of post-transplantation recovery and function, with economic and social implications. As survival rates for HSCT continue to improve, greater emphasis can be placed on factors affecting the quality of post-transplantation survival, including the ability to resume employment. A sample of recipients of autologous or allogeneic HSCT was accrued (n = 1000) to complete a longitudinal lifestyle survey before transplantation and at 1 year after transplantation. The present study examines associations between employment and patient characteristics, disease variables, illness status, and quality of life among 1-year survivors (n = 702). Participants had a mean age of 55 years (range, 18 to 78) and were predominately male (59.7%), married/partnered (77.1%), and non-Hispanic Caucasian (89.5%); most (79.4%) had received autologous transplantation. Of the 690 participants reporting some form of employment before illness diagnosis, 62.4% had returned to work by 1 year after HSCT. Full-time employment at 1 year after HSCT was significantly associated with remission of illness, improved illness, fewer post-transplantation hospitalizations, less fatigue and pain, higher quality of life, and higher rating of perceived health. Those unemployed because of their health reported the highest rates of fatigue and pain and lowest quality of life, and they were most likely to report poor perceived health. These findings highlight work reintegration as an important outcome and marker of survivors' overall adjustment after transplantation. Identifying factors affecting post-transplantation employment offers opportunities for behavioral interventions to target modifiable risk factors to optimize post-transplantation survivorship, inclusive of increased rates of return to work and decreased rates of associated disability. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by

  20. Distress screening in allogeneic hematopoietic stem cell (HSCT) caregivers and patients.

    Science.gov (United States)

    Bevans, Margaret; Wehrlen, Leslie; Prachenko, Olena; Soeken, Karen; Zabora, James; Wallen, Gwenyth R

    2011-06-01

    Family caregivers of allogeneic hematopoietic stem cell transplant (HSCT) patients are at risk for experiencing significant psychological distress yet screening caregivers has not been well studied. This analysis explored the psychometric characteristics of the Distress Thermometer (DT) by examining its relationship, sensitivity, and specificity relative to the Brief Symptom Inventory 18 (BSI-18) and the Multidimensional Fatigue Symptom Inventory (MFSI) in a sample of allogeneic HSCT caregivers and patients. Longitudinal data were drawn from an ongoing intervention study for HSCT caregivers and patients. Data from one hundred and fifty-six English-speaking adults where patients (n = 65) were receiving their first allogeneic HSCT with at least one adult caregiver (n = 91) were eligible for this analysis. Study questionnaires were administered at baseline, initial discharge, and 6 weeks following discharge. Construct validity was supported by significant relationships (pcaregivers and patients. The diagnostic utility of the DT for patients was good (AUC = 0.85±0.05, p = 0.001), while for caregivers it was poor (AUC = 0.61±0.08, p = 0.28). A DT cut point of 5 was supported for patients (sensitivity = 1.0, specificity = 0.68), while for caregivers there was less confidence (sensitivity = 0.70, specificity = 0.52). Caregivers and patients reporting a higher number of problems had a greater level of distress (pcaregivers and patients. Although the diagnostic utility of the DT for HSCT caregivers may be limited, understanding factors associated with distress can guide practice for this understudied population. Copyright © 2011 John Wiley & Sons, Ltd.

  1. Half-dose ganciclovir preemptive treatment of cytomegalovirus infection after pediatric allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Ju, H Y; Kang, H J; Hong, C R; Lee, J W; Kim, H; Park, K D; Shin, H Y; Park, J D; Choi, E H; Lee, H J; Ahn, H S

    2016-06-01

    Ganciclovir (GCV) has been widely used as preemptive therapy after hematopoietic stem cell transplantation (HSCT), although bone marrow suppression is a known accompaniment, with secondary infection or bleeding as potential complications. Our aim was to evaluate clinical outcomes in pediatric patients with low cytomegalovirus (CMV) antigenemia levels using half the dosage of GCV generally given preemptively. Patients received half doses of intravenous GCV (5 mg/kg once daily, 6 days/week) at CMV antigenemia levels <10/200,000 cells. At higher levels of CMV antigenemia, conventional doses of GCV (5 mg/kg every 12 h) were administered. A total of 130 patients were evaluated, detecting CMV antigenemia in 87 (66.9%). Of these patients, 74 (85.1%) were treated preemptively with half-dose GCV, which proved effective as sole therapy in 51 (68.9%). CMV retinitis developed in 4 patients, 2 of whom initially were given half-dose GCV. All infections resolved successfully, with no CMV-related deaths. CMV seropositivity in recipients was the only significant risk factor for positive CMV antigenemia (hazard ratio [HR] = 10.05, P = 0.046). Compared with half-dose GCV administration, conventional GCV dosing resulted in a higher rate of severe neutropenia, defined as absolute neutrophil count <0.5 × 10(9) /L (HR = 4.30, P = 0.015). Half-dose GCV therapy at CMV antigenemia levels <10/200,000 cells is an effective and safe means of preemptively treating pediatric CMV infection after HSCT. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Subclinical hypothyroidism in children and adolescents after hematopoietic stem cells transplantation without irradiation

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    Milenković Tatjana

    2014-01-01

    Full Text Available Background/Aim. Although total body irradiation (TBI was considered to be the primary cause of thyroid dysfunction following hematopoietic stem cells transplantation (HSCT, a significant prevalence of subclinical hypothyroidism after HSCT with chemotherapy-only conditioning regimens has been observed in several studies. The aim of this study was to assess changes in thyroid stimulating hormone (TSH levels in children after HSCT, without the use of irradiation at any time in the course of the treatment. Methods. Our cohort consisted of 41 children and adolescents who underwent autologous or allogeneic HSCT and were available for follow-up for at least one year after transplantation. Irradiation was not performed in any of the subjects, neither during pretransplatation therapy, nor during conditioning. The median duration of follow-up was 2.9 years. The indications for HSCT were hematologic malignancy (41.5%, solid malignant tumor (34.1%, and other disorders (24.4%. The thyroid status of all the subjects was assessed prior to HSCT and after follow-up period. Results. Thyroid dysfunction after HSCT was present in 27 (65.8% subjects. Subclinical hypothyroidism was the most common abnormality, presenting in 23 (56.1% patients, primary hypothyroidism was present in one (2.4% patient, while 3 (7.3% subjects had low free T4 with normal TSH values. Significantly (p < 0.01 higher elevations in TSH levels were present in the patients who received chemotherapy for the underlying disease prior to HSCT. Conclusion. Our findings emphasize the need for long-term monitoring of thyroid function following HSCT, regardless of whether or not irradiation was used.

  3. The Changing Epidemiology of Bloodstream Infections and Resistance in Hematopoietic Stem Cell Transplantation Recipients

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    Mücahit Yemişen

    2016-08-01

    Full Text Available Objective: Patients receiving hematopoietic stem cell transplantation (HSCT are exposed to highly immunosuppressive conditions and bloodstream infections (BSIs are one of the most common major complications within this period. Our aim, in this study, was to evaluate the epidemiology of BSIs in these patients retrospectively. Materials and Methods: The epidemiological properties of 312 patients with HSCT were retrospectively evaluated. Results: A total of 312 patients, followed between 2000 and 2011, who underwent autologous (62% and allogeneic (38% HSCT were included in the study. The most common underlying malignancies were multiple myeloma (28% and Hodgkin lymphoma (21.5%. A total of 142 (45% patients developed at least 1 episode of BSI and 193 separate pathogens were isolated from the blood cultures. There was a trend of increase in the numbers of BSIs in 2005-2008 and a relative increase in the proportion of gram-positive infections in recent years (2009-2011, and central venous catheter-related BSI was found to be most common source. Coagulase-negative staphylococci (49.2% and Acinetobacter baumannii (8.8% were the most common pathogens. Extended-spectrum beta-lactamase-producing strains were 23% and 22% among Escherichia coli and Klebsiella spp. isolates, respectively. Quinolone resistance was detected in 10% of Enterobacteriaceae. Resistance to carbapenems was not detected in Enterobacteriaceae, while it was seen at 11.1% and 23.5% in Pseudomonas and Acinetobacter strains, respectively. Conclusion: A shift was detected from gram-negative bacteria to gram-positive in the etiology over the years and central lines were the most common sources of BSIs.

  4. New photobiomodulation protocol prevents oral mucositis in hematopoietic stem cell transplantation recipients-a retrospective study.

    Science.gov (United States)

    Weissheimer, Camila; Curra, Marina; Gregianin, Lauro J; Daudt, Liane E; Wagner, Vivian P; Martins, Marco Antonio T; Martins, Manoela D

    2017-12-01

    Oral mucositis (OM) is an adverse side effect among hematopoietic stem cell transplantation (HSCT) recipients. The objective of this retrospective study was to evaluate the preventive effect of photobiomodulation (PBM) applied three times per week versus seven times per week in patients undergoing HSCT. The risk factors related to the incidence and severity of OM were also assessed. This was a retrospective study that evaluated 99 HSCT recipients who received different PBM protocols. Group I received three sessions per week, and group II received daily treatment. PBM was applied using a continuous-wave diode laser (InGaAlP; MM Optics, São Carlos, SP, Brazil) at a wavelength of 660 nm (visible-red) and a total radiant energy of 0.24 J per point. The baseline disease, type of transplant, type of conditioning, prophylaxis against graft-versus-host disease, OM grade, absolute leukocyte and platelet counts, and levels of liver and renal function markers were collected from medical records. The patients' age ranged from 13 to 71 years (mean/SD, 40.54 ± 16.45). No significant difference was observed between groups I and II regarding sex, age, ethnic, diagnosis, donor type, and conditioning treatment. Both PBM protocols were equally efficient in preventing OM (p = 0.34, ANOVA). Independent of the PBM protocol used, patients who received allogeneic transplant (p < 0.01-Fischer's exact test), total body irradiation (TBI-12Gy) (p = 0.01-chi-square test), busulfan + cyclophosphamide (p < 0.01-chi-square test), or methotrexate-containing regimens (p < 0.01-Fischer's exact test) demonstrated higher OM incidence and severity. Myelosuppression (p < 0.01-Mann-Whitney test) and impaired renal function (p = 0.02-Mann-Whitney test) were also considered risk factors for OM. Based on this retrospective data, PBM was effective in preventing OM in patients undergoing HSCT even when it was applied three times a week. A prospective study might be necessary to confirm

  5. The Microtubule Plus-End Tracking Protein CLASP2 Is Required for Hematopoiesis and Hematopoietic Stem Cell Maintenance

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    Ksenija Drabek

    2012-10-01

    Full Text Available Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription.

  6. CD14+ cells from peripheral blood positively regulate hematopoietic stem and progenitor cell survival resulting in increased erythroid yield

    OpenAIRE

    Heideveld, Esther; Masiello, Francesca; Marra, Manuela; Esteghamat, Fatemehsadat; Yağcı, Nurcan; von Lindern, Marieke; Migliaccio, Anna Rita F.; van den Akker, Emile

    2015-01-01

    Expansion of erythroblasts from human peripheral blood mononuclear cells is 4- to 15-fold more efficient than that of CD34+ cells purified from peripheral blood mononuclear cells. In addition, purified CD34+ and CD34− populations from blood do not reconstitute this erythroid yield, suggesting a role for feeder cells present in blood mononuclear cells that increase hematopoietic output. Immunodepleting peripheral blood mononuclear cells for CD14+ cells reduced hematopoietic stem and progenitor...

  7. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia

    OpenAIRE

    Qian, Zhijian; Fernald, Anthony A.; Godley, Lucy A.; Larson, Richard A.; Le Beau, Michelle M.

    2002-01-01

    One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34+ hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to ...

  8. Generation of HIV-1 Resistant and Functional Macrophages From Hematopoietic Stem Cell–derived Induced Pluripotent Stem Cells

    Science.gov (United States)

    Kambal, Amal; Mitchell, Gaela; Cary, Whitney; Gruenloh, William; Jung, Yunjoon; Kalomoiris, Stefanos; Nacey, Catherine; McGee, Jeannine; Lindsey, Matt; Fury, Brian; Bauer, Gerhard; Nolta, Jan A; Anderson, Joseph S

    2011-01-01

    Induced pluripotent stem cells (iPSCs) have radically advanced the field of regenerative medicine by making possible the production of patient-specific pluripotent stem cells from adult individuals. By developing iPSCs to treat HIV, there is the potential for generating a continuous supply of therapeutic cells for transplantation into HIV-infected patients. In this study, we have used human hematopoietic stem cells (HSCs) to generate anti-HIV gene expressing iPSCs for HIV gene therapy. HSCs were dedifferentiated into continuously growing iPSC lines with four reprogramming factors and a combination anti-HIV lentiviral vector containing a CCR5 short hairpin RNA (shRNA) and a human/rhesus chimeric TRIM5α gene. Upon directed differentiation of the anti-HIV iPSCs toward the hematopoietic lineage, a robust quantity of colony-forming CD133+ HSCs were obtained. These cells were further differentiated into functional end-stage macrophages which displayed a normal phenotypic profile. Upon viral challenge, the anti-HIV iPSC-derived macrophages exhibited strong protection from HIV-1 infection. Here, we demonstrate the ability of iPSCs to develop into HIV-1 resistant immune cells and highlight the potential use of iPSCs for HIV gene and cellular therapies. PMID:21119622

  9. The use of covalently immobilized stem cell factor to selectively affect hematopoietic stem cell activity within a gelatin hydrogel.

    Science.gov (United States)

    Mahadik, Bhushan P; Pedron Haba, Sara; Skertich, Luke J; Harley, Brendan A C

    2015-10-01

    Hematopoietic stem cells (HSCs) are a rare stem cell population found primarily in the bone marrow and responsible for the production of the body's full complement of blood and immune cells. Used clinically to treat a range of hematopoietic disorders, there is a significant need to identify approaches to selectively expand their numbers ex vivo. Here we describe a methacrylamide-functionalized gelatin (GelMA) hydrogel for in vitro culture of primary murine HSCs. Stem cell factor (SCF) is a critical biomolecular component of native HSC niches in vivo and is used in large dosages in cell culture media for HSC expansion in vitro. We report a photochemistry based approach to covalently immobilize SCF within GelMA hydrogels via acrylate-functionalized polyethylene glycol (PEG) tethers. PEG-functionalized SCF retains the native bioactivity of SCF but can be stably incorporated and retained within the GelMA hydrogel over 7 days. Freshly-isolated murine HSCs cultured in GelMA hydrogels containing covalently-immobilized SCF showed reduced proliferation and improved selectivity for maintaining primitive HSCs. Comparatively, soluble SCF within the GelMA hydrogel network induced increased proliferation of differentiating hematopoietic cells. We used a microfluidic templating approach to create GelMA hydrogels containing gradients of immobilized SCF that locally direct HSC response. Together, we report a biomaterial platform to examine the effect of the local presentation of soluble vs. matrix-immobilized biomolecular signals on HSC expansion and lineage specification. This approach may be a critical component of a biomaterial-based artificial bone marrow to provide the correct sequence of niche signals to grow HSCs in the laboratory. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Eradication of HIV by Transplantation of CCR5-Deficient Hematopoietic Stem Cells

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    Gero Hütter

    2011-01-01

    Full Text Available Today, 30 years after the onset of the HIV pandemic, although treatment strategies have considerably improved, there is still no cure for the disease. Recently, we described a successful hematopoietic stem cell transplantation in an HIV-1–infected patient, transferring donor-derived cells with a natural resistance against HIV infection. These hematopoietic stem cells engrafted, proliferated, and differentiated into mature myeloid and lymphoid cells. To date, the patient has not required any antiretroviral treatment, more than 4 years after allogeneic transplantation. In the analysis of peripheral blood cells and different tissue samples, including gut, liver, and brain, no viral load or proviral DNA could be detected. Our report raises the hope for further targeted treatment strategies against HIV and represents a successful personalized treatment with allogeneic stem cells carrying a beneficial gene. However, this case has ignited a controversy regarding the question of whether this patient has achieved complete eradication of HIV or not. Here we give an update on open questions, unsolved aspects, and clinical consequences concerning this unique case.

  11. Oncolytic viral purging of leukemic hematopoietic stem and progenitor cells with Myxoma virus.

    Science.gov (United States)

    Rahman, Masmudur M; Madlambayan, Gerard J; Cogle, Christopher R; McFadden, Grant

    2010-01-01

    High-dose chemotherapy and radiation followed by autologous blood and marrow transplantation (ABMT) has been used for the treatment of certain cancers that are refractory to standard therapeutic regimes. However, a major challenge with ABMT for patients with hematologic malignancies is disease relapse, mainly due to either contamination with cancerous hematopoietic stem and progenitor cells (HSPCs) within the autograft or the persistence of residual therapy-resistant disease niches within the patient. Oncolytic viruses represent a promising therapeutic approach to prevent cancer relapse by eliminating tumor-initiating cells that contaminate the autograft. Here we summarize an ex vivo "purging" strategy with oncolytic Myxoma virus (MYXV) to remove cancer-initiating cells from patient autografts prior to transplantation. MYXV, a novel oncolytic poxvirus with potent anti-cancer properties in a variety of in vivo tumor models, can specifically eliminate cancerous stem and progenitor cells from samples obtained from acute myelogenous leukemia (AML) patients, while sparing normal CD34+ hematopoietic stem and progenitor cells capable of rescuing hematopoiesis following high dose conditioning. We propose that a broader subset of patients with intractable hematologic malignancies who have failed standard therapy could become eligible for ABMT when the treatment schema is coupled with ex vivo oncolytic therapy. 2010 Elsevier Ltd. All rights reserved.

  12. Nutritional Intake and Nutritional Status by the Type of Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Lee, Ji Sun; Kim, Jee Yeon

    2012-01-01

    The aim of this study was to investigate the changes of nutritional intake and nutritional status and analyze the association between them during hematopoietic stem cell transplantation. This was a retrospective cross sectional study on 36 patients (9 Autologous transplantation group and 27 Allogeneic transplantation group) undergoing hematopoietic stem cell transplantation at The Catholic University of Korea, Seoul St. Mary's Hospital from May to August 2010. To assess oral intake and parenteral nutrition intake, 24-hour recall method and patient's charts review was performed. Nutritional status was measured with the scored patient-generated subjective global assessment (PG-SGA). The subjects consisted of 6 (66.7%) males and 3 (33.3%) females in the autologous transplantation group (auto), 12 (44.4%) males and 15 (55.6%) females in the allogeneic transplantation group (allo). The mean age was 40.9 ± 13.6 years (auto) and 37.8 ± 11.0 years (allo). The average hospitalized period was 25.2 ± 3.5 days (auto) and 31.6 ± 6.6 days (allo), which were significant different (p Nutritional intake was lowest at Post+1wk in two groups. In addition, calorie intake by oral diet to recommended intake at Post+2wk was low (20.8% auto and 20.5% allo) but there were no significant differences in change of nutritional intake over time (Admission, Pre-1day, Post+1wk, Post+2wk) between auto group and allo group by repeated measures ANOVA test. The result of nutritional assessment through PG-SGA was significantly different at Pre-1day only (p nutritional status during Post+2wk and the oral calorie/protein intake to recommended amount measured during Post+1wk and Post+2wk (p nutritional care guidelines for patients during hematopoietic stem cell transplantation. PMID:23430590

  13. Prevalence of viral infections and hemorrhagic cystitis in hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Shakiba, Elaheh; Yaghobi, Ramin; Ramzi, Mani

    2011-12-01

    About 7% to 70% of hemorrhagic cystitis is classified as early and late-onset incidence in hematopoietic stem cell transplant patients. The association between the prevalence of viral infections and hemorrhagic cystitis was evaluated in pretransplant and posttransplant recipients and donors. Ethylenediaminetetra-acetic acid-treated blood and urine samples of 30 recipients and 24 donors were collected before hematopoietic stem cell transplant patients, and monitored for 100 days after transplant. Prevalence of BK virus DNA was investigated by polymerase chain reaction. Prevalence of adenovirus and cytomegalovirus DNA was evaluated by polymerase chain reaction. Type of transplant, conditioning regimens, graft-versus-host disease clinical grading, demographic data, hematologic, and biochemical indexes also were analyzed. Different grades of hematuria were found in 16 of 30 of the recipients with hemorrhagic cystitis. Severe hematuria and diffuse thickening of the bladder were found in 5 of 30 transplant patients. Multiple infections of BK virus, adenovirus, and cytomegalovirus were seen in 5 patients with severe hemorrhagic cystitis. The viruria of these viruses was decreased in patients with hemorrhagic cystitis as follows: BK virus (5 of 5), adenovirus (2 of 5), and cytomegalovirus (not detected). Also, a significant relation was found between hemorrhagic cystitis and risk factors including donor-recipient sex mismatches, familial relationships, leukemia as an underlying disease, older age, allogenic type of transplant, prophylactic and therapeutic dose of anti-graft-versus-host-disease regimens. Detection of single and multiple infections of BK virus, adenovirus, and cytomegalovirus in blood and/or urine samples of hematopoietic stem cell transplant recipients, in combination with 1 or more inducing factors of hemorrhagic cystitis were enforced on the important role these risk factors play in the cause of hemorrhagic cystitis.

  14. Nutritional intake and nutritional status by the type of hematopoietic stem cell transplantation.

    Science.gov (United States)

    So, Eun Jin; Lee, Ji Sun; Kim, Jee Yeon

    2012-07-01

    The aim of this study was to investigate the changes of nutritional intake and nutritional status and analyze the association between them during hematopoietic stem cell transplantation. This was a retrospective cross sectional study on 36 patients (9 Autologous transplantation group and 27 Allogeneic transplantation group) undergoing hematopoietic stem cell transplantation at The Catholic University of Korea, Seoul St. Mary's Hospital from May to August 2010. To assess oral intake and parenteral nutrition intake, 24-hour recall method and patient's charts review was performed. Nutritional status was measured with the scored patient-generated subjective global assessment (PG-SGA). The subjects consisted of 6 (66.7%) males and 3 (33.3%) females in the autologous transplantation group (auto), 12 (44.4%) males and 15 (55.6%) females in the allogeneic transplantation group (allo). The mean age was 40.9 ± 13.6 years (auto) and 37.8 ± 11.0 years (allo). The average hospitalized period was 25.2 ± 3.5 days (auto) and 31.6 ± 6.6 days (allo), which were significant different (p Nutritional intake was lowest at Post+1wk in two groups. In addition, calorie intake by oral diet to recommended intake at Post+2wk was low (20.8% auto and 20.5% allo) but there were no significant differences in change of nutritional intake over time (Admission, Pre-1day, Post+1wk, Post+2wk) between auto group and allo group by repeated measures ANOVA test. The result of nutritional assessment through PG-SGA was significantly different at Pre-1day only (p nutritional status during Post+2wk and the oral calorie/protein intake to recommended amount measured during Post+1wk and Post+2wk (p evidence-based nutritional care guidelines for patients during hematopoietic stem cell transplantation.

  15. Body composition of Fanconi anemia patients after hematopoietic stem cell transplantation.

    Science.gov (United States)

    Silva, Priscilla Peixoto Policarpo da; Schmit, Daniella; Bonfim, Carmem; Campos, Denise Johnsson; Rabito, Estela Iraci; Vilela, Regina Maria

    Fanconi anemia is a rare genetic disease linked to bone marrow failure; a possible treatment is hematopoietic stem cell transplantation. Changes in the nutritional status of Fanconi anemia patients are not very well known. This study aimed to characterize body composition of adult, children and adolescent patients with Fanconi anemia who were submitted to hematopoietic stem cell transplantation or not. This cross-sectional study enrolled 63 patients (29 adults and 34 children and adolescents). Body composition was assessed based on diverse methods, including triceps skin fold, arm circumference, arm muscle area and bioelectrical impedance analysis, as there is no established consensus for this population. Body mass index was also considered as reference according to age. Almost half (48.3%) of the transplanted adult patients were underweight considering body mass index whereas eutrophic status was observed in 66.7% of the children and adolescents submitted to hematopoietic stem cell transplantation and in 80% of those who were not. At least 50% of all groups displayed muscle mass depletion. Half of the transplanted children and adolescents presented short/very short stature for age. All patients presented low muscle stores, underweight was common in adults, and short stature was common in children and adolescents. More studies are needed to detect whether muscle mass loss measured at the early stages of treatment results in higher risk of mortality, considering the importance of muscle mass as an essential body component to prevent mortality related to infectious and non-infectious diseases and the malnutrition inherent to Fanconi anemia. Copyright © 2017 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.

  16. AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN WITH SEVERE RESISTANT MULTIPLE SCLEROSIS

    Directory of Open Access Journals (Sweden)

    K. I. Kirgizov

    2013-01-01

    Full Text Available Unique experience of high-dose chemotherapy with consequent autologous hematopoietic stem cell transplantation in children with severe resistant multiple sclerosis (n=7 is shown in this article. At present time there is enough data on chemotherapy with consequent hematopoietic stem cell transplantation in children with severe resistant multiple sclerosis. This method was proved to be efficient and safe with immunoablative conditioning chemotherapy regimen. In patients included in this study the mean rate according to the Expanded Disability Status Scale was 5,94±0,2 (from 3 to 9 points. All the patients had disseminated demyelination loci, accumulating the contrast substance, in the brain and the spinal cord. After cyclophosphamide treatment in combination with anti-monocytes globulin the fast stabilization of the condition and prolonged (the observation period was 3-36 moths clinical and radiologic as well as immunophenotypic remission with marked positive dynamics according to the Expanded Disability Status Scale were noted. No pronounced side-effects and infectious complications were mentioned. The maximal improvement according to the Expanded Disability Status Scale (EDSS was 5,5 points, the mean — 2,7±0,1 (from 2 to 5,5 points accompanied with positive dynamics on the magneto-resonance imaging.  The efficacy of the treatment was also proved by the positive changes in the lymphocytes subpopulation status in peripheral blood. The timely performed high-dose chemotherapy with consequent hematopoietic stem cell transplantation is an effective and safe method to slowdown the autoimmune inflammatory process. This method can be recommended to use in treatment of children with severe resistant multiple sclerosis. 

  17. Important drug interactions in hematopoietic stem cell transplantation: what every physician should know.

    Science.gov (United States)

    Glotzbecker, Brett; Duncan, Christine; Alyea, Edwin; Campbell, Bonnie; Soiffer, Robert

    2012-07-01

    Morbidity is increased in patients undergoing hematopoietic stem cell transplantation when drug-drug interactions lead to unexpected outcomes. These interactions occur as a result of exposure to complicated medical regimens with drugs with narrow therapeutic windows and high toxicity profiles. In this report, we review the available evidence and possible mechanisms of the most clinically relevant drug interactions, including those involving inhibitors and inducers of the P450 isoenzyme system. We identify key interactions that should be familiar to any physician caring for patients after hematopoietic stem cell transplantation. We discuss drug metabolism in children and in the elderly and examine how age-related differences in metabolism make complicate drug regimens in these populations. A better understanding of these interactions and the responsible mechanisms will promote efficient delivery of the safest medical regimens to patients undergoing hematopoietic stem cell transplantation. Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy.

    Science.gov (United States)

    Kohn, Donald B

    2017-10-01

    Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications. Gene editing using site-specific endonucleases is emerging as a promising technology for gene therapy and is moving into clinical trials. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Granulocytic invasion of the central nervous system after hematopoietic stem cell transplantation for systemic lupus erythematosus.

    Science.gov (United States)

    Muraro, Paolo A; Nikolov, Nikolay P; Butman, John A; Abati, Andrea; Gea-Banacloche, Juan; Gress, Ronald; Lipsky, Peter; Illei, Gabor; Pavletic, Steven

    2006-06-01

    We report on the likely mechanism of an exacerbation of neurological symptoms developed during immune reconstitution after autologous non-myeloablative hematopoietic stem cell transplantation in a 33-year-old man with systemic lupus erythematosus- associated recurrent transverse myelitis. Cerebrospinal fluid examination revealed prominent neutrophilic pleocytosis and no evidence of infection or of reactivation of lupus. Following a course of corticosteroid treatment the exacerbation resolved completely and the patient's neurological function continued to improve, resulting in net gain above pre-treatment for over 1 year follow-up without maintenance immunosuppression. Granulocytic invasion of the central nervous system represents a novel and possibly preventable cause of neurological complications during haematologic reconstitution.

  20. SEROLOGICAL MONITORING OF A Toxoplasma INFECTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION

    OpenAIRE

    ROSSI, Cláudio L.; Nascimento,Fernanda S.; Sílvia de Barros-Mazon; Dias,Daniela F.; Vigorito,Antonio C.; Cármino A. de Souza

    2010-01-01

    We report a primary response to Toxoplasma gondii following a hematopoietic stem cell transplantation in a patient with multiple myeloma. The primary response to T. gondii was supported by IgM, IgG and IgA seroconversion. The patient was promptly treated and there were no complications related to toxoplasmosis in the subsequent months.Esse relato de caso descreve uma resposta primária ao Toxoplasma gondii após transplante de células progenitoras hematopoiéticas em paciente com mieloma múltipl...

  1. Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

    Directory of Open Access Journals (Sweden)

    Anne M. Dickinson

    2017-06-01

    Full Text Available The success of hematopoietic stem cell transplantation (HSCT lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL, caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter.

  2. Oral cyclosporine A treatment is feasible after myeloablative conditioning in allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Nygaard, M; Hovgaard, D; Schjødt, I M

    2015-01-01

    WHAT IS KNOWN AND OBJECTIVE: The target level and route of administration of cyclosporine A (CsA) differ between transplantation centres. It is unclear whether oral CsA is sufficient to maintain target level of CsA. CASE SUMMARY: We retrospectively analysed data from 48 adult patients, who...... underwent myeloablative hematopoietic stem cell transplantation. Twenty-one patients (44%) tolerated CsA orally throughout the transplantation period without increased incidence of acute graft versus host disease(aGVHD). Low concentration of CsA in week 2 was associated with increased incidence of a...

  3. Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant.

    Science.gov (United States)

    Rotz, Seth J; Ryan, Thomas D; Hlavaty, Joel; George, Stephen A; El-Bietar, Javier; Dandoy, Christopher E

    2017-11-01

    Cardiomyopathy is common in long-term survivors of pediatric hematopoietic stem cell transplant (HSCT). Events occurring before and after HSCT when combined with specific insults during HSCT likely contribute to long-term risk. Strategies for detecting subclinical cardiomyopathy prior to patients developing overt heart failure are under investigation. Changes in HSCT preparative regimens and cardioprotective medications administered during chemotherapy may alter the risk for cardiomyopathy. Interventions in long-term survivors such as lifestyle modification and cardioactive medications are of increasing importance. Herein we review the causes of cardiac injury, discuss strategies for detection of cardiomyopathy, and evaluate therapeutic options for long-term HSCT survivors. © 2017 Wiley Periodicals, Inc.

  4. BK virus encephalitis with thrombotic microangiopathy in an allogeneic hematopoietic stem cell transplant recipient.

    Science.gov (United States)

    Lopes da Silva, R; Ferreira, I; Teixeira, G; Cordeiro, D; Mafra, M; Costa, I; Bravo Marques, J M; Abecasis, M

    2011-04-01

    BK virus (BKV) infection occurs most often in immunocompromised hosts, in the setting of renal or bone marrow transplantation. Hemorrhagic cystitis is the commonest manifestation but in recent years infections in other organ systems have been reported. We report an unusual case of biopsy-proven BKV encephalitis in a hematopoietic stem cell transplant patient who subsequently developed thrombotic microangiopathy. As far as we know, this is the first report of such an association in a transplant patient. © 2010 John Wiley & Sons A/S.

  5. Diffuse hemorrhagic colitis in a patient with dyskeratosis congenita after nonmyeloablative allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Ehlert, Karoline; Rossig, Claudia; Groll, Andreas H; Beyna, Torsten; Froehlich, Birgit; Juergens, Heribert

    2015-01-01

    Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmentation, oral cavity leukoplakia, and nail dystrophy. Bone marrow failure in DC can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). After a nonmyeloablative, matched unrelated donor transplant, the 21-year-old patient experienced severe lower gastrointestinal tract hemorrhage caused by diffuse colitis. The etiology remained unclear. Diffuse colitis with life-threatening hemorrhage has now been reported in 3 DC patients after unrelated allogeneic HSCT. To identify the underlying causes and the disease-specific risks, and to allow for prevention and/or optimal management, data should be prospectively collected.

  6. Immune re-education following autologous hematopoietic stem cell transplantation.

    Science.gov (United States)

    Abrahamsson, Sofia; Muraro, Paolo A

    2008-12-01

    The encounter with different environmental antigens during immune maturation from childhood through early adulthood could play a role in the development of autoimmune disease in individuals with a susceptible genetic background. Autologous haematopoietic stem cell transplantation (HSCT) is an experimental treatment for autoimmunity that could offer a second possibility to correct for an aberrant immune reactivity. The premise is that eradication of the existing and pathogenic immune repertoire, in combination with the reinfusion of precursor cells, could reset the immunological clock to an earlier, latent phase of disease. Re-education of the adaptive immune system would occur during the reconstitution of cells under extreme lymphopenia, in which the antigenic priming takes place with a different sequence and timing than during the previous immunological history of the individual, resulting in a different immune repertoire. In this article, we discuss different mechanisms that could contribute to the development of tolerance during immune re-education and address the role of immune renewal and the qualitative reshaping of immunological memory.

  7. HEPATITIS B AND C IN HEMATOPOIETIC STEM CELL TRANSPLANT

    Directory of Open Access Journals (Sweden)

    Anna Locasciulli

    2009-11-01

    Full Text Available Although  the risk of acquisition of hepatitis B or hepatitis C virus through blood products has considerably reduced since the last decade, some infected patients are candidates to stem cell transplantation. Others may have no alternative than an infected donor. In all these cases, recipients of transplant are prone to short and long term liver complications. The evolution of liver tests under chemotherapy before transplant may give useful information to anticipate on  the risk of hepatitis reactivation after transplant, both for HBv and HCv. More than sixty percent of the patients who are HBsAg-positive before transplant reactivate after transplant, and 3% develop acute severe liver failure. Because both viral replication and immune reconstitution are the key factors for reactivation, it is crucial to closely follow liver function tests and viral load during the first months of transplant, and to pay a special attention in slowly tapering the immunosuppression in these patients. Lamivudine reduces HBv viremia, but favors the emergence of HBv polymerase gene mutants and should be individually discussed. Both in case of HBv or HCv hepatitis reactivation with ALT > 10N concomitantly to an increase in viral load at time of immune reconstitution, steroids should be given. In case there is no alternative than a HBv or HCv positive geno-identical donor, the risk of viral hepatitis, including acute liver failure and late complications, should be balanced with the benefit of transplant in a given situation.

  8. The hematopoietic stem cell transplantation in Indonesia: an unsolved dilemma.

    Science.gov (United States)

    Hariman, H

    2008-08-01

    Allogeneic BMT was performed in Indonesia, but had to be stopped prematurely because of the small number of patients. In the beginning, only patients with sufficient financial resources to travel to western countries could undergo transplant procedures. When neighbouring countries (Singapore and Malaysia) began performing transplant, patients were referred to those centres. In both countries, the procedure is more economical and therefore patients come from a broader range of economic classes. The Indonesian hematologist must deal with the post-transplantation side effects, such as GVHD, which are mostly of the chronic type of GVHD. The types of the post-transplant complications do not differ too much from other centres and need the same treatment used in the transplant centres. Hematologists in Indonesia also treat complications of HSCT performed in other countries. When there is no recovery of HSCT development in Indonesia so far, many commercially oriented companies or centres from other countries see Indonesia as a good commercial market and offer services, some of which are not scientifically sound. One of the main problems is umbilical cord blood stem cell banking from foreign countries, which is eagerly offered to parents expecting a baby. Moreover, parents are not fully protected by law. In conclusion, Indonesia needs to revive its own HSCT program to serve and protect its own patients of being used as commercial targets by other countries.

  9. Transient activation of hematopoietic stem and progenitor cells by IFNγ during acute bacterial infection.

    Science.gov (United States)

    MacNamara, Katherine C; Jones, Maura; Martin, Olga; Winslow, Gary M

    2011-01-01

    How hematopoietic stem cells (HSCs) respond to inflammatory signals during infections is not well understood. Our studies have used a murine model of ehrlichiosis, an emerging tick-born disease, to address how infection impacts hematopoietic function. Infection of C57BL/6 mice with the intracellular bacterium, Ehrlichia muris, results in anemia and thrombocytopenia, similar to what is observed in human ehrlichiosis patients. In the mouse, infection promotes myelopoiesis, a process that is critically dependent on interferon gamma (IFNγ) signaling. In the present study, we demonstrate that E. muris infection also drives the transient proliferation and expansion of bone marrow Lin-negative Sca-1(+) cKit(+) (LSK) cells, a population of progenitor cells that contains HSCs. Expansion of the LSK population in the bone marrow was associated with a loss of dormant, long-term repopulating HSCs, reduced engraftment, and a bias towards myeloid lineage differentiation within that population. The reduced engraftment and myeloid bias of the infection-induced LSK cells was transient, and was most pronounced on day 8 post-infection. The infection-induced changes were accompanied by an expansion of more differentiated multipotent progenitor cells, and required IFNγ signaling. Thus, in response to inflammatory signals elicited during acute infection, HSCs can undergo a rapid, IFNγ-dependent, transient shift from dormancy to activity, ostensibly, to provide the host with additional or better-armed innate cells for host defense. Similar changes in hematopoietic function likely underlie many different infections of public health importance.

  10. Transient activation of hematopoietic stem and progenitor cells by IFNγ during acute bacterial infection.

    Directory of Open Access Journals (Sweden)

    Katherine C MacNamara

    Full Text Available How hematopoietic stem cells (HSCs respond to inflammatory signals during infections is not well understood. Our studies have used a murine model of ehrlichiosis, an emerging tick-born disease, to address how infection impacts hematopoietic function. Infection of C57BL/6 mice with the intracellular bacterium, Ehrlichia muris, results in anemia and thrombocytopenia, similar to what is observed in human ehrlichiosis patients. In the mouse, infection promotes myelopoiesis, a process that is critically dependent on interferon gamma (IFNγ signaling. In the present study, we demonstrate that E. muris infection also drives the transient proliferation and expansion of bone marrow Lin-negative Sca-1(+ cKit(+ (LSK cells, a population of progenitor cells that contains HSCs. Expansion of the LSK population in the bone marrow was associated with a loss of dormant, long-term repopulating HSCs, reduced engraftment, and a bias towards myeloid lineage differentiation within that population. The reduced engraftment and myeloid bias of the infection-induced LSK cells was transient, and was most pronounced on day 8 post-infection. The infection-induced changes were accompanied by an expansion of more differentiated multipotent progenitor cells, and required IFNγ signaling. Thus, in response to inflammatory signals elicited during acute infection, HSCs can undergo a rapid, IFNγ-dependent, transient shift from dormancy to activity, ostensibly, to provide the host with additional or better-armed innate cells for host defense. Similar changes in hematopoietic function likely underlie many different infections of public health importance.

  11. Lineage tracing of Pf4-Cre marks hematopoietic stem cells and their progeny.

    Science.gov (United States)

    Calaminus, Simon D J; Guitart, Amelie V; Guitart, Amelie; Sinclair, Amy; Schachtner, Hannah; Watson, Steve P; Holyoake, Tessa L; Kranc, Kamil R; Machesky, Laura M

    2012-01-01

    The development of a megakaryocyte lineage specific Cre deleter, using the Pf4 (CXCL4) promoter (Pf4-Cre), was a significant step forward in the specific analysis of platelet and megakaryocyte cell biology. However, in the present study we have employed a sensitive reporter-based approach to demonstrate that Pf4-Cre also recombines in a significant proportion of both fetal liver and bone marrow hematopoietic stem cells (HSCs), including the most primitive fraction containing the long-term repopulating HSCs. Consequently, we demonstrate that Pf4-Cre activity is not megakaryocyte lineage-specific but extends to other myeloid and lymphoid lineages at significant levels between 15-60%. Finally, we show for the first time that Pf4 transcripts are present in adult HSCs and primitive hematopoietic progenitor cells. These results have fundamental implications for the use of the Pf4-Cre mouse model and for our understanding of a possible role for Pf4 in the development of the hematopoietic lineage.

  12. Lineage tracing of Pf4-Cre marks hematopoietic stem cells and their progeny.

    Directory of Open Access Journals (Sweden)

    Simon D J Calaminus

    Full Text Available The development of a megakaryocyte lineage specific Cre deleter, using the Pf4 (CXCL4 promoter (Pf4-Cre, was a significant step forward in the specific analysis of platelet and megakaryocyte cell biology. However, in the present study we have employed a sensitive reporter-based approach to demonstrate that Pf4-Cre also recombines in a significant proportion of both fetal liver and bone marrow hematopoietic stem cells (HSCs, including the most primitive fraction containing the long-term repopulating HSCs. Consequently, we demonstrate that Pf4-Cre activity is not megakaryocyte lineage-specific but extends to other myeloid and lymphoid lineages at significant levels between 15-60%. Finally, we show for the first time that Pf4 transcripts are present in adult HSCs and primitive hematopoietic progenitor cells. These results have fundamental implications for the use of the Pf4-Cre mouse model and for our understanding of a possible role for Pf4 in the development of the hematopoietic lineage.

  13. MiR-24 is required for hematopoietic differentiation of mouse embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Lynn Roy

    2015-01-01

    Full Text Available Overexpression of miRNA, miR-24, in mouse hematopoietic progenitors increases monocytic/ granulocytic differentiation and inhibits B cell development. To determine if endogenous miR-24 is required for hematopoiesis, we antagonized miR-24 in mouse embryonic stem cells (ESCs and performed in vitro differentiations. Suppression of miR-24 resulted in an inability to produce blood and hematopoietic progenitors (HPCs from ESCs. The phenotype is not a general defect in mesoderm production since we observe production of nascent mesoderm as well as mesoderm derived cardiac muscle and endothelial cells. Results from blast colony forming cell (BL-CFC assays demonstrate that miR-24 is not required for generation of the hemangioblast, the mesoderm progenitor that gives rise to blood and endothelial cells. However, expression of the transcription factors Runx1 and Scl is greatly reduced, suggesting an impaired ability of the hemangioblast to differentiate. Lastly, we observed that known miR-24 target, Trib3, is upregulated in the miR-24 antagonized embryoid bodies (EBs. Overexpression of Trib3 alone in ESCs was able to decrease HPC production, though not as great as seen with miR-24 knockdown. These results demonstrate an essential role for miR-24 in the hematopoietic differentiation of ESCs. Although many miRNAs have been implicated in regulation of hematopoiesis, this is the first miRNA observed to be required for the specification of mammalian blood progenitors from early mesoderm.

  14. Transcriptional profiling of Foxo3a and Fancd2 regulated genes in mouse hematopoietic stem cells

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    Xiaoli Li

    2015-06-01

    Full Text Available Functional maintenance of hematopoietic stem cells (HSCs is constantly challenged by stresses like DNA damage and oxidative stress. Foxo factors particularly Foxo3a function to regulate the self-renewal of HSCs and contribute to the maintenance of the HSC pool during aging by providing resistance to oxidative stress. Fancd2-deficient mice had multiple hematopoietic defects including HSC loss in early development and in response to cellular stresses including oxidative stress. The cellular mechanisms underlying HSC loss in Fancd2-deficient mice include abnormal cell cycle status loss of quiescence and compromised hematopoietic repopulating capacity of HSCs. To address on a genome wide level the genes and pathways that are impacted by deletion of the Fancd2 and Foxo3a we performed microarray analysis on phenotypic HSCs (Lin−ckit+Sca-1+CD150+CD48− from Fancd2 single knockout Foxo3a single knockout and Fancd2−/−Foxo3a−/− double-knockout (dKO mice. Here we provide detailed methods and analysis on these microarray data which has been deposited in Gene Expression Omnibus (GEO: GSE64215.

  15. Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Singh, Pratibha; Hoggatt, Jonathan; Kamocka, Malgorzata M; Mohammad, Khalid S; Saunders, Mary R; Li, Hongge; Speth, Jennifer; Carlesso, Nadia; Guise, Theresa A; Pelus, Louis M

    2017-11-13

    Endothelial cells (ECs) are components of the hematopoietic microenvironment and regulate hematopoietic stem and progenitor cell (HSPC) homeostasis. Cytokine treatments that cause HSPC trafficking to peripheral blood are associated with an increase in dipeptidylpeptidase 4/CD26 (DPP4/CD26), an enzyme that truncates the neurotransmitter neuropeptide Y (NPY). Here, we show that enzymatically altered NPY signaling in ECs caused reduced VE-cadherin and CD31 expression along EC junctions, resulting in increased vascular permeability and HSPC egress. Moreover, selective NPY2 and NPY5 receptor antagonists restored vascular integrity and limited HSPC mobilization, demonstrating that the enzymatically controlled vascular gateway specifically opens by cleavage of NPY by CD26 signaling via NPY2 and NPY5 receptors. Mice lacking CD26 or NPY exhibited impaired HSPC trafficking that was restored by treatment with truncated NPY. Thus, our results point to ECs as gatekeepers of HSPC trafficking and identify a CD26-mediated NPY axis that has potential as a pharmacologic target to regulate hematopoietic trafficking in homeostatic and stress conditions.

  16. Effects of nonpharmacological interventions on reducing fatigue after hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Hedayat Jafari

    2017-01-01

    Full Text Available Fatigue is one of the main complaints of patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT. Since nonpharmacological interventions are cost-effective and causes fewer complications, this study aimed to review the studies performed on the effects of nonpharmacological interventions on fatigue in patients undergoing HSCT during September 2016. MEDLINE, CINAHL, Scientific Information Database, IranMedex, PubMed, ScienceDirect, Scopus, Magiran, and IRANDOC databases were searched using Persian and English keywords. A total of 1217 articles were retrieved, 21 of which were used in this study. Exercise is known as an effective intervention in alleviating physical and mental problems of patients undergoing stem cell transplant. This review-based study showed that nonpharmacological methods such as exercise might be effective in decreasing fatigue in patients undergoing stem cell transplant. There is a multitude of studies on some of the complementary and alternative therapy methods, such as music therapy, yoga, relaxation, and therapeutic massage. These studies demonstrated the positive effects of the aforementioned therapies on reduction of fatigue in patients undergoing stem cell transplantation. All the investigated methods in this study were nonaggressive, safe, and cost-effective and could be used along with common treatments or even as an alternative for pharmacological treatments for the reduction, or elimination of fatigue in patients undergoing stem cell transplantation. Given the advantages of complementary and alternative medicine, conducting further studies on this issue is recommended to reduce fatigue in patients after stem cell transplantation.

  17. Effects of nonpharmacological interventions on reducing fatigue after hematopoietic stem cell transplantation.

    Science.gov (United States)

    Jafari, Hedayat; Jannati, Yadollah; Nesheli, Hassan Mahmoodi; Hassanpour, Somayeh

    2017-01-01

    Fatigue is one of the main complaints of patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT). Since nonpharmacological interventions are cost-effective and causes fewer complications, this study aimed to review the studies performed on the effects of nonpharmacological interventions on fatigue in patients undergoing HSCT during September 2016. MEDLINE, CINAHL, Scientific Information Database, IranMedex, PubMed, ScienceDirect, Scopus, Magiran, and IRANDOC databases were searched using Persian and English keywords. A total of 1217 articles were retrieved, 21 of which were used in this study. Exercise is known as an effective intervention in alleviating physical and mental problems of patients undergoing stem cell transplant. This review-based study showed that nonpharmacological methods such as exercise might be effective in decreasing fatigue in patients undergoing stem cell transplant. There is a multitude of studies on some of the complementary and alternative therapy methods, such as music therapy, yoga, relaxation, and therapeutic massage. These studies demonstrated the positive effects of the aforementioned therapies on reduction of fatigue in patients undergoing stem cell transplantation. All the investigated methods in this study were nonaggressive, safe, and cost-effective and could be used along with common treatments or even as an alternative for pharmacological treatments for the reduction, or elimination of fatigue in patients undergoing stem cell transplantation. Given the advantages of complementary and alternative medicine, conducting further studies on this issue is recommended to reduce fatigue in patients after stem cell transplantation.

  18. Effects of nonpharmacological interventions on reducing fatigue after hematopoietic stem cell transplantation

    Science.gov (United States)

    Jafari, Hedayat; Jannati, Yadollah; Nesheli, Hassan Mahmoodi; Hassanpour, Somayeh

    2017-01-01

    Fatigue is one of the main complaints of patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT). Since nonpharmacological interventions are cost-effective and causes fewer complications, this study aimed to review the studies performed on the effects of nonpharmacological interventions on fatigue in patients undergoing HSCT during September 2016. MEDLINE, CINAHL, Scientific Information Database, IranMedex, PubMed, ScienceDirect, Scopus, Magiran, and IRANDOC databases were searched using Persian and English keywords. A total of 1217 articles were retrieved, 21 of which were used in this study. Exercise is known as an effective intervention in alleviating physical and mental problems of patients undergoing stem cell transplant. This review-based study showed that nonpharmacological methods such as exercise might be effective in decreasing fatigue in patients undergoing stem cell transplant. There is a multitude of studies on some of the complementary and alternative therapy methods, such as music therapy, yoga, relaxation, and therapeutic massage. These studies demonstrated the positive effects of the aforementioned therapies on reduction of fatigue in patients undergoing stem cell transplantation. All the investigated methods in this study were nonaggressive, safe, and cost-effective and could be used along with common treatments or even as an alternative for pharmacological treatments for the reduction, or elimination of fatigue in patients undergoing stem cell transplantation. Given the advantages of complementary and alternative medicine, conducting further studies on this issue is recommended to reduce fatigue in patients after stem cell transplantation. PMID:28458705

  19. A Preliminary Online Study on Menstruation Recovery in Women After Autologous Hematopoietic Stem Cell Transplant for Autoimmune Diseases.

    Science.gov (United States)

    Maciejewska, Martyna; Snarski, Emilian; Wiktor-Jędrzejczak, Wiesław

    2016-12-01

    Autologous hematopoietic stem cell transplant has become a successful treatment option in aggressive autoimmune diseases. Young women who are consulted before this treatment are faced with an absence of data on the transplant's effect on their fertility. The aim of our study was to analyze information on menstruation recovery after autologous hematopoietic stem cell transplant for autoimmune diseases. An anonymous online questionnaire was distributed among members of an international Web forum of patients who had autologous hematopoietic stem cell transplant for autoimmune disease. Data were collated and analyzed. We obtained responses from 28 female patients to the questionnaire. The conditioning regimens used in this population were cyclophosphamide ± antibodies or BCNU (carmustine), etoposide, Ara-C (cytarabine), and melphalan chemotherapy. All patients who were transplanted at the age of 32 years or younger showed restored menstruation after an average (standard deviation) of 5.38 months (5.34 mo). In patients aged 33 to 41 years, menstruation was restored in 38%. We found that 73% of patients already had children before autologous hematopoietic stem cell transplant, and only 15% of responders declared desire for pregnancy after transplant. Our online analysis showed feasibility as a questionnaire for assessing fertility after autologous hematopoietic stem cell transplant. The results show that menstruation is restored in all patients of 32 years of age or younger, regardless of the conditioning regimen. Many of these women are likely to maintain fertility and may eventually become pregnant. However, a significant number of responders who underwent autologous hematopoietic stem cell transplant for autoimmune diseases already had children before transplant and indicated no desire for pregnancy after transplant; the data on pregnancy occurrence in this group should be interpreted in this context.

  20. Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    McKinney, A M; Benson, J; Nascene, D R; Eisengart, J; Salmela, M B; Loes, D J; Zhang, L; Patel, K; Raymond, G V; Miller, W P

    2016-09-01

    MR perfusion has shown abnormalities of affected WM in cerebral X-linked adrenoleukodystrophy, but serial data is needed to explore the import of such findings after hematopoietic stem cell transplantation. Our aim was to prospectively measure MR perfusion parameters in patients with cerebral adrenoleukodystrophy pre- and post-hematopoietic stem cell transplantation, and to correlate those measurements with clinical outcome. Ten patients with cerebral adrenoleukodystrophy prospectively underwent DSC-MR perfusion imaging at adrenoleukodystrophy at each time point and compared with those in controls. Correlations were calculated between the pre-hematopoietic stem cell transplantation MR perfusion values and 1-year clinical scores, with P value adjustment for multiple comparisons. At baseline in patients with cerebral adrenoleukodystrophy, both relative CBV and relative CBF within the splenium of the corpus callosum and parieto-occipital WM significantly differed from those in controls (P = .005-.031) and remained so 1 year post-hematopoietic stem cell transplantation (P = .003-.005). Meanwhile, no MR perfusion parameter within the leading enhancing edge differed significantly from that in controls at baseline or at 1 year (P = .074-.999) or significantly changed by 1 year post-hematopoietic stem cell transplantation (P = .142-.887). Baseline Loes scores correlated with 1-year clinical neurologic function (r = 0.813, P adrenoleukodystrophy, suggesting local disease stabilization. Meanwhile, parieto-occipital WM and splenium of the corpus callosum relative CBV and relative CBF values worsened; this change signified irreversible injury. Baseline splenium of the corpus callosum relative CBV may predict clinical outcomes following hematopoietic stem cell transplantation. © 2016 by American Journal of Neuroradiology.

  1. The effect of lithium on hematopoietic, mesenchymal and neural stem cells.

    Science.gov (United States)

    Ferensztajn-Rochowiak, Ewa; Rybakowski, Janusz K

    2016-04-01

    Lithium has been used in modern psychiatry for more than 65 years, constituting a cornerstone for the long-term treatment of bipolar disorder. A number of biological properties of lithium have been discovered, including its hematological, antiviral and neuroprotective effects. In this article, a systematic review of the effect of lithium on hematopoietic, mesenchymal and neural stem cells is presented. The beneficial effects of lithium on the level of hematopoietic stem cells (HSC) and growth factors have been reported since 1970s. Lithium improves homing of stem cells, the ability to form colonies and HSC self-renewal. Lithium also exerts a favorable influence on the proliferation and maintenance of mesenchymal stem cells (MSC). Studies on the effect of lithium on neurogenesis have indicated an increased proliferation of progenitor cells in the dentate gyrus of the hippocampus and enhanced mitotic activity of Schwann cells. This may be connected with the neuroprotective and neurotrophic effects of lithium, reflected in an improvement in synaptic plasticity promoting cell survival and inhibiting apoptosis. In clinical studies, lithium treatment increases cerebral gray matter, mainly in the frontal lobes, hippocampus and amygdala. Recent findings also suggest that lithium may reduce the risk of dementia and exert a beneficial effect in neurodegenerative diseases. The most important mediators and signaling pathways of lithium action are the glycogen synthase kinase-3 and Wnt/β-catenin pathways. Recently, to study of bipolar disorder pathogenesis and the mechanism of lithium action, the induced pluripotent stem cells (iPSC) obtained from bipolar patients have been used. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  2. Mesenchymal stem cell derived hematopoietic cells are permissive to HIV-1 infection

    Directory of Open Access Journals (Sweden)

    Mondal Debasis

    2011-01-01

    Full Text Available Abstract Background Tissue resident mesenchymal stem cells (MSCs are multipotent, self-renewing cells known for their differentiation potential into cells of mesenchymal lineage. The ability of single cell clones isolated from adipose tissue resident MSCs (ASCs to differentiate into cells of hematopoietic lineage has been previously demonstrated. In the present study, we investigated if the hematopoietic differentiated (HD cells derived from ASCs could productively be infected with HIV-1. Results HD cells were generated by differentiating clonally expanded cultures of adherent subsets of ASCs (CD90+, CD105+, CD45-, and CD34-. Transcriptome analysis revealed that HD cells acquire a number of elements that increase their susceptibility for HIV-1 infection, including HIV-1 receptor/co-receptor and other key cellular cofactors. HIV-1 infected HD cells (HD-HIV showed elevated p24 protein and gag and tat gene expression, implying a high and productive infection. HD-HIV cells showed decreased CD4, but significant increase in the expression of CCR5, CXCR4, Nef-associated factor HCK, and Vpu-associated factor BTRC. HIV-1 restricting factors like APOBEC3F and TRIM5 also showed up regulation. HIV-1 infection increased apoptosis and cell cycle regulatory genes in HD cells. Although undifferentiated ASCs failed to show productive infection, HIV-1 exposure increased the expression of several hematopoietic lineage associated genes such as c-Kit, MMD2, and IL-10. Conclusions Considering the presence of profuse amounts of ASCs in different tissues, these findings suggest the possible role that could be played by HD cells derived from ASCs in HIV-1 infection. The undifferentiated ASCs were non-permissive to HIV-1 infection; however, HIV-1 exposure increased the expression of some hematopoietic lineage related genes. The findings relate the importance of ASCs in HIV-1 research and facilitate the understanding of the disease process and management strategies.

  3. HEMATOPOIETIC STEM CELL TRNSPLANTATION IN THALASSEMIA AND RELATED DISORDERS

    Directory of Open Access Journals (Sweden)

    Emanuele Angelucci

    2009-06-01

    Full Text Available The   basis of allogeneic hemopoietic stem cell (HSC transplantation in thalassemia consists in substituting the ineffective thalassemic erythropoiesis with and allogeneic effective one. This approach is an efficient way to obtain a long lasting, probably permanent, clinical effective correction of the anaemia avoiding transfusion requirement and subsequent complications like iron overload.   The first HSC transplant for thalassemia was performed in Seattle on Dec 2, 1981. In the early eighties transplantation procedure was limited to very few centres worldwide. Subsequently between 17 December 1981 and 31 January 2003, over  1000 consecutive patients, aged from 1 to 35 years, underwent transplantation in Pesaro. After the  pioneering work by the Seattle  and Peasaro groups,  this therapeutic approach is now widely applied worldwide. Medical therapy of thalassemia is one of the most spectacular successes of the medical practice in the last decades. In recent years advances in knowledge of iron overload patho-physiopathology, improvement and diffusion of diagnostic capability together with the development of new effective and safe oral chelators  promise to further increase success of medical therapy. Nevertheless situation is dramatically different in non-industrialized countries were the very large majority of patients live today . Transplantation technologies have improved substantially during the last years and transplantation outcome is likely to be much better today than in the ‘80s. Recent data indicated a probability of overall survival and thalassemia free survival of 97% and 89% for patients with no advanced disease and of 87% and 80% for patients with advanced disease.  Thus the central role of HSC in thalassemia has now been fully established. Thalassemia remains the only definitive curative therapy for thalassemia and other hemoblobinopathies. The development of oral chelators has not changed this position. However this

  4. The Total Body Irradiation Schedule Affects Acute Leukemia Relapse After Matched T Cell–Depleted Hematopoietic Stem Cell Transplantation

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    Aristei, Cynthia, E-mail: cynthia.aristei@unipg.it [Radiation Oncology Section, Department of Surgery and Biomedical Sciences, University of Perugia and Perugia General Hospital, Perugia (Italy); Carotti, Alessandra [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Palazzari, Elisa [Radiation Oncology Section, University of Perugia, Perugia (Italy); Amico, Lucia; Ruggeri, Loredana [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Perrucci, Elisabetta; Falcinelli, Lorenzo [Radiation Oncology Division, Perugia General Hospital, Perugia (Italy); Lancellotta, Valentina [Radiation Oncology Section, University of Perugia, Perugia (Italy); Palumbo, Isabella [Radiation Oncology Section, Department of Surgery and Biomedical Sciences, University of Perugia and Perugia General Hospital, Perugia (Italy); Falzetti, Franca [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Aversa, Franco [Hematology and Bone Marrow Transplant Unit, Department of Clinical and Experimental Medicine, Parma General Hospital and University, Parma (Italy); Merluzzi, Mara; Velardi, Andrea; Martelli, Massimo Fabrizio [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy)

    2016-11-15

    Purpose: We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials: The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results: All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI (P=.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI (P=.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI (P=.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS (P=.01 and P=.03, respectively). Conclusions: In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

  5. Mesenchymal stem cells versus mesenchymal stem cells combined with cord blood for engraftment failure after autologous hematopoietic stem cell transplantation: a pilot prospective, open-label, randomized trial.

    Science.gov (United States)

    Xiong, Yi-Ying; Fan, Qian; Huang, Fen; Zhang, Yu; Wang, Yu; Chen, Xiao-Yong; Fan, Zhi-Ping; Zhou, Hong-Sheng; Xiao, Yang; Xu, Xiao-Jun; Dai, Min; Xu, Na; Sun, Jing; Xiang, Peng; Huang, Xiao-Jun; Liu, Qi-Fa

    2014-02-01

    Engraftment failure (EF) after autologous hematopoietic stem cell transplantation is a serious complication. We prospectively evaluated the effects and safeties of mesenchymal stem cells (MSCs) alone and MSCs combined with cord blood (CB) for EF. Twenty-two patients were randomized to receive MSCs (MSC group; n = 11) or MSCs plus CB (CB group; n = 11). Patients with no response (NR) to MSCs received the therapeutic schedule in the CB group, and those patients with partial response (PR) in the MSC group and patients without complete remission (CR) in the CB group received another cycle of MSC treatment. Patients who did not achieve CR after 2 cycles of treatments received other treatments, including allogeneic HSCT. After the first treatment cycle, response was seen in 7 of 11 patients in the MSC group and in 9 of 11 in the CB group (P = .635), with a significant difference in neutrophil reconstruction between the 2 groups (P = .030). After 2 treatment cycles, 16 patients achieved CR, 3 achieved PR, and 3 had NR. No patient experienced graft-versus-host disease (GVHD). With a median follow-up of 345 d (range, 129 to 784 d) post-transplantation, 18 patients remained alive and 4 had died (3 from primary disease relapse and 1 from cytomegalovirus pneumonia). The 2-year overall survival, disease-free survival, and cumulative incidence of tumor relapse post-transplantation were 75.2% ± 12.0%, 79.5% ± 9.4%, and 20.5% ± 9.4%, respectively. Our data indicate that the 2 strategies are effective for EF and do not result in GVHD or increase the risk of tumor relapse, but the MSC plus CB regimen has a superior effect on neutrophil reconstruction. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  6. 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

  7. Hematopoietic Stem Cell Transplantation: Need for Research & Potential Applications. It’s status in India

    Directory of Open Access Journals (Sweden)

    Shripad D. Banavali

    2009-01-01

    Full Text Available Stem cells are undifferentiated cells that through replications have the capabilities of both self-renewal and differentiation into mature specialized cells. Broadly, there are two types of stem cells, embryonic stem cells and adult stem cells. Embryonic stem cell biology has been associated with ethical controversy and also their growth is difficult to control. Adult stem cells are located in tissues throughout the body and function as a reservoir to replace damaged or aging cells. Embryonic stem cells are by definitions, the master cells capable of differentiating into every type of cells either in-vitro or in-vivo. Several lines of evidence suggests, however, that adult stem cells and even terminally differentiated somatic cells under appropriate micro-environmental cues are able to be reprogrammed and contribute to a much wider spectrum of differentiated progeny than previously anticipated. Hematopoietic Stem Cells (HSCs, for example, from different sources have been shown to cross the tissue boundaries and give rise to the cells of the other germ layers.In the past few years, the plasticity of adult cells in several post-natal tissues has attracted special attention in regenerative medicine. Stem cell therapies represent a new field of biomedical science which could provide in the future the cure for diseases until now considered incurable. The reconstitution of adult stem cells may be promising source for the regeneration of damaged tissues and for the resolution of organ dysfunction. However, there are two major limitations to the use of such cells:- (i They are rare and (ii Only a few types exist that can be isolated without harming the patient.Due to the inability to efficiently and safely harvest or expand stem cells from most adult organs (e.g. liver, gastrointestinal tract, heart, brain, the majority of human stem cell trials have focused on clinical applications for HSCs, mesenchymal stem cells (MSCs, or both, which can be easily

  8. Evaluation of Hematopoietic Stem Cell Mobilization Rates with Early Plerixafor Administration for Adult Stem Cell Transplantation.

    Science.gov (United States)

    Stover, Jessica T; Shaw, J Ryan; Kuchibhatla, Maragatha; Horwitz, Mitchell E; Engemann, Ashley M

    2017-08-01

    The addition of plerixafor to high-dose colony-stimulating growth factor has been shown to improve stem cell mobilization rates in autologous transplant patients with multiple myeloma and non-Hodgkin lymphoma. This study evaluates the change in administration time of plerixafor to determine if cell mobilization rates are similar between the US Food and Drug Administration-approved administration time of 11 hours before apheresis and an earlier administration time of 16 hours before apheresis. Medical records of patients age ≥ 18 years undergoing autologous stem cell transplantation requiring the use of plerixafor after at least 4 days of granulocyte colony-stimulating factor therapy to complete stem cell mobilization from January 1, 2010 through September 30, 2014 were retrospectively reviewed. The primary outcome was CD34 + cell mobilization success rates when plerixafor was administered 11 ± 2 hours (standard administration group) compared with 16 ± 2 hours before cell apheresis (early administration group), as defined as collection of  ≥2 × 10 6 CD34 + cells/kg. Secondary outcomes included the number of plerixafor therapy days required to collect a total of ≥2 × 10 6 CD34 + cells/kg, the number of apheresis cycles required to achieve ≥2 × 10 6 CD34 + cells/kg, the median CD34 + cells/kg collected in each apheresis session, and the rates of reported adverse events that occurred in the standard administration time group compared with the early administration time group. Of the 197 patients included, 114 patients received plerixafor 11 ± 2 hours before apheresis and 83 patients received plerixafor 16 hours ± 2 hours before apheresis. Ninety-four percent of patients in the early administration group achieved successful stem cell mobilization compared with 81.6% in the standard administration group (P = .0111). The median number of plerixafor days to reach the collection goal of  ≥2 × 10 6 CD34 + cells/kg was 1 day for

  9. HEMATOPOIETIC STEM CELL TRNSPLANTATION IN THALASSEMIA AND RELATED DISORDERS

    Directory of Open Access Journals (Sweden)

    Mario Pani

    2009-06-01

    Full Text Available

    The   basis of allogeneic hemopoietic stem cell (HSC transplantation in thalassemia consists in substituting the ineffective thalassemic erythropoiesis with and allogeneic effective one. This approach is an efficient way to obtain a long lasting, probably permanent, clinical effective correction of the anaemia avoiding transfusion requirement and subsequent complications like iron overload.   The first HSC transplant for thalassemia was performed in Seattle on Dec 2, 1981. In the early eighties transplantation procedure was limited to very few centres worldwide. Subsequently between 17 December 1981 and 31 January 2003, over  1000 consecutive patients, aged from 1 to 35 years, underwent transplantation in Pesaro. After the  pioneering work by the Seattle  and Peasaro groups,  this therapeutic approach is now widely applied worldwide.

    Medical therapy of thalassemia is one of the most spectacular successes of the medical practice in the last decades. In recent years advances in knowledge of iron overload patho-physiopathology, improvement and diffusion of diagnostic capability together with the development of new effective and safe oral chelators[Surgical treatment of severe, refractory hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation: a report of 17 patients].

    Science.gov (United States)

    Tang, F F; Zhang, X H; Chen, H; Chen, Y Y; Han, W; Wang, J Z; Wang, F R; Chen, Y; Huang, X J; Xu, L P

    2017-06-01

    Objective: To investigate the clinical effect and safety of surgical treatment for severe, refractory hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Patients with severe HC, who were admitted to Peking University Institute of Hematology from January 2010 to December 2015, were enrolled in this study.All patients were refractory to medical managements and received bladder surgery including mucous electrocoagulation and/or selective transcatheter arterial embolization. Results: A total of 17 patients with severe HC (grade Ⅲ, n =5; grade Ⅳ, n =12) received surgical treatment, including 11 embolization and 18 mucous electrocoagulation.The median time from allo-HSCT to surgery was 107 d (46-179 d) and 75 d after HC.Eight patients only received embolization.Four patients only received mucous electrocoagulation.Five patients were given combined embolization and electrocoagulation.HC was cured in 11 patients, improved in 1 patient, which corresponded to a response rate of 70.6% and complete remission rate of 64.7%.Five patients didn't respond to these methods.In patients with response, macroscopic hematuria disappeared 3 to 10 days after treatments whereas microscopic hematuria vanished after 25 to 32 days.Both procedures were well tolerated and no severe adverse effects were observed. Conclusion: Surgery of bladder mucous electrocoagulation and/or selective arterial embolization are safe and effective for severe HC.

  10. [Comparative study on the usefulness of antibacterial prophylaxis with levofloxacin in patients submitted to hematopoietic stem cell transplantation].

    Science.gov (United States)

    Fernandez Sojo, Jesús; Batlle Massana, Montserrat; Morgades, Mireia; Vives Polo, Susana; Quesada, María Dolores; Ribera Santasusana, Josep María

    2016-01-01

    Bacterial infection remains a frequent complication in patients receiving a hematopoietic stem cell transplantation (HSCT). However, the impact of the antibacterial prophylaxis mortality in these patients is controversial. Retrospective comparison of 2 consecutive groups of patients undergoing HSCT receiving (n=132) or not (n=107) antibacterial prophylaxis with levofloxacin. 41% of patients receiving prophylaxis with levofloxacin had microbiologically documented infection (MDI) with bacteremia, compared with 40% of those not receiving levofloxacin. The frequency of gram-negative bacteremia was 11 and 38%, the resistance to levofloxacin was 39 and 14%, and the mortality was 8 and 7%, respectively. In our experience, the use of levofloxacin as prophylaxis in HSCT was associated with a lower frequency of gram-negative bacteremia but was not associated with a decreased rate of MDI and did not influence their outcome. In contrast, there was an increase in quinolone resistance in patients treated with levofloxacin. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  11. Hematopoietic stem cell transplantation in sickle cell disease: patient selection and special considerations

    Directory of Open Access Journals (Sweden)

    Bhatia M

    2015-07-01

    Full Text Available Monica Bhatia,1 Sujit Sheth21Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, 2Division of Pediatric Hematology and Oncology, Weill Cornell Medical College, New York, NY, USAAbstract: Hematopoietic stem cell transplantation remains the only curative treatment currently in use for patients with sickle cell disease (SCD. The first successful hematopoietic stem cell transplantation was performed in 1984. To date, approximately 1,200 transplants have been reported. Given the high prevalence of this disorder in Africa, and its emergence in the developed world through immigration, this number is relatively small. There are many reasons for this; primary among them are the availability of a donor, the risks associated with this complex procedure, and the cost and availability of resources in the developing world. Of these, it is fair to say that the risks associated with the procedure have steadily decreased to the point where, if currently performed in a center with experience using a matched sibling donor, overall survival is close to 100% and event-free survival is over 90%. While there is little controversy around offering hematopoietic stem cell transplantation to symptomatic SCD patients with a matched sibling donor, there is much debate surrounding the use of this modality in “less severe” patients. An overview of the current state of our understanding of the pathology and treatment of SCD is important to show that our current strategy is not having the desired impact on survival of homozygous SCD patients, and should be changed to significantly impact the small proportion of these patients who have matched siblings and could be cured, especially those without overt clinical manifestations. Both patient families and providers must be made to understand the progressive nature of SCD, and should be encouraged to screen full siblings of patients with homozygous SCD for their potential to

  12. Circulating hematopoietic stem cell count is a valuable predictor of prematurity complications in preterm newborns

    Directory of Open Access Journals (Sweden)

    Kotowski Maciej

    2012-09-01

    Full Text Available Abstract Background The frequency of preterm labour has risen over the last few years. Hence, there is growing interest in the identification of markers that may facilitate prediction and prevention of premature birth complications. Here, we studied the association of the number of circulating stem cell populations with the incidence of complications typical of prematurity. Methods The study groups consisted of 90 preterm (23–36 weeks of gestational age and 52 full-term (37–41 weeks infants. Non-hematopoietic stem cells (non-HSCs; CD45-lin-CD184+, enriched in very small embryonic-like stem cells (VSELs, expressing pluripotent (Oct-4, Nanog, early neural (β-III-tubulin, and oligodendrocyte lineage (Olig-1 genes as well as hematopoietic stem cells (HSCs; CD45+lin-CD184+, and circulating stem/progenitor cells (CSPCs; CD133+CD34+; CD133-CD34+ in association with characteristics of prematurity and preterm morbidity were analyzed in cord blood (CB and peripheral blood (PB until the sixth week after delivery. Phenotype analysis was performed using flow cytometry methods. Clonogenic assays suitable for detection of human hematopoietic progenitor cells were also applied. The quantitative parameters were compared between groups by the Mann–Whitney test and between time points by the Friedman test. Fisher’s exact test was used for qualitative variables. Results We found that the number of CB non-HSCs/VSELs is inversely associated with the birth weight of preterm infants. More notably, a high number of CB HSCs is strongly associated with a lower risk of prematurity complications including intraventricular hemorrhage, respiratory distress syndrome, infections, and anemia. The number of HSCs remains stable for the first six weeks of postnatal life. Besides, the number of CSPCs in CB is significantly higher in preterm infants than in full-term neonates (p  Conclusion We conclude that CB HSCs are markedly associated with the development of premature

  13. Studying cell behavior in whole zebrafish embryos by confocal live imaging: application to hematopoietic stem cells.

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    Renaud, Olivier; Herbomel, Philippe; Kissa, Karima

    2011-11-10

    Confocal live imaging is a key tool for studying cell behavior in the whole zebrafish embryo. Here we provide a detailed protocol that is adaptable for imaging any progenitor cell behavior in live zebrafish embryos. As an example, we imaged the emergence of the first hematopoietic stem cells from the aorta. We discuss the importance of selecting the appropriate zebrafish transgenic line as well as methods for immobilization of embryos to be imaged. In addition, we highlight the confocal microscopy acquisition parameters required for stem cell imaging and the software tools we used to analyze 4D movies. The whole protocol takes 2 h 15 min and allows confocal live imaging from a few hours to several days.

  14. Automated Identification and Localization of Hematopoietic Stem Cells in 3D Intravital Microscopy Data

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    Reema A. Khorshed

    2015-07-01

    Full Text Available Measuring three-dimensional (3D localization of hematopoietic stem cells (HSCs within the bone marrow microenvironment using intravital microscopy is a rapidly expanding research theme. This approach holds the key to understanding the detail of HSC-niche interactions, which are critical for appropriate stem cell function. Due to the complex tissue architecture of the bone marrow and to the progressive introduction of scattering and signal loss at increasing imaging depths, there is no ready-made software to handle efficient segmentation and unbiased analysis of the data. To address this, we developed an automated image analysis tool that simplifies and standardizes the biological interpretation of 3D HSC microenvironment images. The algorithm identifies HSCs and measures their localization relative to surrounding osteoblast cells and bone collagen. We demonstrate here the effectiveness, consistency, and accuracy of the proposed approach compared to current manual analysis and its wider applicability to analyze other 3D bone marrow components.

  15. Concise review: Current concepts in bone marrow microenvironmental regulation of hematopoietic stem and progenitor cells.

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    Smith, Julianne N P; Calvi, Laura M

    2013-06-01

    Hematopoietic stem cell (HSC) behavior is governed in large part by interactions of the blood system with the bone microenvironment. Increasing evidence demonstrates the profound role the local HSC microenvironment or niche plays in normal stem cell function, in therapeutic activation and in the setting of malignancy. A number of cellular and molecular components of the microenvironment have been identified thus far, several of which are likely to provide exciting therapeutic targets in the near future. Clinically effective strategies for niche manipulation, however, require careful study of the interaction of these niche components. Some of the key findings defining these regulatory interactions are explored in this concise review, with special emphasis on potential translational applications. Copyright © 2013 AlphaMed Press.

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

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    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.

  17. Catalase inhibits ionizing radiation-induced apoptosis in hematopoietic stem and progenitor cells.

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    Xiao, Xia; Luo, Hongmei; Vanek, Kenneth N; LaRue, Amanda C; Schulte, Bradley A; Wang, Gavin Y

    2015-06-01

    Hematologic toxicity is a major cause of mortality in radiation emergency scenarios and a primary side effect concern in patients undergoing chemo-radiotherapy. Therefore, there is a critical need for the development of novel and more effective approaches to manage this side effect. Catalase is a potent antioxidant enzyme that coverts hydrogen peroxide into hydrogen and water. In this study, we evaluated the efficacy of catalase as a protectant against ionizing radiation (IR)-induced toxicity in hematopoietic stem and progenitor cells (HSPCs). The results revealed that catalase treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells and hematopoietic progenitor cells. Subsequent colony-forming cell and cobble-stone area-forming cell assays showed that catalase-treated HSPCs can not only survive irradiation-induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells. Moreover, transplantation of catalase-treated irradiated HSPCs results in high levels of multi-lineage and long-term engraftments, whereas vehicle-treated irradiated HSPCs exhibit very limited hematopoiesis reconstituting capacity. Mechanistically, catalase treatment attenuates IR-induced DNA double-strand breaks and inhibits reactive oxygen species. Unexpectedly, we found that the radioprotective effect of catalase is associated with activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway and pharmacological inhibition of STAT3 abolishes the protective activity of catalase, suggesting that catalase may protect HSPCs against IR-induced toxicity via promoting STAT3 activation. Collectively, these results demonstrate a previously unrecognized mechanism by which catalase inhibits IR-induced DNA damage and apoptosis in HSPCs.

  18. Gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with STAT5.

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    Geqiang Li

    2010-02-01

    Full Text Available Grb2-associated binding (Gab adapter proteins play major roles in coordinating signaling downstream of hematopoietic cytokine receptors. In hematopoietic cells, Gab2 can modulate phosphatidylinositol-3 kinase and mitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoietic stem cells (HSCs. Gab2 may also act in a linear pathway upstream or downstream of signal transducer and activator of transcription-5 (STAT5, a major positive regulator of HSC function. Therefore, we aimed to determine whether Gab2 and STAT5 function in hematopoiesis in a redundant or non-redundant manner.To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth response to early-acting cytokines from sorted double mutant c-Kit(+Lin(-Sca-1(+ (KLS cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5 mutant background. Fetal liver cells isolated from homozygous STAT5 mutant mice lacking Gab2 showed significant reduction in HSC number (KLS CD150(+CD48(-, reduced HSC survival, and dramatic loss of self-renewal potential as measured by serial transplantation.These data demonstrate new functions for Gab2 in hematopoiesis in a manner that is non-redundant with STAT5. Furthermore, important synergy between STAT5 and Gab2 was observed in HSC self-renewal, which might be exploited to optimize stem cell-based therapeutics.

  19. Resetting autoimmunity in the nervous system: The role of hematopoietic stem cell transplantation.

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    Muraro, Paolo A; Abrahamsson, Sofia V

    2010-11-01

    According to current concepts for multiple sclerosis (MS), a fundamental pathogenic role is played by T- and B-cells that inappropriately recognize self antigens and initiate a cell-mediated or humoral inflammatory reaction that injures myelin and axons, and results in neural dysfunction and loss. Transplantation of bone marrow-derived hematopoietic stem cells following high-dose immunosuppression is being evaluated as an experimental treatment for severe forms of immune-mediated disorders, including MS. The primary goal of this therapeutic approach is to induce medication-free remission from new disease activity by correcting the immune aberrations that promote the attack against self tissue; this approach is termed 'immune repair'. In this review, the clinical experience gained from the use of autologous hematopoietic stem cell transplantation in treating severe forms of MS are presented, and the current understanding of the mechanisms underlying the mode of action of this treatment, including depletion of disease-mediating immune cells, rejuvenation of the immune repertoire and improvement of regulatory cell function, is discussed.

  1. Bmi1 confers resistance to oxidative stress on hematopoietic stem cells.

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    Shunsuke Nakamura

    Full Text Available The polycomb-group (PcG proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC 1, maintained self-renewing hematopoietic stem cells (HSCs during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed.In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FLBmi1. Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FLBmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS.Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.

  2. Less is More: unveiling the functional core of hematopoietic stem cells through knockout mice

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    Rossi, Lara; Lin, Kuanyin K.; Boles, Nathan C.; Yang, Liubin; King, Katherine Y.; Jeong, Mira; Mayle, Allison; Goodell, Margaret A.

    2012-01-01

    Summary Hematopoietic stem cells (HSCs) represent one of the first recognized somatic stem cells. As such, nearly 200 genes have been examined for roles in HSC function in knockout mice. In this review, we compile the majority of these reports to provide a broad overview of the functional modules revealed by these genetic analyses and highlight some key regulatory pathways involved, including cell cycle control, TGF-β signaling, Pten/AKT signaling, Wnt signaling, and cytokine signaling. Finally, we propose recommendations for characterization of HSC function in knockout mice to facilitate cross-study comparisons that would generate a more cohesive picture of HSC biology. In the field of design, the minimalist movement stripped down buildings and objects to their most basic features, a sentiment that architect Ludwig Mies van der Rohe summarized in his motto “less is more”. By depleting HSCs of specific genes, knockout studies transpose the minimalist approach into research biology, providing insights into the essential core of genetic features that is indispensable for a well-functioning hematopoietic system. PMID:22958929

  3. Factors Influencing Hematopoietic Stem Cell Donation Intention in Hong Kong: A Web-Based Survey.

    Science.gov (United States)

    Kwok, Janette; Leung, Eva; Wong, William; Leung, Kate; Lee, Cheuk Kwong; Lam, Wendy; Ip, Patrick

    2015-10-08

    Hematopoietic stem cell transplantation (HSCT) has become increasingly common for treatment of severe hematological disorders. However, the number of compatible hematopoietic stem cell (HSC) donors is usually limited. Expanding donor pool size would enhance matching success by increasing donor frequency and introducing allelic diversity within the registry. Identifying factors that affect public willingness towards HSC donation allows better strategic recruitment planning to facilitate donor pool expansion. Previous studies in white populations showed knowledge, family attitude, trust towards the healthcare system, fear, self-identity, and social identity are important factors related to HSC donation intention. However, given the differences in cultural and society values that exist across different regions, in particular between the East and West, whether these factors influence HSC donation willingness in Hong Kong remained to be determined. The objective of this study was to identify factors associated with HSC donation motivation in Hong Kong. A large-scale, cross-sectional, observational study involving 3479 local participants. There is a positive correlation of HSC donation intention with younger age (18-32, OR: 1.80, p≤0·001) and higher education (OR: 1·47, p≤0.001). Better HSCT knowledge is also related to greater HSC donation intention (OR: 2.55, p£0.001). Our data suggests HSCT education could help to improve donor recruitment and that more resources should be allocated for public education.

  4. Therapeutic role of hematopoietic stem cells in autism spectrum disorder-related inflammation

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    Dario eSiniscalco

    2013-06-01

    Full Text Available Autism and autism spectrum disorders (ASDs are heterogeneous, severe neurodevelopmental disorders with core symptoms of dysfunctions in social interactions and communication skills, restricted interests, repetitive - stereotypic verbal and non-verbal behaviours. Biomolecular evidence points to complex gene-environmental interactions in ASDs. Several biochemical processes are associated with ASDs: oxidative stress (including endoplasmic reticulum stress, decreased methylation capacity, limited production of glutathione; mitochondrial dysfunction, intestinal dysbiosis, increased toxic metal burden and various immune abnormalities. The known immunological disorders include: T-lymphocyte populations and function, gene expression changes in monocytes, several autoimmune-related findings, high levels of N-acetylgalactosaminidase (which precludes macrophage activation, and primary immune deficiencies. These immunological observations may result in minicolumn structural changes in the brain, as well as, abnormal immune mediation of synaptic functions. Equally, these immune dysregulations serve as the rationale for immune-directed interventions such as hematopoietic stem cells (HSCs, which are pivotal in controlling chronic inflammation and in the restoration of immunological balance. These properties make them intriguing potential agents for ASD treatments. This prospective review will focus on the current state-of-the-art knowledge and challenges intrinsic in the application of hematopoietic stem cells for ASD-related immunological disorders.

  5. The TIF1β-HP1 System Maintains Transcriptional Integrity of Hematopoietic Stem Cells

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    Satoru Miyagi

    2014-02-01

    Full Text Available TIF1β is a transcriptional corepressor that recruits repressive chromatin modifiers to target genes. Its biological function and physiological targets in somatic stem cells remain largely unknown. Here, we show that TIF1β is essential for the maintenance of hematopoietic stem cells (HSCs. Deletion of Tif1b in mice induced active cycling and apoptosis of HSCs and promoted egression of HSCs from the bone marrow, leading to rapid depletion of HSCs. Strikingly, Tif1b-deficient HSCs showed a strong trend of ectopic expression of nonhematopoietic genes. Levels of heterochromatin protein 1 (HP1α, β and γ proteins, which form a complex with TIF1β, were significantly reduced in the absence of TIF1β and depletion of HP1 recapitulated a part of the phenotypes of Tif1b-deficient HSCs. These results demonstrate that the TIF1β-HP1 system functions as a critical repressive machinery that targets genes not normally activated in the hematopoietic compartment, thereby maintaining the transcriptional signature specific to HSCs.

  6. Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation

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    Server, Andres [Oslo University Hospital-Rikshospitalet, Section of Neuroradiology, Department of Radiology and Nuclear Medicine, Oslo (Norway); Bargallo, Nuria [Universitat de Barcelona, Section of Neuroradiology, Department of Radiology, Hospital Clinic, Barcelona (Spain); Institut d' investigacions Biomediques August Pi i Sunyer (IDIBARS), Resonance Magnetic Image Core Facility, Barcelona (Spain); Floeisand, Yngvar [Oslo University Hospital-Rikshospitalet, Department of Hematology, Oslo (Norway); Sponheim, Jon [Oslo University Hospital-Rikshospitalet, Section of Gastroenterology, Department of Transplantation Medicine, Oslo (Norway); Graus, Francesc [Universitat de Barcelona, Department of Neurology, Hospital Clinic, Barcelona (Spain); Institut d' investigacions Biomediques August Pi i Sunyer (IDIBARS), Neuroimmunology Program, Barcelona (Spain); Hald, John K. [Oslo University Hospital-Rikshospitalet, Section of Neuroradiology, Department of Radiology and Nuclear Medicine, Oslo (Norway); University of Oslo, Faculty of Medicine, Oslo (Norway)

    2017-02-15

    Neurologic complications are common after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and affect 30-60% of transplant recipients. The aim of this article is to provide a practical imaging approach based on the timeline and etiology of CNS abnormalities, and neurologic complications related to transplantation of specific organs. The lesions will be classified based upon the interval from HSCT procedure: pre-engraftment period <30 days, early post-engraftment period 30-100 days, late post-engraftment period >100 days, and the interval from SOT procedure: postoperative phase 1-4 weeks, early posttransplant syndromes 1-6 months, late posttransplant syndromes >6 months. Further differentiation will be based on etiology: infections, drug toxicity, metabolic derangements, cerebrovascular complications, and posttransplantation malignancies. In addition, differentiation will be based on complications specific to the type of transplantation: allogeneic and autologous hematopoietic stem cells (HSC), heart, lung, kidney, pancreas, and liver. Thus, in this article we emphasize the strategic role of neuroradiology in the diagnosis and response to treatment by utilizing a methodical approach in the work up of patients with neurologic complications after transplantation. (orig.)

  7. Determining c-Myb protein levels can isolate functional hematopoietic stem cell subtypes.

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    Sakamoto, Hiroshi; Takeda, Naoki; Arai, Fumio; Hosokawa, Kentaro; Garcia, Paloma; Suda, Toshio; Frampton, Jon; Ogawa, Minetaro

    2015-02-01

    The transcription factor c-Myb was originally identified as a transforming oncoprotein encoded by two avian leukemia viruses. Subsequently, through the generation of mouse models that affect its expression, c-Myb has been shown to be a key regulator of hematopoiesis, including having critical roles in hematopoietic stem cells (HSCs). The precise function of c-Myb in HSCs although remains unclear. We have generated a novel c-myb allele in mice that allows direct observation of c-Myb protein levels in single cells. Using this reporter line we demonstrate that subtypes of HSCs can be isolated based upon their respective c-Myb protein expression levels. HSCs expressing low levels of c-Myb protein (c-Myb(low) HSC) appear to represent the most immature, dormant HSCs and they are a predominant component of HSCs that retain bromodeoxyuridine labeling. Hematopoietic stress, induced by 5-fluorouracil ablation, revealed that in this circumstance c-Myb-expressing cells become critical for multilineage repopulation. The discrimination of HSC subpopulations based on c-Myb protein levels is not reflected in the levels of c-myb mRNA, there being no more than a 1.3-fold difference comparing c-Myb(low) and c-Myb(high) HSCs. This illustrates how essential it is to include protein studies when aiming to understand the regulatory networks that control stem cell behavior. © 2014 AlphaMed Press.

  8. Caregiver and health care provider preferences of nutritional support in a hematopoietic stem cell transplant unit.

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    Williams-Hooker, Ruth; Adams, Marissa; Havrilla, David A; Leung, Wing; Roach, Robin R; Mosby, Terezie T

    2015-08-01

    Many pediatric oncology patients undergoing hematopoietic stem cell transplantation (HSCT) require nutritional support (NS) because of their inability to consume adequate caloric intake enough calories orally. Although NS can be provided either enteraly (EN) or parenteraly (PN), EN is the preferred method of NS as long as if the gastrointestinal tract is functioning. In this qualitative study, we determined the type of NS preferences and the reservations of caregivers of pediatric HSCT patients undergoing hematopoietic stem cell transplantation (HSCT) as well as those of health care (HC) providers working on the HSCT unit. A survey was developed and completed anonymously by HC providers and caregivers. The hypothesis was that HC providers and caregivers would prefer PN because it is convenient to use in patients who already have a central line in place. Most caregivers preferred PN to EN, while most HC providers preferred EN to PN. The barrier between EN initiation and caregivers' approval was the caregivers' perception that EN was invasive and painful, most common obstacle for initiation of EN among caregivers was that it hurts/is invasive, while the barrier with HC providers was vomiting and/abdominal pain associated with EN. If caregivers were better educated about NS and the advantages/disadvantages of the different forms of NS, their preferences may change. There have been policy changes at St. Jude have been implemented since this study, and an outpatient dietitian now provides education to caregivers about NS during the pre-evaluation for HSCT. © 2015 Wiley Periodicals, Inc.

  9. The GNASR201C mutation associated with clonal hematopoiesis supports transplantable hematopoietic stem cell activity.

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    Ostrander, Elizabeth L; Koh, Won Kyun; Mallaney, Cates; Kramer, Ashley C; Wilson, W Casey; Zhang, Bo; Challen, Grant A

    2018-01-01

    Genome sequencing efforts have identified virtually all of the important mutations in adult myeloid malignancies. More recently, population studies have identified cancer-associated variants in the blood of otherwise healthy individuals as they age, a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). This suggests that these mutations may occur in hematopoietic stem cells (HSCs) long before any clinical presentation but are not necessarily harbingers of transformation because only a fraction of individuals with CHIP develop hematopoietic pathologies. Delineation between CHIP variants that predispose for disease versus those that are more benign could be used as a prognostic factor to identify individuals at greater risk for transformation. To achieve this, the biological impact of CHIP variants on HSC function must be validated. One variant that has been identified recurrently in CHIP is a gain-of-function missense mutation in the imprinted gene GNAS (Guanine Nucleotide Binding Protein, Alpha Stimulating). In this study, we examined the effect of the GNASR201C variant on HSC function. Ectopic expression of GNASR201C supported transplantable HSC activity and improved lymphoid output in secondary recipients. Because declining lymphoid output is a hallmark of aging, GNASR201C mutations may sustain lymphoid-biased HSCs over time and maintain them in a developmental state favorable for transformation. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  10. Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency.

    Science.gov (United States)

    Carmo, Marlene; Risma, Kimberly A; Arumugam, Paritha; Tiwari, Swati; Hontz, Adrianne E; Montiel-Equihua, Claudia A; Alonso-Ferrero, Maria E; Blundell, Michael P; Schambach, Axel; Baum, Christopher; Malik, Punam; Thrasher, Adrian J; Jordan, Michael B; Gaspar, H Bobby

    2015-04-01

    Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL.

  11. Milestones of Hematopoietic Stem Cell Transplantation – from First Human Studies to Current Developments

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    Hildegard Theresia Greinix

    2016-11-01

    Full Text Available Since the early beginnings, in the 1950’s, hematopoietic stem cell transplantation (HSCT has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia effector cells contained in the stem cell graft. Exciting insights into the genetics of the human leukocyte antigen (HLA system allowed improved donor selection , including HLA-identical related and unrelated donors. Besides bone marrow (BM other stem cell sources like G-CSF-mobilized peripheral blood stem cells and cord blood stem cells have been established in clinical routine. Use of reduced-intensity or non-myeloablative conditioning regimens has been associated with a marked reduction of non-hematological toxicities and eventually, non-relapse mortality allowing older patients and individuals with comorbidities to undergo allogeneic HSCT and to benefit from graft-versus-leukemia or anti-tumour effects. Whereas in the early years malignant disease eradication by high-dose chemotherapy or radiotherapy was the ultimate goal, nowadays allogeneic HSCT has been recognized as cellular immunotherapy relying prominently on immune mechanisms and to a lesser extent on non-specific direct cellular toxicity.This chapter will summarise the key milestones of HSCT and introduce current developments.

  12. Milestones of Hematopoietic Stem Cell Transplantation – From First Human Studies to Current Developments

    Science.gov (United States)

    Juric, Mateja Kralj; Ghimire, Sakhila; Ogonek, Justyna; Weissinger, Eva M.; Holler, Ernst; van Rood, Jon J.; Oudshoorn, Machteld; Dickinson, Anne; Greinix, Hildegard T.

    2016-01-01

    Since the early beginnings, in the 1950s, hematopoietic stem cell transplantation (HSCT) has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary, and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity, and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia (GvL) effector cells contained in the stem cell graft. Exciting insights into the genetics of the human leukocyte antigen (HLA) system allowed improved donor selection, including HLA-identical related and unrelated donors. Besides bone marrow, other stem cell sources like granulocyte-colony stimulating-mobilized peripheral blood stem cells and cord blood stem cells have been established in clinical routine. Use of reduced-intensity or non-myeloablative conditioning regimens has been associated with a marked reduction of non-hematological toxicities and eventually, non-relapse mortality allowing older patients and individuals with comorbidities to undergo allogeneic HSCT and to benefit from GvL or antitumor effects. Whereas in the early years, malignant disease eradication by high-dose chemotherapy or radiotherapy was the ultimate goal; nowadays, allogeneic HSCT has been recognized as cellular immunotherapy relying prominently on immune mechanisms and to a lesser extent on non-specific direct cellular toxicity. This chapter will summarize the key milestones of HSCT and introduce current developments. PMID:27881982

  13. Routine filtration of hematopoietic stem cell products: the time has arrived.

    Science.gov (United States)

    Paulson, Kristjan; Gilpin, Scott G; Shpiruk, Tanner A; Anjos, Karla; Tulloch, Marie; Giftakis, Angleine; Blankstein, Anna R; Szwajcer, David; Wall, Donna A

    2015-08-01

    Most blood products are infused at the time of transfusion through a standard blood filter, designed to capture macroaggregates and cellular debris that might be harmful to the patient if infused. Hematopoietic stem cell products are not universally filtered, likely due to concern about loss of viable stem cells in the filtration process. We conducted a two-phase study to better understand the safety of routine filtration. First, surplus cryopreserved stem cell products were thawed and filtered, with markers of viability and potency measured. Second, routine filtration was implemented as part of routine practice at our center, and date of neutrophil and platelet (PLT) recovery was compared to historical controls. In the first phase, there was no difference seen in any markers of viability or potency for products after routine filtration. Based on those results, routine filtration was implemented. There was no difference in neutrophil or PLT engraftment. Thus, in this study, routine filtration did not impact the number of viable stem cells and did not delay engraftment. Given the very real harm posed by infusion of macroaggregates and cellular debris, and no clear disadvantage to filtration, routine filtration of stem cell products should be considered the standard of care. © 2015 AABB.

  14. CD56 expression in normal immature granulocytes after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Muroi, Kazuo; Fujiwara, Shin-Ichiro; Tatara, Raine; Sugimoto, Miyuki; Yamamoto, Chihiro; Uehara, Eisuke; Meguro, Akiko; Hatano, Kaoru; Okazuka, Kiyoshi; Oh, Iekuni; Ohmine, Ken; Suzuki, Takahiro; Mori, Masaki; Nagai, Tadashi; Ozawa, Keiya

    2013-01-01

    Bone marrow mononuclear cells from 93 patients with hematological malignancies after allogeneic hematopoietic stem cell transplantation (AHSCT) were analyzed using flow cytometry (FCM). The disease was acute myeloblastic leukemia (50 patients), acute lymphoblastic leukemia, and others. Conditioning was myeloablative (80 patients) or reduced intensity. The stem cell source was bone marrow (75 patients), peripheral blood stem cells, or cord blood. After AHSCT, granulocyte colony-stimulating factor was given to all patients. All patients showed engraftment of the donor cells. FCM was conducted on a median of 22 days after AHSCT. The gate was set around a granulocytic region consisting of immature granulocytes. The positivity rates of CD13, CD14, CD15, CD33, CD34, CD56, and HLA-DR in the cells were 59.9 ± 27.4%, 5.8 ± 8.8%, 98.3 ± 1.9%, 92.3 ± 12.4%, 2.6 ± 5.8%, 24.3 ± 16.7%, and 9.1 ± 6.6%, respectively. The greatest value of CD56 positivity was 73.1%. On the basis of CD56 expression, cases of more than 24% CD56 positivity were assigned to the CD56-high group (39 patients), while the rest were assigned to the CD56-low/negative group. There were no significant differences between the two groups in terms of disease status, sex, donor, hematopoietic stem cells, days of FCM analysis, or peripheral blood cell counts around the days of performing FCM. These results indicate that CD56 can be expressed in normal immature granulocytes at a variety of expression levels in regenerative bone marrow. Attention should be paid when evaluating aberrant antigen expression of CD56 in granulocytes.

  15. TAK1 (MAP3K7 signaling regulates hematopoietic stem cells through TNF-dependent and -independent mechanisms.

    Directory of Open Access Journals (Sweden)

    Giichi Takaesu

    Full Text Available A cytokine/stress signaling kinase Tak1 (Map3k7 deficiency is known to impair hematopoietic progenitor cells. However, the role of TAK1 signaling in the stem cell function of the hematopoietic system is not yet well defined. Here we characterized hematopoietic stem cells (HSCs harboring deletion of Tak1 and its activators, Tak1 binding proteins 1 and 2 (Tab1 and Tab2 using a competitive transplantation assay in a mouse model. Tak1 single or Tab1/Tab2 double deletions completely eliminated the reconstitution activity of HSCs, whereas Tab1 or Tab2 single deletion did not cause any abnormality. Tak1 single or Tab1/Tab2 double deficient lineage-negative, Sca-1(+, c-Kit(+ (LSK cells did not proliferate and underwent cell death. We found that Tnfr1 deficiency restored the reconstitution activity of Tak1 deficient bone marrow cells for 6-18 weeks. However, the reconstitution activity of Tak1- and Tnfr1-double deficient bone marrow cells declined over the long term, and the number of phenotypically identified long-term hematopoietic stem cells were diminished. Our results indicate that TAB1- or TAB2-dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms: one is prevention of TNF-dependent cell death and the other is TNF-independent maintenance of long-term HSC.

  16. 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.

  17. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

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    Diez Cabezas, B.

    2015-07-01

    Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

  18. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type.

    Science.gov (United States)

    Silva, Leandro de Padua; Patah, Poliana A; Saliba, Rima M; Szewczyk, Nicholas A; Gilman, Lisa; Neumann, Joyce; Han, Xiang-Yang; Tarrand, Jeffrey; Ribeiro, Rachel; Gulbis, Alison; Shpall, Elizabeth J; Jones, Roy; Popat, Uday; Walker, Julia A; Petropoulos, Demetrios; Chiattone, Alexandre; Stewart, John; El-Zimaity, Maha; Anderlini, Paolo; Giralt, Sergio; Champlin, Richard E; de Lima, Marcos

    2010-07-01

    Hemorrhagic cystitis is a common cause of morbidity after allogeneic stem cell transplantation, frequently associated with BK virus infection. We hypothesized that patients with positive BK viruria before unrelated or mismatched related donor allogeneic hematopoietic stem cell transplantation have a higher incidence of hemorrhagic cystitis. To test this hypothesis, we prospectively studied 209 patients (median age 49 years, range 19-71) with hematologic malignancies who received bone marrow (n=78), peripheral blood (n=108) or umbilical cord blood (n=23) allogeneic hematopoietic stem cell transplantation after myeloablative (n=110) or reduced intensity conditioning (n=99). Donors were unrelated (n=201) or haploidentical related (n=8). Twenty-five patients developed hemorrhagic cystitis. Pre-transplant BK viruria detected by quantitative PCR was positive in 96 patients. The one-year cumulative incidence of hemorrhagic cystitis was 16% in the PCR-positive group versus 9% in the PCR-negative group (P=0.1). The use of umbilical cord blood or a haploidentical donor was the only significant predictor of the incidence of hemorrhagic cystitis on univariate analysis. There was also a trend for a higher incidence after myeloablative conditioning. Multivariate analysis showed that patients who had a positive PCR pre-transplant and received haploidentical or cord blood grafts with myeloablative conditioning had a significantly higher risk of developing hemorrhagic cystitis (58%) than all other recipients (7%, PHemorrhagic cystitis is the result of a complex interaction of donor type, preparative regimen intensity, and BK viruria.

  19. The rate of protein synthesis in hematopoietic stem cells is limited partly by 4E-BPs.

    Science.gov (United States)

    Signer, Robert A J; Qi, Le; Zhao, Zhiyu; Thompson, David; Sigova, Alla A; Fan, Zi Peng; DeMartino, George N; Young, Richard A; Sonenberg, Nahum; Morrison, Sean J

    2016-08-01

    Adult stem cells must limit their rate of protein synthesis, but the underlying mechanisms remain largely unexplored. Differences in protein synthesis among hematopoietic stem cells (HSCs) and progenitor cells did not correlate with differences in proteasome activity, total RNA content, mRNA content, or cell division rate. However, adult HSCs had more hypophosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2 as compared with most other hematopoietic progenitors. Deficiency for 4E-BP1 and 4E-BP2 significantly increased global protein synthesis in HSCs, but not in other hematopoietic progenitors, and impaired their reconstituting activity, identifying a mechanism that promotes HSC maintenance by attenuating protein synthesis. © 2016 Signer et al.; Published by Cold Spring Harbor Laboratory Press.

  20. Dpp dependent Hematopoietic stem cells give rise to Hh dependent blood progenitors in larval lymph gland of Drosophila.

    Science.gov (United States)

    Dey, Nidhi Sharma; Ramesh, Parvathy; Chugh, Mayank; Mandal, Sudip; Mandal, Lolitika

    2016-10-26

    Drosophila hematopoiesis bears striking resemblance with that of vertebrates, both in the context of distinct phases and the signaling molecules. Even though, there has been no evidence of Hematopoietic stem cells (HSCs) in Drosophila, the larval lymph gland with its Hedgehog dependent progenitors served as an invertebrate model of progenitor biology. Employing lineage-tracing analyses, we have now identified Notch expressing HSCs in the first instar larval lymph gland. Our studies clearly establish the hierarchical relationship between Notch expressing HSCs and the previously described Domeless expressing progenitors. These HSCs require Decapentapelagic (Dpp) signal from the hematopoietic niche for their maintenance in an identical manner to vertebrate aorta-gonadal-mesonephros (AGM) HSCs. Thus, this study not only extends the conservation across these divergent taxa, but also provides a new model that can be exploited to gain better insight into the AGM related Hematopoietic stem cells (HSCs).

  1. [Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease].

    Science.gov (United States)

    Hladun, R; Elorza, I; Olivé, T; Dapena, J L; Llort, A; Sánchez de Toledo, J; Díaz de Heredia, C

    2013-08-01

    The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival

  2. Immunophenotype of hematopoietic stem cells from placental/umbilical cord blood after culture

    Directory of Open Access Journals (Sweden)

    P. Pranke

    2005-12-01

    Full Text Available Identification and enumeration of human hematopoietic stem cells remain problematic, since in vitro and in vivo stem cell assays have different outcomes. We determined if the altered expression of adhesion molecules during stem cell expansion could be a reason for the discrepancy. CD34+CD38- and CD34+CD38+ cells from umbilical cord blood were analyzed before and after culture with thrombopoietin (TPO, FLT-3 ligand (FL and kit ligand (KL; or stem cell factor in different combinations: TPO + FL + KL, TPO + FL and TPO, at concentrations of 50 ng/mL each. Cells were immunophenotyped by four-color fluorescence using antibodies against CD11c, CD31, CD49e, CD61, CD62L, CD117, and HLA-DR. Low-density cord blood contained 1.4 ± 0.9% CD34+ cells, 2.6 ± 2.1% of which were CD38-negative. CD34+ cells were isolated using immuno-magnetic beads and cultured for up to 7 days. The TPO + FL + KL combination presented the best condition for maintenance of stem cells. The total cell number increased 4.3 ± 1.8-fold, but the number of viable CD34+ cells decreased by 46 ± 25%. On the other hand, the fraction of CD34+CD38- cells became 52.0 ± 29% of all CD34+ cells. The absolute number of CD34+CD38- cells was expanded on average 15 ± 12-fold when CD34+ cells were cultured with TPO + FL + KL for 7 days. The expression of CD62L, HLA-DR and CD117 was modulated after culture, particularly with TPO + FL + KL, explaining differences between the adhesion and engraftment of primary and cultured candidate stem cells. We conclude that culture of CD34+ cells with TPO + FL + KL results in a significant increase in the number of candidate stem cells with the CD34+CD38- phenotype.

  3. Changes in Antioxidant Defense System Using Different Lipid Emulsions in Parenteral Nutrition in Children after Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Baena-Gómez, María Auxiliadora; De La Torre Aguilar, María José; Mesa, María Dolores; Pérez Navero, Juan Luis; Gil-Campos, Mercedes

    2015-01-01

    Background: Traditionally, lipids used in parenteral nutrition (PN) are based on ω-6 fatty acid-rich vegetable oils, such as soybean oil, with potential adverse effects involving oxidative stress. Methods: We evaluated the antioxidant defense system in children, after hematopoietic stem cell transplantation (HSCT), who were randomized to use a lipid emulsion with fish oil or soybean oil. Blood samples at baseline, at 10 days, and at the end of the PN were taken to analyze plasma retinol, α-tocopherol, β-carotene, coenzyme Q9 and coenzyme Q10 levels, and catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPOX), and superoxide dismutase (SOD) levels in lysed erythrocytes. Results: An increase in plasma α-tocopherol levels in the group of patients receiving the fish oil-containing emulsion (FO) compared with the group receiving the soybean emulsion was observed at day 10 of PN. Concurrently, plasma α-tocopherol increased in the FO group and β-carotene decreased in both groups at day 10 compared with baseline levels, being more significant in the group receiving the FO emulsion. Conclusion: FO-containing emulsions in PN could improve the antioxidant profile by increasing levels of α-tocopherol in children after HSCT who are at higher risk of suffering oxidative stress and metabolic disorders. PMID:26343717

  4. Changes in Antioxidant Defense System Using Different Lipid Emulsions in Parenteral Nutrition in Children after Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    María Auxiliadora Baena-Gómez

    2015-08-01

    Full Text Available Background: Traditionally, lipids used in parenteral nutrition (PN are based on ω-6 fatty acid-rich vegetable oils, such as soybean oil, with potential adverse effects involving oxidative stress. Methods: We evaluated the antioxidant defense system in children, after hematopoietic stem cell transplantation (HSCT, who were randomized to use a lipid emulsion with fish oil or soybean oil. Blood samples at baseline, at 10 days, and at the end of the PN were taken to analyze plasma retinol, α-tocopherol, β-carotene, coenzyme Q9 and coenzyme Q10 levels, and catalase (CAT, glutathione reductase (GR, glutathione peroxidase (GPOX, and superoxide dismutase (SOD levels in lysed erythrocytes. Results: An increase in plasma α-tocopherol levels in the group of patients receiving the fish oil-containing emulsion (FO compared with the group receiving the soybean emulsion was observed at day 10 of PN. Concurrently, plasma α-tocopherol increased in the FO group and β-carotene decreased in both groups at day 10 compared with baseline levels, being more significant in the group receiving the FO emulsion. Conclusion: FO-containing emulsions in PN could improve the antioxidant profile by increasing levels of α-tocopherol in children after HSCT who are at higher risk of suffering oxidative stress and metabolic disorders.

  5. Generation of hematopoietic stem cells from human embryonic stem cells using a defined, stepwise, serum-free, and serum replacement-free monolayer culture method.

    Science.gov (United States)

    Kim, So-Jung; Jung, Ji-Won; Ha, Hye-Yeong; Koo, Soo Kyung; Kim, Eung-Gook; Kim, Jung-Hyun

    2017-03-01

    Embryonic stem cells (ESCs) can be expanded infinitely in vitro and have the potential to differentiate into hematopoietic stem cells (HSCs); thus, they are considered a useful source of cells for HSC production. Although several technical in vitro methods for engineering HSCs from pluripotent stem cells have been developed, clinical application of HSCs engineered from pluripotent stem cells is restricted because of the possibility of xenogeneic contamination resulting from the use of murine materials. Human ESCs (CHA-hES15) were cultured on growth factor-reduced Matrigel-coated dishes in the mTeSR1 serum-free medium. When the cells were 70% confluent, we initiated HSC differentiation by three methods involving (1) knockout serum replacement (KSR), cytokines, TGFb1, EPO, and FLT3L; (2) KSR, cytokines, and bFGF; or (3) cytokines and bFGF. Among the three differentiation methods, the minimal number of cytokines without KSR resulted in the greatest production of HSCs. The optimized method resulted in a higher proportion of CD34+CD43+ hematopoietic progenitor cells (HPCs) and CD34+CD45+ HPCs compared to the other methods. In addition, the HSCs showed the potential to differentiate into multiple lineages of hematopoietic cells in vitro. In this study, we optimized a two-step, serum-free, animal protein-free, KSR-free, feeder-free, chemically defined monolayer culture method for generation of HSCs and hematopoietic stem and progenitor cells (HSPCs) from human ESCs.

  6. The Effect of Folinic Acid on Methylenetetrahydrofolate Reductase Polymorphisms in Methotrexate-Treated Allogeneic Hematopoietic Stem Cell Transplants

    NARCIS (Netherlands)

    Murphy, Nicholas M.; Diviney, Mary; Szer, Jeff; Bardy, Peter; Grigg, Andrew; Hoyt, Rosemary; King-Kalimanis, Bellinda; Holdsworth, Rhonda; McCluskey, James; Tait, Brian D.

    2012-01-01

    This study examined the contribution single nucleotide polymorphisms (SNPs) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have on clinical outcomes in hematopoietic stem cell transplant patients treated with the antiproliferative drug methotrexate. Two common SNPs, 677C>T and 1298A>C,

  7. Subsets of CD34+ cells and rapid hematopoietic recovery after peripheral-blood stem-cell transplantation

    NARCIS (Netherlands)

    Dercksen, M. W.; Rodenhuis, S.; Dirkson, M. K.; Schaasberg, W. P.; Baars, J. W.; van der Wall, E.; Slaper-Cortenbach, I. C.; Pinedo, H. M.; von dem Borne, A. E.; van der Schoot, C. E.

    1995-01-01

    To study whether there is a relationship between transplanted cell dose and rate of hematopoietic recovery after peripheral-blood stem-cell (PBSC) transplantation, and to obtain an indication whether specific subsets of CD34+ cell populations contribute to rapid recovery of neutrophils or platelets.

  8. Physical exercise for patients undergoing hematopoietic stem cell transplantation: systematic review and meta-analyses of randomized controlled trials

    NARCIS (Netherlands)

    Haren, I.E.P.M.; Timmerman, H.; Potting, C.M.J.; Blijlevens, N.M.A.; Staal, J.B.; Nijhuis-Van der Sanden, M.W.G.

    2013-01-01

    BACKGROUND: The treatment-related burden for patients undergoing hematopoietic stem cell transplantation (HSCT) may be relieved by physical exercises. PURPOSE: The purpose of this study was to summarize and analyze the evidence provided by randomized controlled trials (RCTs) on physical exercise

  9. Psychosocial Changes Associated with Participation in Art Therapy Interventions for Siblings of Pediatric Hematopoietic Stem Cell Transplant Patients

    Science.gov (United States)

    Wallace, Jo; Packman, Wendy; Huffman, Lynne C.; Horn, Biljana; Cowan, Morton; Amylon, Michael D.; Kahn, Colleen; Cordova, Matt; Moses, Jim

    2014-01-01

    Hematopoietic stem cell transplantation (HSCT) is an accepted medical treatment for many serious childhood diseases. HSCT is a demanding procedure that creates both physical and emotional challenges for patients and their family members. Research has demonstrated that siblings of children undergoing HSCT are at risk for developing psychosocial…

  10. Natural killer cell differentiation from hematopoietic stem cells: a comparative analysis of heparin- and stromal cell-supported methods

    NARCIS (Netherlands)

    Dezell, S.A.; Ahn, Y.O.; Spanholtz, J.; Wang, H.; Weeres, M.; Jackson, S.; Cooley, S.; Dolstra, H.; Miller, J.S.; Verneris, M.R.

    2012-01-01

    Natural killer (NK) cells differentiated from hematopoietic stem cells (HSCs) may have significant clinical benefits over NK cells from adult donors, including the ability to choose alloreactive donors and potentially more robust in vivo expansion. Stromal-based methods have been used to study the

  11. Pericardial effusion and cardiac tamponade: clinical manifestation of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    David Cavalcanti Ferreira

    2014-04-01

    Full Text Available The authors report a case with pericardial effusion and cardiac tamponade as a rare clinical manifestation of chronic graft-versus-host disease in a young man with acute myelogenous leukemia submitted to an allogeneic hematopoietic stem cell transplantation from a related donor.

  12. Patient-Reported Measures of Hearing Loss and Tinnitus in Pediatric Cancer and Hematopoietic Stem Cell Transplantation: A Systematic Review

    Science.gov (United States)

    Stark, Daniel; Rosenberg, Abby R.; Johnston, Donna; Knight, Kristin; Caperon, Lizzie; Uleryk, Elizabeth; Frazier, A. Lindsay; Sung, Lillian

    2016-01-01

    Purpose: We identified studies that described use of any patient-reported outcome scale for hearing loss or tinnitus among children and adolescents and young adults (AYAs) with cancer or hematopoietic stem cell transplantation (HSCT) recipients. Method: In this systematic review, we performed electronic searches of OvidSP MEDLINE, EMBASE, and…

  13. Symptomatic BK Virus Infection Is Associated with Kidney Function Decline and Poor Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients

    Science.gov (United States)

    Abudayyeh, Ala; Hamdi, Amir; Lin, Heather; Abdelrahim, Maen; Rondon, Gabriela; Andersson, Borje S; Afrough, Aimaz; Martinez, Charles S; Tarrand, Jeffrey J; Kontoyiannis, Dimitrios P.; Marin, David; Gaber, A. Osama; Salahudeen, Abdulla; Oran, Betul; Chemaly, Roy F.; Olson, Amanda; Jones, Roy; Popat, Uday; Champlin, Richard E; Shpall, Elizabeth J.; Winkelmayer, Wolfgang C.; Rezvani, Katayoun

    2017-01-01

    Nephropathy due to BK virus infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation. We hypothesized that BKV infection was a marker of Kidney Function Decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic hematopoietic stem cell transplantation at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the CKD-EPI equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline and Fine and Gray’s method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic hematopoietic stem cell transplantation, BK viruria was detected in 25% (n=629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease, chronic graft versus host disease, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (P <0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. Post-allogeneic hematopoietic stem cell transplantation, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT. PMID:26608093

  14. The Ly-6A (Sca-1) GFP transgene is expressed in all adult mouse hematopoietic stem cells

    NARCIS (Netherlands)

    X. Ma (Xiaoqian); C.I. Robin; K. Ottersbach (Katrin); E.A. Dzierzak (Elaine)

    2002-01-01

    textabstractThe Sca-1 cell surface glycoprotein is used routinely as a marker of adult hematopoietic stem cells (HSCs), allowing a >100-fold enrichment of these rare cells from the bone marrow of the adult mouse. The Sca-1 protein is encoded by the Ly-6A/E gene, a small 4-exon gene

  15. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial

    NARCIS (Netherlands)

    Laar, J.M. van; Farge, D.; Sont, J.K.; Naraghi, K.; Marjanovic, Z.; Larghero, J.; Schuerwegh, A.J.; Marijt, E.W.; Vonk, M.C.; Schattenberg, A.V.M.B.; Matucci-Cerinic, M.; Voskuyl, A.E.; Loosdrecht, A.A. van de; Daikeler, T.; Kotter, I.; Schmalzing, M.; Martin, T.; Lioure, B.; Weiner, S.M.; Kreuter, A.; Deligny, C.; Durand, J.M.; Emery, P.; Machold, K.P.; Sarrot-Reynauld, F.; Warnatz, K.; Adoue, D.F.; Constans, J.; Tony, H.P.; Papa, N. Del; Fassas, A.; Himsel, A.; Launay, D. de; Monaco, A. Lo; Philippe, P.; Quere, I.; Rich, E.; Westhovens, R.; Griffiths, B.; Saccardi, R.; Hoogen, F.H.J. van den; Fibbe, W.E.; Socie, G.; Gratwohl, A.; Tyndall, A.

    2014-01-01

    IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of

  16. Impact of genomic risk factors on outcome after hematopoietic stem cell transplantation for patients with chronic myeloid leukemia.

    NARCIS (Netherlands)

    Dickinson, A.M.; Pearce, K.F.; Norden, J.; O'Brien, S.G.; Holler, E.; Bickeboller, H.; Balavarca, Y.; Rocha, V.; Kolb, H.J.; Hromadnikova, I.; Sedlacek, P.; Niederwieser, D.; Brand, R.; Ruutu, T.; Apperley, J.; Szydlo, R.; Goulmy, E.; Siegert, W.; Witte, T.J.M. de; Gratwohl, A.

    2010-01-01

    BACKGROUND: Non-HLA gene polymorphisms have been shown to influence outcome after allogeneic hematopoietic stem cell transplantation. Results were derived from heterogeneous, small populations and their value remains a matter of debate. DESIGN AND METHODS: In this study, we assessed the effect of

  17. Concise Review: Hematopoietic Stem Cell Origins: Lessons from Embryogenesis for Improving Regenerative Medicine.

    Science.gov (United States)

    De La Garza, Adriana; Sinha, Arpan; Bowman, Teresa V

    2017-01-01

    Hematopoietic stem cells (HSCs) have extensive regenerative capacity to replace all blood cell types, an ability that is harnessed in the clinic for bone marrow transplantation. Finding appropriate donors remains a major limitation to more extensive usage of HSC-based therapies. Derivation of patient-specific HSCs from pluripotent stem cells offers great promise to remedy this problem if scientists could crack the code on how to make robust, transplantable HSCs in a dish. Studies delving into the native origins of HSC production during embryonic development should supply the necessary playbook. This review presents recent discoveries from animal models, with a focus on zebrafish, and discusses the implications of these new advances in the context of prior knowledge. The focus is on the latest research exploring the role of epigenetic regulation, signaling pathways, and niche components needed for proper HSC formation. These studies provide new directions that should be explored for de novo generation and expansion of HSCs for regenerative therapies. Stem Cells Translational Medicine 2017;6:60-67. © 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  18. Subsequent vitiligo after hematopoietic stem cell transplantation: A nationwide population-based cohort study from Korea.

    Science.gov (United States)

    Bae, Jung Min; Choi, Kwang Hyun; Jung, Han Mi; Kim, Sook Young; Kim, Miri; Kim, Gyung Moon; Yu, Dong Soo; Lee, Young Bok

    2017-03-01

    Subsequent vitiligo after hematopoietic stem cell transplantation (HSCT) has been described sporadically in case series. To investigate the incidence and risk factors of subsequent vitiligo after HSCT. A nationwide, population-based cohort study was performed using the Korean National Health Insurance Claims Database from 2009 to 2013. All HSCT recipients who had undergone HSCT between 2010 and 2011 and not treatment for vitiligo in 2009 (to exclude preexisting active vitiligo) were included in the HSCT recipient group, and an age- and sex-matched control group without HSCT was also established. A total of 2747 HSCT recipients and 8241 controls were enrolled. Newly acquired vitiligo occurred in 1.06% of HSCT recipients between 2010 and 2013, and there was a significant increase (OR 3.130, 95% CI 1.859-5.271) in cases of vitiligo in HSCT recipients compared with controls (0.34%). Allogeneic HSCT (OR 5.593, 95% CI 1.628-19.213) and bone marrow-sourced stem cells (as compared with peripheral blood-sourced stem cells; OR 2.492, 95% CI 1.114-5.576) were independently associated with the development of vitiligo after HSCT. Medical record review was not available. Vitiligo developed at a significantly increased rate after HSCT compared with controls. Allogeneic HSCT and bone marrow-sourced stem cells were independent risk factors. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  19. Hematopoietic stem cells improve dopaminergic neuron in the MPTP-mice.

    Science.gov (United States)

    Lu, Jingwei; Kanji, Suman; Aggarwal, Reeva; Das, Manjusri; Joseph, Matthew; Wu, Lai-Chu; Mao, Hai-Quan; Pompili, Vincent J; Hadjiconstantinou, Maria; Das, Hiranmoy

    2013-06-01

    Because of their ability for self-renewal and neural differentiation, stem cells are believed to be ideal for cell replacement therapy in Parkinson's disease (PD). Nanofiber-expanded human umbilical cord hematopoietic stem cells (HUHSCs) are advantageous to other stem cells as they provide a source of unlimited stem cell production for clinical application. In this study, we investigated whether 1. nanofiber-expanded HUHSCs are capable of neural differentiation in vitro, and 2. they could improve dopaminergic neuron morphology in the caudate/putamen (CPu) and substantia nigra pars compacta (SNc) of the MPTP-mouse model of PD. When cultured under neural differentiation conditions, nanofiber-expanded HUHSCs were able to undergo neural differentiation in vitro, as determined by gene and protein expression of neural markers such as MAP2, NeuN, HuC, GFAP and Oligo2. Thirty days after a single intracardioventricular injection of HUHSCs to MPTP-mice there was a significant recovery of tyrosine hydroxylase (TH) immunostaining in CPu. There was an increase in the size and staining density of TH+ cells in SNc, while their number was unchanged.

  20. [Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain].

    Science.gov (United States)

    Hladun, R; Badell, I; González, M; Martínez, A M; Sánchez de Toledo, J; Olivé, M T; González, M E; Elorza, I; Díaz de Heredia, C

    2015-02-01

    Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option. Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children. One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days - 168 months) and the median patient age at transplant was 12 months (range: 1 month - 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem cells was bone marrow in 68 (43%), cord blood in 52 (33%), and peripheral blood in 39 (24%). Ninety eight (61.6%) are alive, 57 (35.9%) died. Event-free survival at 10 years was 63%, with 90% for children transplanted from identical siblings, 36% for those transplanted from alternative family donors, and 66% for those transplanted from unrelated donors. The best results have been obtained with identical siblings, but other options may be considered. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  1. Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia.

    Science.gov (United States)

    Gadalla, Shahinaz M; Wang, Tao; Dagnall, Casey; Haagenson, Michael; Spellman, Stephen R; Hicks, Belynda; Jones, Kristine; Katki, Hormuzd A; Lee, Stephanie J; Savage, Sharon A

    2016-12-01

    We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages survival, but further analysis identified differences by recipient age and stem cell source as the likely explanation. In patients survival benefit only in <40-year-old patients receiving bone marrow graft (HR comparing longest and middle RTL tertiles with shortest = .69; 95% CI, .50 to .95, P = .02). The study suggested that the association between donor RTL and post-HCT outcomes in recipients with SAA may vary by recipient age and stem cell source. A larger study is needed to account for multiple comparisons and to further test the generalizability of our findings. Published by Elsevier Inc.

  2. Biosimilar G-CSF versus filgrastim and lenograstim in healthy unrelated volunteer hematopoietic stem cell donors.

    Science.gov (United States)

    Farhan, Roiya; Urbanowska, Elżbieta; Zborowska, Hanna; Król, Małgorzata; Król, Maria; Torosian, Tigran; Piotrowska, Iwona; Bogusz, Krzysztof; Skwierawska, Kamila; Wiktor-Jędrzejczak, Wiesław; Snarski, Emilian

    2017-10-01

    The World Marrow Donor Organization recommends original granulocyte-colony stimulating factor (G-CSF) for the mobilization of stem cells in healthy unrelated hematopoietic stem cell donors. We report the comparison of a biosimilar G-CSF (Zarzio) with two original G-CSFs (filgrastim and lenograstim) in mobilization in unrelated donors. We included data of 313 consecutive donors who were mobilized during the period from October 2014 to March 2016 at the Medical University of Warsaw. The primary endpoints of this study were the efficiency of CD34+ cell mobilization to the circulation and results of the first apheresis. The mean daily dose of G-CSF was 9.1 μg/kg for lenograstim, 9.8 μg/kg for biosimilar filgrastim, and 9.3 μg/kg for filgrastim (p donors mobilized with lenograstim and in 93% donors mobilized with original and biosimilar filgrastim (p = 0.005). The mobilized apheresis outcomes (mean number of CD34+ cells/kg of donor collected during the first apheresis) was similar with lenograstim, biosimilar filgrastim, and filgrastim: 6.2 × 106, 7.6 × 106, and 7.3 × 106, respectively, p = 0.06. There was no mobilization failure in any of the donors. Biosimilar G-CSF is as effective in the mobilization of hematopoietic stem cells in unrelated donors as original G-CSFs. Small and clinically irrelevant differences seen in the study can be attributed to differences in G-CSF dose and collection-related factors. Active safety surveillance concurrent to clinical use and reporting to donor outcome registry (e.g., EBMT donor outcome registry or WMDA SEAR/SPEAR) might help to evaluate the possible short- and long-term complications of biosimilar G-CSF.

  3. Infections Caused by Nontuberculous Mycobacteria in Recipients of Hematopoietic Stem Cell Transplantation

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    Khalid Ahmed Al-Anazi

    2014-11-01

    Full Text Available Nontuberculous mycobacteria (NTM are acid-fast bacteria that are ubiquitous in the environment and can colonize soil, dust particles, water sources and food supplies. They are divided into rapidly growing mycobacteria such as Mycobacterium fortuitum, Mycobacterium chelonae and Mycobacterium abscessus as well as slowly growing species such as Mycobacterium avium, Mycobacterium kansasii and Mycobacterium marinum. About 160 different species, which can cause community acquired and health care-associated infections, have been identified. NTM are becoming increasingly recognized in recipients of hematopoietic stem cell transplantation with incidence rates ranging between 0.4% and 10%. These infections are 50 to 600 times commoner in transplant recipients than in the general population and the time of onset ranges from day 31 to day 1055 post-transplant. They have been reported following various forms of hematopoietic stem cell transplantation. Several risk factors predispose to NTM infections in recipients of stem cell transplantation and these are related to the underlying medical condition and its treatment, the pre-transplant conditioning therapies as well as the transplant procedure and its complications. Clinically, NTM may present with: unexplained fever, lymphadenopathy, osteomyelitis, soft tissue and skin infections, central venous catheter infections, bacteremia, lung and gastrointestinal tract involvement. However, disseminated infections are commonly encountered in severely immunocompromised individuals and bloodstream infections are almost always associated with catheter-related infections. It is usually difficult to differentiate colonization from true infection, thus the threshold for starting therapy remains undetermined. Respiratory specimens such as sputum, pleural fluid and bronchoalveolar lavage in addition to cultures of blood, bone, skin and soft tissues are essential diagnostically. Susceptibility testing of mycobacterial

  4. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.

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    Mortera-Blanco, Teresa; Dimitriou, Marios; Woll, Petter S; Karimi, Mohsen; Elvarsdottir, Edda; Conte, Simona; Tobiasson, Magnus; Jansson, Monika; Douagi, Iyadh; Moarii, Matahi; Saft, Leonie; Papaemmanuil, Elli; Jacobsen, Sten Eirik W; Hellström-Lindberg, Eva

    2017-08-17

    Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal (SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. © 2017 by The American Society of Hematology.

  5. Constitutive Expression of Inducible Cyclic Adenosine Monophosphate Early Repressor (ICER) in Cycling Quiescent Hematopoietic Cells: Implications for Aging Hematopoietic Stem Cells.

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    Greco, Steven J; Yehia, Ghassan; Potian, Julius A; Molina, Carlos A; Rameshwar, Pranela

    2017-02-01

    Despite extensive insights on the interaction between hematopoietic stem cells (HSCs) and the supporting bone marrow (BM) stroma in hematopoietic homeostasis there remains unanswered questions on HSC regulation. We report on the mechanism by which HSCs attain cycling quiescence by addressing a role for inducible cyclic AMP early repressor (ICER). ICER negatively transcriptional regulators of cAMP activators such as CREM and CREB. These activators can be induced by hematopoietic stimulators such as cytokines. We isolated subsets of hematopoietic cells from ten healthy donors: CD34(+)CD38(-)/c-kit (+) (primitive progenitor), CD34(+)CD38(+)/c-kit(low) (mature progenitor) and CD34(-)CD38(+/-)/c-kit(low/-) (differentiated lineage-). The relative maturity of the progenitors were verified in long-term culture initiating assay. Immunoprecipitation indicated the highest level of ICER in the nuclear extracts of CD34(+)/CD38(-) cells. Phospho (p)-CREM was also present suggesting a balance between ICER and p-CREM in HSC. ICER seems to be responsible for decrease in G1 transition, based on reduced Cdk4 protein, decreased proliferation and functional studies with propidium iodide. There were no marked changes in the cycling inhibitors, p15 and p-Rb, suggesting that ICER may act independently of other cycling inhibitors. The major effects of ICER were validated with BM mononuclear cells (BMNCs) in which ICER was ectopically expressed, and with BMNCs resistant to 5-fluorouracil- or cyclophosphamide. In total, this study ascribes a novel role for ICER in G1 checkpoint regulation in HSCs. These findings are relevant to gene therapy that require engineering of HSCs, age-related disorders that are associated with hematopoietic dysfunction and other hematological disorders.

  6. Angelica Sinensis Polysaccharide Prevents Hematopoietic Stem Cells Senescence in D-Galactose-Induced Aging Mouse Model

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    Xinyi Mu

    2017-01-01

    Full Text Available Age-related regression in hematopoietic stem/progenitor cells (HSC/HPCs limits replenishment of the blood and immune system and hence contributes to hematopoietic diseases and declined immunity. In this study, we employed D-gal-induced aging mouse model and observed the antiaging effects of Angelica Sinensis Polysaccharide (ASP, a major active ingredient in dong quai (Chinese Angelica Sinensis, on the Sca-1+ HSC/HPCs in vivo. ASP treatment prevents HSC/HPCs senescence with decreased AGEs levels in the serum, reduced SA-β-Gal positive cells, and promoted CFU-Mix formation in the D-gal administrated mouse. We further found that multiple mechanisms were involved: (1 ASP treatment prevented oxidative damage as total antioxidant capacity was increased and levels of reactive oxygen species (ROS, 8-OHdG, and 4-HNE were declined, (2 ASP reduced the expression of γ-H2A.X which is a DNA double strand breaks (DSBs marker and decreased the subsequent ectopic expressions of effectors in p16Ink4a-RB and p19Arf-p21Cip1/Waf senescent pathways, and (3 ASP inhibited the excessive activation of Wnt/β-catenin signaling in aged HSC/HPCs, as the expressions of β-catenin, phospho-GSK-3β, and TCF-4 were decreased, and the cyto-nuclear translocation of β-catenin was inhibited. Moreover, compared with the positive control of Vitamin E, ASP exhibited a better antiaging effect and a weaker antioxidation ability, suggesting a novel protective role of ASP in the hematopoietic system.

  7. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

    Science.gov (United States)

    Imanirad, Parisa; Kartalaei, Parham Solaimani; Crisan, Mihaela; Vink, Chris; Yamada-Inagawa, Tomoko; de Pater, Emma; Kurek, Dorota; Kaimakis, Polynikis; van der Linden, Reiner; Speck, Nancy; Dzierzak, Elaine

    2014-01-01

    Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC) function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α), a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver), and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO) approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPC) are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPC and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages. PMID:24141110

  8. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

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    Parisa Imanirad

    2014-01-01

    Full Text Available Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α, a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver, and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPCs are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPCs and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages.

  9. BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo.

    Science.gov (United States)

    Crisan, Mihaela; Solaimani Kartalaei, Parham; Neagu, Alex; Karkanpouna, Sofia; Yamada-Inagawa, Tomoko; Purini, Caterina; Vink, Chris S; van der Linden, Reinier; van Ijcken, Wilfred; Chuva de Sousa Lopes, Susana M; Monteiro, Rui; Mummery, Christine; Dzierzak, Elaine

    2016-03-08

    Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo

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    Mihaela Crisan

    2016-03-01

    Full Text Available Hematopoietic stem cells (HSC, the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment.

  11. Predicting clonal self-renewal and extinction of hematopoietic stem cells.

    Science.gov (United States)

    Sieburg, Hans B; Rezner, Betsy D; Muller-Sieburg, Christa E

    2011-03-15

    A single hematopoietic stem cell (HSC) can generate a clone, consisting of daughter HSCs and differentiated progeny, which can sustain the hematopoietic system of multiple hosts for a long time. At the same time, this massive expansion potential must be restrained to prevent abnormal, leukemic proliferation. We used an interdisciplinary approach, combining transplantation assays with mathematical and computational methods, to systematically analyze the proliferative potential of individual HSCs. We show that all HSC clones examined have an intrinsically limited life span. Daughter HSCs within a clone behaved synchronously in transplantation assays and eventually exhausted at the same time. These results indicate that each HSC is programmed to have a finite life span. This program and the memory of the life span of the mother HSC are inherited by all daughter HSCs. In contrast, there was extensive heterogeneity in life spans between individual HSC clones, ranging from 10 to almost 60 mo. We used model-based machine learning to develop a mathematical model that efficiently predicts the life spans of individual HSC clones on the basis of a few initial measurements of donor type cells in blood. Computer simulations predict that the probability of self-renewal decays with a logistic kinetic over the life span of a normal HSC clone. Other decay functions lead to either graft failure or leukemic proliferation. We propose that dynamical fate probabilities are a crucial condition that leads to self-limiting clonal proliferation.

  12. Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

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    Anja Geiselhart

    2012-01-01

    Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.

  13. A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche.

    Science.gov (United States)

    Charbord, Pierre; Pouget, Claire; Binder, Hans; Dumont, Florent; Stik, Grégoire; Levy, Pacifique; Allain, Fabrice; Marchal, Céline; Richter, Jenna; Uzan, Benjamin; Pflumio, Françoise; Letourneur, Franck; Wirth, Henry; Dzierzak, Elaine; Traver, David; Jaffredo, Thierry; Durand, Charles

    2014-09-04

    Despite progress in identifying the cellular composition of hematopoietic stem/progenitor cell (HSPC) niches, little is known about the molecular requirements of HSPC support. To address this issue, we used a panel of six recognized HSPC-supportive stromal lines and less-supportive counterparts originating from embryonic and adult hematopoietic sites. Through comprehensive transcriptomic meta-analyses, we identified 481 mRNAs and 17 microRNAs organized in a modular network implicated in paracrine signaling. Further inclusion of 18 additional cell strains demonstrated that this mRNA subset was predictive of HSPC support. Our gene set contains most known HSPC regulators as well as a number of unexpected ones, such as Pax9 and Ccdc80, as validated by functional studies in zebrafish embryos. In sum, our approach has identified the core molecular network required for HSPC support. These cues, along with a searchable web resource, will inform ongoing efforts to instruct HSPC ex vivo amplification and formation from pluripotent precursors. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Generation and Characterization of Anti-CD34 Monoclonal Antibodies that React with Hematopoietic Stem Cells.

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    Aghebati Maleki, Leili; Majidi, Jafar; Baradaran, Behzad; Movassaghpour, Aliakbar; Abdolalizadeh, Jalal

    2014-01-01

    CD34 is a type I membrane protein with a molecular mass of approximately 110 kDa. This antigen is associated with human hematopoietic progenitor cells and is a differentiation stage-specific leukocyte antigen. In this study we have generated and characterized monoclonal antibodies (mAbs) directed against a CD34 marker. Mice were immunized with two keyhole lympet hemocyanin (KLH)-conjugated CD34 peptides. Fused cells were grown in hypoxanthine, aminopterine and thymidine (HAT) selective medium and cloned by the limiting dilution (L.D) method. Several monoclones were isolated by three rounds of limited dilutions. From these, we chose stable clones that presented sustained antibody production for subsequent characterization. Antibodies were tested for their reactivity and specificity to recognize the CD34 peptides and further screened by enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. One of the mAbs (3D5) was strongly reactive against the CD34 peptide and with native CD34 from human umbilical cord blood cells (UCB) in ELISA and Western blotting analyses. The results have shown that this antibody is highly specific and functional in biomedical applications such as ELISA and Western blot assays. This monoclonal antibodies (mAb) can be a useful tool for isolation and purification of human hematopoietic stem cells (HSCs).

  15. Cytokine-Regulated GADD45G Induces Differentiation and Lineage Selection in Hematopoietic Stem Cells

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    Frederic B. Thalheimer

    2014-07-01

    Full Text Available The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC must be strictly controlled to maintain blood homeostasis and to prevent leukemogenesis. Hematopoietic cytokines can induce differentiation in LT-HSCs; however, the molecular mechanism orchestrating this delicate balance requires further elucidation. We identified the tumor suppressor GADD45G as an instructor of LT-HSC differentiation under the control of differentiation-promoting cytokine receptor signaling. GADD45G immediately induces and accelerates differentiation in LT-HSCs and overrides the self-renewal program by specifically activating MAP3K4-mediated MAPK p38. Conversely, the absence of GADD45G enhances the self-renewal potential of LT-HSCs. Videomicroscopy-based tracking of single LT-HSCs revealed that, once GADD45G is expressed, the development of LT-HSCs into lineage-committed progeny occurred within 36 hr and uncovered a selective lineage choice with a severe reduction in megakaryocytic-erythroid cells. Here, we report an unrecognized role of GADD45G as a central molecular linker of extrinsic cytokine differentiation and lineage choice control in hematopoiesis.

  16. Expansion and homing of umbilical cord blood hematopoietic stem and progenitor cells for clinical transplantation.

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    Bari, Sudipto; Seah, Kevin Kwee Hong; Poon, Zhiyong; Cheung, Alice Man Sze; Fan, Xiubo; Ong, Shin-Yeu; Li, Shang; Koh, Liang Piu; Hwang, William Ying Khee

    2015-06-01

    The successful expansion of hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood (UCB) for transplantation could revolutionize clinical practice by improving transplantation-related outcomes and making available UCB units that have suboptimal cell doses for transplantation. New cytokine combinations appear able to promote HSPC growth with minimal differentiation into mature precursors and new agents, such as insulin-like growth factor-binding protein 2, are being used in clinical trials. Molecules that simulate the HSPC niche, such as Notch ligand, have also shown promise. Further improvements have been made with the use of mesenchymal stromal cells, which have made possible UCB expansion without a potentially deleterious prior CD34/CD133 cell selection step. Chemical molecules, such as copper chelators, nicotinamide, and aryl hydrocarbon antagonists, have shown excellent outcomes in clinical studies. The use of bioreactors could further add to HSPC studies in future. Drugs that could improve HSPC homing also appear to have potential in improving engraftment times in UCB transplantation. Technologies to expand HSPC from UCB and to enhance the homing of these cells appear to have attained the goal of accelerating hematopoietic recovery. Further discoveries and clinical studies are likely to make the goal of true HSPC expansion a reality for many applications in future. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Increasing Hematopoietic Stem Cell Yield to Develop Mice with Human Immune Systems

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    Juan-Carlos Biancotti

    2013-01-01

    Full Text Available Hematopoietic stem cells (HSCs are unique in their capacity to give rise to all mature cells of the immune system. For years, HSC transplantation has been used for treatment of genetic and neoplastic diseases of the hematopoietic and immune systems. The sourcing of HSCs from human umbilical cord blood has salient advantages over isolation from mobilized peripheral blood. However, poor sample yield has prompted development of methodologies to expand HSCs ex vivo. Cytokines, trophic factors, and small molecules have been variously used to promote survival and proliferation of HSCs in culture, whilst strategies to lower the concentration of inhibitors in the culture media have recently been applied to promote HSC expansion. In this paper, we outline strategies to expand HSCs in vitro, and to improve engraftment and reconstitution of human immune systems in immunocompromised mice. To the extent that these “humanized” mice are representative of the endogenous human immune system, they will be invaluable tools for both basic science and translational medicine.

  18. Hematopoietic Stem and Progenitor Cells Can Be Enriched by Implanting Biomaterial into Spatium Intermusculare

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    Jia-Bei Tong

    2015-01-01

    Full Text Available Hematopoietic stem and progenitor cells (HSPCs have been used successfully to treat patients with cancer and disorders of the blood and immune systems. In this study, we tried to enrich HSPCs by implanting biomaterials into the spatium intermusculare of mice hind limbs. Gelatine sponges were implanted into the spatium intermusculare of mice and then retrieved after 12 days. The presence of HSPCs in the migrating cells (MCs was detected by phenotypically probing with CD34+Sca-1+ and functionally confirming the presence of using colony-forming cell assay and assessing the long-term reconstitution ability. The frequency of CD34+, Sca-1+, and CD34+Sca-1+ cells and colony formation unit in the MCs was much higher than that in the bone marrow (BM. Moreover, transplanted MCs were able to home to BM, muscle, and spleen, which induced an efficient long-term hematopoietic reconstitution in vivo. In addition, HSPCs within the MCs originated from the BM. Furthermore, the administration of G-CSF greatly reduced the time of implantation, and increased the number of MCs and frequency of HSPCs in the MCs. These data provide compelling evidence that HSPCs can be enriched by implanting biomaterial into spatium intermusculare. Implantation of biomaterial may be seen as the first step to a proof of their applicability to clinical practice in enriching HSPCs.

  19. High Levels of Canonical Wnt Signaling Lead to Loss of Stemness and Increased Differentiation in Hematopoietic Stem Cells

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    Farbod Famili

    2016-05-01

    Full Text Available Canonical Wnt signaling regulates the self-renewal of most if not all stem cell systems. In the blood system, the role of Wnt signaling has been the subject of much debate but there is consensus that high Wnt signals lead to loss of reconstituting capacity. To better understand this phenomenon, we have taken advantage of a series of hypomorphic mutant Apc alleles resulting in a broad range of Wnt dosages in hematopoietic stem cells (HSCs and performed whole-genome gene expression analyses. Gene expression profiling and functional studies show that HSCs with APC mutations lead to high Wnt levels, enhanced differentiation, and diminished proliferation but have no effect on apoptosis, collectively leading to loss of stemness. Thus, we provide mechanistic insight into the role of APC mutations and Wnt signaling in HSC biology. As Wnt signals are explored in various in vivo and ex vivo expansion protocols for HSCs, our findings also have clinical ramifications.

  20. Response of hematopoietic stem cells to ionizing radiation; Reponse des cellules souches hematopoitiques aux radiations ionisantes

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    Simonnet, A

    2008-12-15

    Hematopoietic stem cells (HSCs) maintain blood and immune system throughout life and restore them after hematological injuries. Exposure of an organism to ionizing radiation (IR) causes rapid and acute myelosuppression and challenges the replenishment capacity of HSCs. Yet, the precise damages that are generated remain largely unexplored. To better understand these effects, phenotypic and functional changes in the stem/progenitor compartments of sublethally irradiated mice were monitored over a ten week period after radiation exposure. We report that shortly after sublethal IR-exposure, HSCs, defined by their repopulating ability, still segregate in the Hoechst dye excluding side population (SP); yet, their Sca-1 (S) and c-Kit (K) expression levels are increased and severely reduced, respectively, with a concurrent increase in the proportion of SP{sup SK} cells positive for established indicators of HSC presence: CD150{sup +} and CD105{sup +}. A great proportion of HSCs quickly but transiently enter the cell cycle to replenish the bone marrow of myelo-ablated mice. Ten weeks after, whereas bone marrow cellularity has recovered and hematopoietic homeostasis is restored, major phenotypic modifications can be observed within the Lin{sup -/low} Sca-1{sup +} c-Kit{sup +} (LSK) stem/progenitor compartment: CD150{sup +}/Flk2{sup -} and CD150{sup -}/Flk2{sup +} LSK cell frequencies are increased and dramatically reduced, respectively. CD150{sup +} LSK cells also show impaired reconstitution capacity, accrued number of {gamma}-H2AX foci and increased tendency to apoptosis. This demonstrates that the LSK compartment is not properly restored 10 weeks after sublethal exposure, and that long-term IR-induced injury to the bone marrow proceeds, at least partially, through direct damage to the stem cell pool. Thrombopoietin (TPO) has been shown to promote the survival of lethally irradiated mice when administrated quickly after exposure. We investigated the mechanisms underlying