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Sample records for autologous hematopoietic stem

  1. Autologous hematopoietic stem cell transplantation for autoimmune diseases.

    NARCIS (Netherlands)

    Gratwohl, A.; Passweg, J.R.; Bocelli-Tyndall, C.; Fassas, A.; Laar, J.M. van; Farge, D.; Andolina, M.; Arnold, R.; Carreras, E.; Finke, J.; Kotter, I.; Kozak, T.; Lisukov, I.; Lowenberg, B.; Marmont, A.; Moore, J.; Saccardi, R.; Snowden, J.A.; Hoogen, F.H.J. van den; Wulffraat, N.M.; Zhao, X.; Tyndall, A.

    2005-01-01

    Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune

  2. Herpes zoster after autologous hematopoietic stem cell transplantation

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    Kelli Borges dos Santos

    Full Text Available ABSTRACT Background: The autologous hematopoietic stem cell transplantation procedure involves immunosuppression of the patient. Thus, the patient has an elevated risk for several diseases, such as infections with the varicella-zoster virus. Prevention protocols have been proposed based on the use of acyclovir from the first day of conditioning, and maintaining this drug for 30-100 days after the procedure or for as much as one year. The objective of this work was to evaluate the incidence of herpes zoster after autologous transplantations related to the early suspension of acyclovir. Methods: A retrospective study was carried out based on the collection of data from 231 medical records of transplant patients in the Bone Marrow Transplant Unit of the teaching hospital of the Universidade Federal de Juiz de Fora in the period between 2004 and 2014. Results: Fourteen (6.1% patients had herpes zoster in the post-transplant period on average within six months of the procedure. Patients with multiple myeloma (64.3% were the most affected. There was a statistically significant difference in the age of the patients, with older individuals having a greater chance of developing the infection (p-value = 0.002. There were no significant differences for the other variables analyzed. Conclusion: The early suspension of acyclovir can be safe in patients who receive autologous hematopoietic stem cell transplants. However some groups may benefit from extended prophylaxis with acyclovir, particularly older patients and patients with multiple myeloma.

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

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    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

  4. Autologous hematopoietic stem cells for refractory Crohn's disease.

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    DiNicola, C A; Zand, A; Hommes, D W

    2017-05-01

    Autologous hematopoietic stem cells are gaining ground as an effective and safe treatment for treating severe refractory Crohn's disease (CD). Autologous hematopoietic stem cell therapy (AHSCT) induces resetting of the immune system by de novo regeneration of T-cell repertoire and repopulation of epithelial cells by bone-marrow derived cells to help patients achieve clinical and endoscopic remission. Areas covered: Herein, the authors discuss the use of AHSCT in treating patients with CD. Improvements in disease activity have been seen in patients with severe autoimmune disease and patients with severe CD who underwent AHSCT for a concomitant malignant hematological disease. Clinical and endoscopic remission has been achieved in patients treated with AHSCT for CD. The only randomized trial published to date, the ASTIC Trial, did not support further use of AHSCT to treat CD. Yet, critics of this trial have deemed AHSCT as a promising treatment for severe refractory CD. Expert opinion: Even with the promising evidence presented for HSCT for refractory CD, protocols need to be refined through the collaboration of GI and hemato-oncology professionals. The goal is to incorporate safe AHSCT and restore tolerance by delivering an effective immune 'cease fire' as a treatment option for severe refractory CD.

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

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    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.

  6. IMMUNE STATE IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES AT LATE TERMS AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION

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    N. V. Minaeva

    2012-01-01

    Full Text Available Abstract. Autologous hematopoietic stem cell transplantation (auto-HSCT is one of the most effective methods for treatment of patients with various forms of hemoblastoses, both in adults and children. However, high-dose chemotherapy protocols used in this procedure are characterized by pronounced myeloand immunotoxicity. Appropriate data concerning immune state at long terms after high-dose chemotherapy and auto-HSCT are sparse and controversial, and there is no consensus on time dynamics of immune system reconstitution. The aim of this study was a comprehensive evaluation of immunity in recipients of auto-HSCT at longer terms. Clinical and immunological testing was performed in ninety-eight patients with hematological malignancies before starting a high-dose chemotherapy, and at late post-transplant period. The state of cellular immunity was assessed as expression of surface CD3+, CD4+, CD8+, CD16+, CD19+ lymphocyte antigens. Humoral immunity was evaluated by serum IgG, IgA, and IgM levels. The studies have revealed disorders of cellular and humoral immunity, as well as nonspecific immune resistance factors in recipients of autologous hematopoietic stem cells at late terms post-transplant. Immune reconstitution in patients receiving highdose consolidation treatment followed by auto-HSCT takes longer time than in patients who did not receive autologous hematopoietic stem cells. Severity of these disturbances and immune reconstitution rates depend on the type of conditioning regimen, and the source of haematopoietic stem cells used for transplantation.

  7. Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma.

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    Nair, Velu; Sharma, Ajay; Sharma, Sanjeevan; Das, Satyaranjan; Bhakuni, Darshan S; Narayanan, Krishnan; Nair, Vivek; Shankar, Subramanian

    2015-03-01

    Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

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

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    Sevgisun Kapucu

    2014-01-01

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

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

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    Thissiane L. Gonçalves

    2009-01-01

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

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

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    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.

  11. 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.; et al.,

    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

  12. Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation.

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    Woolthuis, Carolien M; Mariani, Niccoló; Verkaik-Schakel, Rikst Nynke; Brouwers-Vos, Annet Z; Schuringa, Jan Jacob; Vellenga, Edo; de Wolf, Joost T M; Huls, Gerwin

    2014-06-01

    Most of our knowledge of the effects of aging on the hematopoietic system comes from studies in animal models. In this study, to explore potential effects of aging on human hematopoietic stem and progenitor cells (HSPCs), we evaluated CD34(+) cells derived from young (60 years) adult bone marrow with respect to phenotype and in vitro function. We observed an increased frequency of phenotypically defined stem and progenitor cells with age, but no distinct differences with respect to in vitro functional capacity. Given that regeneration of peripheral blood counts can serve as a functional readout of HSPCs, we compared various peripheral blood parameters between younger patients (≤50 years; n = 64) and older patients (≥60 years; n = 55) after autologous stem cell transplantation. Patient age did not affect the number of apheresis cycles or the amount of CD34(+) cells harvested. Parameters for short-term regeneration did not differ significantly between the younger and older patients; however, complete recovery of all 3 blood lineages at 1 year after transplantation was strongly affected by advanced age, occurring in only 29% of the older patients, compared with 56% of the younger patients (P = .009). Collectively, these data suggest that aging has only limited effects on CD34(+) HSPCs under steady-state conditions, but can be important under consitions of chemotoxic and replicative stress. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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

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    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.

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

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    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. 

  15. Expression of CD226 on NK subsets during reconstitution of immune system by autologous peripheral blood hematopoietic stem cell transplantation

    International Nuclear Information System (INIS)

    Zhang Yun; Jin Boquan; Cheng Guang; You Xianghui; Zhang Hongmei; Ren Jun

    2005-01-01

    The purpose of this paper was to observe the expression of CD226 on NK subsets dur- ing reconstitution of immune system by autologous peripheral blood hematopoietic stem cell transplantation. Double fluorescent staining and flow cytometry analysis were employed to detect the expression of CD226 on CD56 bright and CD56 dim NK subsets during reconstitution of immune system by autologous peripheral blood hematopoietic stem cell transplantation. The results showed that on day 12 after transplantation, the percentage of CD56 + NK cells in PBMC increased to 26.6%. Among CD56 + NK cells, the percentage of CD56 bright NK cells was 87.3% and that of CD56 + CD226 + subpopulation in CD56 + NK cells was 92.1%, and among CD56 + CD226 + cells, CD56 bright CD226 + cells constituted the majority(89.9%). Our conclusions are that CD226 may be a differentiation marker on CD56 bright NK subset which was the very early appearing and predominant subpopulation of NK cells during the reconstitution of immune system by autologous peripheral blood hematopoietic stem cell transplantation. (authors)

  16. Development of model for analysing respective collections of intended hematopoietic stem cells and harvests of unintended mature cells in apheresis for autologous hematopoietic stem cell collection.

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    Hequet, O; Le, Q H; Rodriguez, J; Dubost, P; Revesz, D; Clerc, A; Rigal, D; Salles, G; Coiffier, B

    2014-04-01

    Hematopoietic stem cells (HSCs) required to perform peripheral hematopoietic autologous stem cell transplantation (APBSCT) can be collected by processing several blood volumes (BVs) in leukapheresis sessions. However, this may cause granulocyte harvest in graft and decrease in patient's platelet blood level. Both consequences may induce disturbances in patient. One apheresis team's current purpose is to improve HSC collection by increasing HSC collection and prevent increase in granulocyte and platelet harvests. Before improving HSC collection it seemed important to know more about the way to harvest these types of cells. The purpose of our study was to develop a simple model for analysing respective collections of intended CD34+ cells among HSC (designated here as HSC) and harvests of unintended platelets or granulocytes among mature cells (designated here as mature cells) considering the number of BVs processed and factors likely to influence cell collection or harvest. For this, we processed 1, 2 and 3 BVs in 59 leukapheresis sessions and analysed corresponding collections and harvests with a referent device (COBE Spectra). First we analysed the amounts of HSC collected and mature cells harvested and second the evolution of the respective shares of HSC and mature cells collected or harvested throughout the BV processes. HSC collections and mature cell harvests increased globally (pcells and platelets) influenced both cell collections and harvests (CD34+cells and platelets) (pHSC collections and mature unintended cells harvests (pHSC collections or unintended mature cell harvests were pre-leukapheresis blood cell levels. Our model was meant to assist apheresis teams in analysing shares of HSC collected and mature cells harvested with new devices or with new types of HSC mobilization. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

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    Patrizia Tosi

    2012-11-01

    Full Text Available Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

  18. Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms’ Tumor: A CIBMTR retrospective analysis

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    Malogolowkin, Marcio H.; Hemmer, Michael T.; Le-Rademacher, Jennifer; Hale, Gregory A; Metha, Parinda A.; Smith, Angela R.; Kitko, Carrie; Abraham, Allistair; Abdel-Azim, Hisham; Dandoy, Christopher; Diaz, Miguel Angel; Gale, Robert Peter; Guilcher, Greg; Hayashi, Robert; Jodele, Sonata; Kasow, Kimberly A.; MacMillian, Margaret L.; Thakar, Monica; Wirk, Baldeep M.; Woolfrey, Ann; Thiel, E L

    2017-01-01

    Despite the dramatic improvement in the overall survival for patients diagnosed with Wilms’ tumor (WT), the outcomes for those that experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). The 5-year estimates for event free survival (EFS) and overall survival (OS) were 36% (95% CI; 29 – 43%) and 45% (95% CI; 38 – 51%) respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality (TRM) showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. Since attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus high-dose chemotherapy followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. Since disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy. PMID:28869618

  19. Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease.

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    Urbinati, Fabrizia; Wherley, Jennifer; Geiger, Sabine; Fernandez, Beatriz Campo; Kaufman, Michael L; Cooper, Aaron; Romero, Zulema; Marchioni, Filippo; Reeves, Lilith; Read, Elizabeth; Nowicki, Barbara; Grassman, Elke; Viswanathan, Shivkumar; Wang, Xiaoyan; Hollis, Roger P; Kohn, Donald B

    2017-09-01

    Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem cell final cell product (FCP), as well as an in depth in vivo toxicology study, are critical for advancing this approach to clinical trials. Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/β AS3 -FB vector and cryopreserving CD34 + cells from human bone marrow (BM) at clinical scale. In vitro and in vivo characterization of the FCP was performed, showing that all the release criteria were successfully met. In vivo toxicology studies were conducted to evaluate potential toxicity of the Lenti/β AS3 -FB LV in the context of a murine BM transplant. Primary and secondary transplantation did not reveal any toxicity from the lentiviral vector. Additionally, vector integration site analysis of murine and human BM cells did not show any clonal skewing caused by insertion of the Lenti/β AS3 -FB vector in cells from primary and secondary transplanted mice. We present here a complete protocol, thoroughly optimized to manufacture, characterize and establish safety of a FCP for gene therapy of SCD. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  20. Five Questions Answered: A Review of Autologous Hematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis.

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    Atkins, Harold L; Freedman, Mark S

    2017-10-01

    Multiple sclerosis (MS) is thought to be an autoimmune disease targeting the central nervous system leading to demyelination, and axonal and neuronal damage, resulting in progressive disability. More intensive therapies such as immunodepletion with hematopoietic stem-cell rescue are being used at a time prior to patients becoming irreversibly disabled. Over the last 15 years, there has been a shift away from using autologous hematopoietic stem-cell transplants (aHSCT) to treat patients with progressive MS, towards treating those with active inflammation and relapses. There is an increasing body of evidence that aHSCT improves all measured MS outcomes, including burden of disease on MRI, clinical relapses, accumulation of disability, and quality of life of patients with active MS not controlled with standard therapy. Importantly, the progression-free survival curves of these patients plateau after the first few years demonstrating the impact that aHSCT has in changing the natural history of MS, potentially freeing patients from the relentless accumulation of disability. Concurrently there has been a reduction in procedure-related mortality. The results of randomized trials will likely spur further development of this field.

  1. UPDATE ON THE ROLE OF AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA

    Directory of Open Access Journals (Sweden)

    Patrizia Tosi

    2012-01-01

    Full Text Available

    Autologous stem cell transplantation is considered the standard of care for multiple myeloma patients aged < 65 years with no relevant comorbidities. The addition of drugs acting both on bone marrow microenvironment and on neoplastic plasma cells has significantly increased the proportion of patients achieving a complete remission after induction therapy, and these results are mantained after high-dose melphalan, leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short term consolidation or long-term maintenance therapy can result into disease eradication at the molecular level thus increasing also patients survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achivng a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from autologous stem cell transplantation and for whom the efficacy of new drugs is still matter of debate.

  2. Brazilian experience using high dose sequential chemotherapy followed by autologous hematopoietic stem cell transplantation for malignant lymphomas

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    Bruno Kosa Lino Duarte

    2011-12-01

    Full Text Available OBJECTIVE: To evaluate the use of high-dose sequential chemotherapy in a Brazilian population. METHODS: High-dose cyclophosphamide followed by autologous hematopoietic stem cell transplantation is an effective and feasible therapy for refractory/relapsed lymphomas; this regimen has never before been evaluated in a Brazilian population. All patients (106 with high-grade non-Hodgkin lymphoma and 77 with Hodgkin's lymphoma submitted to this treatment between 1998 and 2006 were analyzed. Chemotherapy consisted of the sequential administration of high-dose cyclophosphamide (4 or 7 g/m² and granulocyte-colony stimulating factor (300 µg/day, followed by peripheral blood progenitor cell harvesting, administration of etoposide (2g/m² and methotrexate (8 g/m² only for Hodgkin's lymphoma and autologous hematopoietic stem cell transplantation. RESULTS: At diagnosis, non-Hodgkin lymphoma patients had a median age of 45 (range: 8-65 years old, 78% had diffuse large B-cell lymphoma and 83% had stage III/IV disease. The Hodgkin's lymphoma patients had a median age of 23 (range: 7-68 years old, 64.9% had the nodular sclerosis subtype and 65% had stage III/IV disease. Nine Hodgkin's lymphoma patients (13% and 10 (9% non-Hodgkin lymphoma patients had some kind of cardiac toxicity. The overall survival, disease-free survival and progression-free survival in Hodgkin's lymphoma were 29%, 59% and 26%, respectively. In non-Hodgkin lymphoma, these values were 40%, 49% and 31%, respectively. High-dose cyclophosphamide-related mortality was 10% for Hodgkin's lymphoma and 5% for non-Hodgkin lymphoma patients. High-dose cyclophosphamide dosing had no impact on toxicity or survival for both groups. CONCLUSIONS: Despite a greater prevalence of poor prognostic factors, our results are comparable to the literature. The incidence of secondary neoplasias is noteworthy. Our study suggests that this approach is efficient and feasible, regardless of toxicity-related mortality.

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

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

    2015-10-01

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

  4. Hematopoietic growth factors including keratinocyte growth factor in allogeneic and autologous stem cell transplantation.

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    Seggewiss, Ruth; Einsele, Hermann

    2007-07-01

    The aim of hematopoietic stem cell transplantation (HSCT) is to cure patients of malignancies, autoimmune diseases, and immunodeficiency disorders by redirecting the immune system: the often described graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effects. Unfortunately, fulfillment of this goal is often hampered by relapse of the underlying disease, graft-versus-host disease (GVHD), or severe opportunistic infections, which account for the majority of post-transplantation deaths. Moreover, studies of long-term survivors of transplantation indicate an accelerated immune aging due to the transplantation procedure itself, preceding chemo- or radiotherapy, and acute and chronic GVHD. Significant advances have been made towards overcoming these obstacles by enhancing immune reconstitution with hematopoietic growth factors (HGFs) such as granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO) or through the application of cytokines. In addition, there are approaches to promote the thymic-dependent development of naive T cells, which are prepared for the interaction with a multitude of pathogens. Examples are the application of keratinocyte growth factor (KGF), neuroendocrine hormones such as growth hormone or prolactin, sex hormone ablation, or the invention of a three-dimensional artificial thymus based on a cytomatrix. Might these measures result in a higher rate of healthy and fully recovered patients? Here we review progress in each of these areas.

  5. Hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Eleftheria Hatzimichael

    2010-08-01

    Full Text Available Eleftheria Hatzimichael1, Mark Tuthill21Department of Haematology, Medical School of Ioannina, University of Ioannina, Ioannina, Greece; 2Department of Medical Oncology, Hammersmith Hospital, Imperial College National Health Service Trust, London, UKAbstract: More than 25,000 hematopoietic stem cell transplantations (HSCTs are performed each year for the treatment of lymphoma, leukemia, immune-deficiency illnesses, congenital metabolic defects, hemoglobinopathies, and myelodysplastic and myeloproliferative syndromes. Before transplantation, patients receive intensive myeloablative chemoradiotherapy followed by stem cell “rescue.” Autologous HSCT is performed using the patient’s own hematopoietic stem cells, which are harvested before transplantation and reinfused after myeloablation. Allogeneic HSCT uses human leukocyte antigen (HLA-matched stem cells derived from a donor. Survival after allogeneic transplantation depends on donor–recipient matching, the graft-versus-host response, and the development of a graft versus leukemia effect. This article reviews the biology of stem cells, clinical efficacy of HSCT, transplantation procedures, and potential complications.Keywords: hematopoietic stem cell transplantation, complications

  6. A risk-based approach to optimize autologous hematopoietic stem cell (HSC) collection with the use of plerixafor.

    Science.gov (United States)

    Abhyankar, S; DeJarnette, S; Aljitawi, O; Ganguly, S; Merkel, D; McGuirk, J

    2012-04-01

    Autologous hematopoietic stem cell (HSC) transplant is an effective treatment for patients with hematological malignancies. Unfortunately, 15-30% of patients fail to mobilize a sufficient number of HSCs for the transplant. Plerixafor is now used as a salvage mobilization regimen, with good success. We describe here a risk-based approach for the use of plerixafor, based on the circulating CD34(+) cell count and the CD34(+) cell dose collected after 4 days of G-CSF, that identifies potential poor HSC mobilizers upfront. A total of 159 patients underwent HSC collections using this approach. Of these, 55 (35%) were identified as high risk owing to low CD34(+) cell number or low yield on day 1 of collection, and received plerixafor on the subsequent days of collection. Of the 159 patients, 151 (95%) were able to provide adequate collections with the first mobilization attempt in a median of 1.7 days using this approach. Of the eight who failed initial mobilization, 5 successfully underwent re-mobilization with plerixafor and G-CSF and 3 (1.9%) were mobilization failures. This approach helped to control the overall cost of HSC collections for our BMT program by decreasing the need for remobilization, reducing the number of collection days and avoiding the use of plerixafor in all patients.

  7. Sequential, autologous hematopoietic stem cell transplant followed by renal transplant in multiple myeloma

    Directory of Open Access Journals (Sweden)

    D Bhowmik

    2017-01-01

    Full Text Available A 30-year-old female was symptomatic with headache, fatigue, and weakness since October 2011 and was told to have anemia. In January 2012, she was admitted outside with pulmonary edema. Investigations revealed advanced azotemia, anemia, and hypercalcemia. Urine showed 2 + proteins and 30–35 red blood cells. There was no history of oral ulcers, rash, Raynaud's phenomenon, or hemoptysis. She was evaluated for causes of rapidly progressive “renal failure.” Hemolytic work-up; antinuclear antibody, double-stranded DNA, and anti-neutrophil cytoplasmic antibody were negative. Kidney biopsy was done and interpreted as acute interstitial nephritis with hyaline casts. She was started on hemodialysis and treated with steroids and cyclophosphamide. She came to our institute in January 2012. Investigations showed evidence of paraproteinemia with kappa restriction. Bone marrow showed 15% plasma cells. Kidney biopsy was reviewed and was diagnostic of cast nephropathy. She was treated with 6 monthly cycles of dexamethasone and bortezomib. She achieved complete remission in July 2012. Maintenance doses of bortezomib were continued until May 2014. Autologous bone marrow transplantation was performed on June 06, 2014. Monthly, bortezomib was continued till April 2015. Subsequently, workup for renal transplantation was started with her father as her donor. Test for sensitization was negative. Renal transplantation was done on January 1, 2016, with prednisolone, mycophenolate, and tacrolimus. She achieved a serum creatinine of 0.6 mg% on the 4th postoperative day. Thereafter, she continues to remain stable.

  8. Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support.

    Science.gov (United States)

    Elias, A D; Wheeler, C; Ayash, L J; Schwartz, G; Ibrahim, J; Mills, L; McCauley, M; Coleman, N; Warren, D; Schnipper, L; Antman, K H; Teicher, B A; Frei, E

    1998-06-01

    Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain

  9. Administration of Autologous Hematopoietic Stem Cell Trans-plan¬tation for Treatment of Type 1 Diabetes Mellitus

    OpenAIRE

    Ensieh NASLI ESFAHANI; Ardeshir GHAVAMZADEH; Nika MOJAHEDYAZDI; SeyyedJafar HASHEMIAN; Kamran ALIMOGHADAM; Nar­jes AGHEL; Behrouz NIKBIN; Bagher LARIJANI

    2015-01-01

    Background: The aim of the present clinical trial was to investigate the efficacy of autologous bone marrow mesenchymal stem cells (BM-MSCs) in glycemic control of diabetic patients without using any immunosuppressive drugs over a nine-month period.Method: Twenty-three patients with T1DM, at 5 to 30 years of age and in both sexes, participated in this study. This trial consisted of two phases; in the end of the first phase (three month after the transplantation), if the patient still needed e...

  10. [Indications and follow-up for autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    Science.gov (United States)

    Pugnet, Grégory; Castilla-Llorente, Christina; Puyade, Mathieu; Terriou, Louis; Badoglio, Manuela; Deligny, Christophe; Guillaume-Jugnot, Perrine; Labeyrie, Céline; Benzidia, Ilham; Faivre, Hélène; Lansiaux, Pauline; Marjanovic, Zora; Bourhis, Jean-Henri; Faucher, Catherine; Furst, Sabine; Huynh, Anne; Martin, Thierry; Vermersch, Patrick; Yakoub-Agha, Ibrahim; Farge, Dominique

    2017-12-01

    The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2017 in Lille, France and updated recommendations for indications and follow-up in autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases, previously published under the auspices of SFGM-TC. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  11. Autologous hematopoietic stem cell transplantation in elderly patients (≥ 70 years) with non-Hodgkin's lymphoma: A French Society of Bone Marrow Transplantation and Cellular Therapy retrospective study.

    Science.gov (United States)

    Hermet, E; Cabrespine, A; Guièze, R; Garnier, A; Tempescul, A; Lenain, P; Bouabdallah, R; Vilque, J P; Frayfer, J; Bordessoule, D; Sibon, D; Janvier, M; Caillot, D; Biron, P; Legros, L; Choufi, B; Drenou, B; Gorin, N C; Bilger, K; Tamburini, J; Soussain, C; Brechignac, S; Bay, J O

    2015-09-01

    Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70 years of age with non-Hodgkin's lymphoma (NHL). In the setting of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70 years of age who received AHSCT. The median age at AHSCT was 72.3 years [70-80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5×10⁹/L neutrophils and 20 × 10(9)/L platelets were of 12 [9-76] days and 12 [0-143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70 years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Prognostic Significance of Blood Transfusion in Newly Diagnosed Multiple Myeloma Patients without Autologous Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Fan, Liping; Fu, Danhui; Zhang, Jinping; Wang, Qingqing; Ye, Yamei; Xie, Qianling

    2017-01-01

    The aim of this study was to evaluate whether blood transfusions affect overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma (MM) patients without hematopoietic stem cell transplantation. A total of 181 patients were enrolled and divided into two groups: 68 patients in the transfused group and 113 patients in the nontransfused group. Statistical analyses showed that there were significant differences in ECOG scoring, Ig isotype, platelet (Plt) counts, hemoglobin (Hb) level, serum creatinine (Scr) level, and β2-microglobulin (β2-MG) level between the two groups. Univariate analyses showed that higher International Staging System staging, Plt counts blood transfusion was associated with PFS but not OS in MM patients. Multivariate analyses showed that blood transfusion was not an independent factor for PFS in MM patients. Our preliminary results suggested that newly diagnosed MM patients may benefit from a liberal blood transfusion strategy, since blood transfusion is not an independent impact factor for survival. PMID:28567420

  13. Association of oxidative stress and DNA damage with grafting time in patients with multiple myeloma and lymphoma submitted to autologous hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Thayna Nogueira dos Santos

    Full Text Available ABSTRACT The aim of the study was to investigate the association between oxidative stress and DNA damage with grafting time in patients submitted to autologous hematopoietic stem-cell transplantation (HSCT. The study included 37 patients submitted to autologous HSCT diagnosed with Multiple Myeloma (MM and lymphoma (Hodgkin’s and non-Hodgkin’s. Biomarkers of oxidative stress and DNA damage index (DI were performed at baseline (pre-CR of the disease and during the conditioning regimen (CR, one day after the HSCT, ten days after HSCT and twenty days after HSCT, as well as in the control group consisting of 30 healthy individuals. The outcomes showed that both groups of patients had an hyperoxidative state with high DI when compared to baseline and to the control group and that the CR exacerbated this condition. However, after the follow-up period of the study, this picture was re-established to the baseline levels of each pathology. The study patients with MM showed a mean grafting time of 10.75 days (8 to 13 days, with 10.15 days (8 to 15 days for the lymphoma patients. In patients with MM, there was a negative correlation between the grafting time and the basal levels of GPx (r = -0.54; p = 0.034, indicating that lower levels of this important enzyme are associated with a longer grafting time. For the DI, the correlation was a positive one (r = 0.529; p = 0.030. In the group with lymphoma, it was observed that the basal levels of NOx were positively correlated with grafting time (r = 0.4664, p = 0.032. The data indicate the potential of these biomarkers as predictors of toxicity and grafting time in patients with MM and Lymphomas submitted to autologous HSCT.

  14. Reduction in incidence of early fatal complications of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in Hodgkin lymphoma patients

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    N. V. Zhukov

    2014-07-01

    Full Text Available Traditionally, the concern of fatal complication is a major obstacle to transfer patients with unfavorable course of Hodgkin’s lymphoma tonational transplantation centers. Early mortality after high-dose chemotherapy with autologous hematopoietic stem cell transplantation(HSCT in the Russia, Ukraine and Belarus was assessed in this retrospective multicenter study.Patients and methods. The study included 372 patients with unfavorable course of Hodgkin’s lymphoma received HSCT between 01.1990and 06.2013: 35.5 % patients with primary resistance, 30.6 % with early relapse, 33.1 % with late relapse and 0.8 % during consolidation offirst complete remission.Results. During first 100 days after HSCT died 14 (3.8 % patients, during first year – 31 (8.4 % patients. During the study period a significant decrease in the 100-day and 1-year mortality rate was observed (p < 0.0001 for both. Among patients received HSCT in 1990–1995, 1996–2000, 2001–2005 and 2006–2013 the 100-day mortality was 19.4 %, 6.3 %, 1.1 % and 0.6 %, respectively. 1-year mortality for the same intervals was 32.3 %, 14.7 %, 4.5 % and 1.9 %, respectively.Conclusions. Currently HSCT in patients with unfavorable course of Hodgkin's lymphoma in national transplant centers, accompanied by an extremely low risk of fatal toxicity.

  15. Atrial Fibrillation in Hematologic Malignancies, Especially After Autologous Hematopoietic Stem Cell Transplantation: Review of Risk Factors, Current Management, and Future Directions.

    Science.gov (United States)

    Mathur, Pankaj; Paydak, Hakan; Thanendrarajan, Sharmilan; van Rhee, Frits

    2016-02-01

    Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with significant morbidity and mortality worldwide. In addition to well-established risk factors, cancer has been increasingly associated with the development of AF. Its increased occurrence in those with hematologic malignancies has been attributed to chemotherapeutic agents and autologous hematopoietic stem cell transplantation (AHSCT). Recently, a few studies have attempted to define the etiopathogenesis of AF in hematologic malignancies. The management of AF in these patients is challenging because of the concurrent complicating factors, such as thrombocytopenia, orthostatic hypotension, and cardiac amyloidosis. More studies are needed to define the management of AF, especially rate versus rhythm control and anticoagulation. Arrhythmias, in particular, AF, have been associated with an increased length of stay, increased intensive care unit admissions, and greater cardiovascular mortality. In the present review, we describe AF in patients with hematologic malignancies, the risk factors, especially after AHSCT, and the current management of AF. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR HIGH-RISK ACUTE LYMPHOBLASTIC LEUKEMIA: NON-RANDOMIZED STUDY WITH A MAXIMUM FOLLOW-UP OF MORE THAN 22 YEARS

    Directory of Open Access Journals (Sweden)

    Grzegorz Helbig

    2014-06-01

    Full Text Available Objective. To evaluate the efficacy and toxicity of autologous hematopoietic stem cell transplantation (AHSCT for high-risk acute lymphoblastic leukemia (ALL. Material and methods. Overall, 128 high-risk ALL patients at a median age of 26 years (range 18-56 years at diagnosis received AHSCT between 1991-2008. Induction treatment was anthracycline-based in all patients. Conditioning regimen consisted of CAV (cyclophosphamide, cytarabine, etoposide in 125 patients whereas 3 subjects received cyclophosphamide and TBI (total body irridation. Bone marrow was stored for 72 hours in 4oC and re-infused 24 hours after conditioning completion. Bone marrow was a source of stem cells in 119 patients, peripheral blood in 2 and 7 subjects received both bone marrow and peripheral blood. Results. With a median follow-up after AHSCT of 1.6 years (range 0.1-22.3 years, the probability of leukemia-free survival (LFS for the whole group at 10 years was 27% and 23% at 20 years. Transplant-related mortality at 100 days after AHSCT was 3.2%.. There was a strong tendency for better LFS for MRD-negative patients if compared with patients who had positive or unknown MRD status at AHSCT (32% vs 23% and 25%, respectively; p=0.06. There was no difference in LFS between B- and T-lineage ALL as well as between patients transplanted in first complete remission (CR1 and CR2. LFS at 10 years for patients with detectable BCR-ABL at transplant was 20% and this was comparable with subjects with negative and missing BCR-ABL status (26% and 28%; p=0.97. Conclusions. The results of AHSCT for high-risk ALL remains unsatisfactory with low probability of long-term LFS.

  17. 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...... for 3 years post-transplant. Magnetic resonance revealed the capacity of autologous HSCT to suppress or markedly reduce gadolinium-enhancing lesions. The progression of brain atrophy declined after two years post-HSCT. The profound immunological changes following autologous HSCT may result...

  18. Microvascular Complications in Type 1 Diabetes: A Comparative Analysis of Patients Treated with Autologous Nonmyeloablative Hematopoietic Stem-Cell Transplantation and Conventional Medical Therapy

    Directory of Open Access Journals (Sweden)

    Jaquellyne G. Penaforte-Saboia

    2017-11-01

    Full Text Available ObjectiveTo explore the impact on microvascular complications, long-term preservation of residual B-cell function and glycemic control of patients with type 1 diabetes treated with autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST compared with conventional medical therapy (CT.Research design and methodsCross-sectional data of patients treated with AHST were compared with patients who received conventional therapy from the Brazilian Type 1 Diabetes Study Group, the largest multicenter observational study in type 1 diabetes mellitus in Brazil. Both groups of patients had diabetes for 8 years on average. An assessment comparison was made on the presence of microvascular complications, residual function of B cell, A1c, and insulin dose of the patients.ResultsAfter a median of 8 years of diagnosis, none of the AHST-treated patients (n = 24 developed microvascular complications, while 21.5% (31/144 had at least one (p < 0.005 complication in the CT group (n = 144. Furthermore, no case of nephropathy was reported in the AHST group, while 13.8% of CT group (p < 0.005 developed nephropathy during the same period. With regard of residual B-cell function, the percentage of individuals with predicted higher C-peptide levels (IDAA1C ≤ 9 was about 10-fold higher in the AHST group compared with CT (75 vs. 8.3% (p < 0.001 group. Among AHST patients, 54.1% (13/24 had the HbA1c < 7.0 compared with 13.1% in the CT (p < 0.001 group.ConclusionPatients with newly diagnosed type 1 diabetes treated with AHST presented lower prevalence of microvascular complications, higher residual B-cell function, and better glycemic control compared with the CT group.

  19. Hispanics have the lowest stem cell transplant utilization rate for autologous hematopoietic cell transplantation for multiple myeloma in the United States: A CIBMTR report.

    Science.gov (United States)

    Schriber, Jeffrey R; Hari, Parameswaran N; Ahn, Kwang Woo; Fei, Mingwei; Costa, Luciano J; Kharfan-Dabaja, Mohamad A; Angel-Diaz, Miguel; Gale, Robert P; Ganguly, Siddharatha; Girnius, Saulius K; Hashmi, Shahrukh; Pawarode, Attaphol; Vesole, David H; Wiernik, Peter H; Wirk, Baldeep M; Marks, David I; Nishihori, Taiga; Olsson, Richard F; Usmani, Saad Z; Mark, Tomer M; Nieto, Yago L; D'Souza, Anita

    2017-08-15

    Race/ethnicity remains an important barrier in clinical care. The authors investigated differences in the receipt of autologous hematopoietic cell transplantation (AHCT) among patients with multiple myeloma (MM) and outcomes based on race/ethnicity in the United States. The Center for International Blood and Marrow Transplant Research database was used to identify 28,450 patients who underwent AHCT for MM from 2008 through 2014. By using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results 18 registries, the incidence of MM was calculated, and a stem cell transplantation utilization rate (STUR) was derived. Post-AHCT outcomes were analyzed among patients ages 18 to 75 years who underwent melphalan-conditioned peripheral cell grafts (N = 24,102). The STUR increased across all groups from 2008 to 2014. The increase was substantially lower among Hispanics (range, 8.6%-16.9%) and non-Hispanic blacks (range, 12.2%-20.5%) compared with non-Hispanic whites (range, 22.6%-37.8%). There were 18,046 non-Hispanic whites, 4123 non-Hispanic blacks, and 1933 Hispanic patients. The Hispanic group was younger (P blacks (42%) compared with non-Hispanic whites (56%). A Karnofsky score 3 were more common in non-Hispanic blacks compared with Hispanic and non-Hispanic whites (P blacks (54%) and non-Hispanic whites (52%; P blacks (45%) and non-Hispanic whites (44%) had a very good partial response or better before transplantation (P = .005). Race/ethnicity did not impact post-AHCT outcomes. Although the STUR increased, it remained low and was significantly lower among Hispanics followed by non-Hispanic blacks compared with non-Hispanic whites. Race/ethnicity did not impact transplantation outcomes. Efforts to increase the rates of transplantation for eligible patients who have MM, with an emphasis on groups that underuse transplantation, are warranted. Cancer 2017;123:3141-9. © 2017 American Cancer Society. © 2017 American Cancer Society.

  20. A Method for Reconstruction of Severely Damaged Spinal Cord using Autologous Hematopoietic Stem Cells and Platelet-rich Protein as a Biological Scaffold.

    Science.gov (United States)

    Ammar, Ahmed Sabry; Osman, Yasser; Hendam, Ahmed Taher; Hasen, Mohammed Ahmed; Al Rubaish, Fatma Abdullah; Al Nujaidi, Danya Yaagoub; Al Abbas, Faisal Mishal

    2017-01-01

    There have been attempts to alter the prognosis of severe spinal cord injury in different centers, but none of which have reliably altered the outcome. Some trials use stem cells (SCs) that produced widely differing results. We hereby add our experience in our center of a surgical reconstruction of the damaged spinal cord using a mixture of SCs and Platelet-Rich Protein (PRP) with fibrin coated as a biological scaffold. Four cases of severely damaged spinal cord have been operated for neurolysis and reconstruction of the spinal cord using SCs and platelet-rich protein (PRP) with fibrin coated harvested from the peripheral circulation of the patient. PRP serves to maintain the position of the SCs. One milliliter suspension contains an average of 2.8 × 10 6 of autologous hematopoietic SCs. Patients were intraoperatively monitored by somatosensory evoked potential, motor evoked potentials, and delta wave. They are clinically followed postoperatively and electromyogram was repeated every 2 weeks. Magnetic resonance imaging (MRI) was repeated regularly. The patients are followed up for a period between 2 and 3 years. One patient demonstrated motor and objective sensory improvement ( P = 0.05), two other patients reported subjective sensory improvement, and the fourth one remained without any improvement ( P = 0.1). None of these patients demonstrated any sign of deterioration or complication either on the surgery or on implanting of the SCs. MRI clearly proved that the inserted biological scaffold remained in place of reconstruction. SCs may play a role in restoring spinal cord functions. However, the unsolved problems of the use of SCs and related ethical issues should be addressed.

  1. Autologous hematopoietic stem cell transplantation in lymphoma patients is associated with a decrease in the double strand break repair capacity of peripheral blood lymphocytes.

    Directory of Open Access Journals (Sweden)

    Sandrine Lacoste

    Full Text Available Patients who undergo autologous hematopoietic stem cell transplantation (aHCT for treatment of a relapsed or refractory lymphoma are at risk of developing therapy related- myelodysplasia/acute myeloid leukemia (t-MDS/AML. Part of the risk likely resides in inherent interindividual differences in their DNA repair capacity (DRC, which is thought to influence the effect chemotherapeutic treatments have on the patient's stem cells prior to aHCT. Measuring DRC involves identifying small differences in repair proficiency among individuals. Initially, we investigated the cell model in healthy individuals (primary lymphocytes and/or lymphoblastoid cell lines that would be appropriate to measure genetically determined DRC using host-cell reactivation assays. We present evidence that interindividual differences in DRC double-strand break repair (by non-homologous end-joining [NHEJ] or single-strand annealing [SSA] are better preserved in non-induced primary lymphocytes. In contrast, lymphocytes induced to proliferate are required to assay base excision (BER or nucleotide excision repair (NER. We established that both NHEJ and SSA DRCs in lymphocytes of healthy individuals were inversely correlated with the age of the donor, indicating that DSB repair in lymphocytes is likely not a constant feature but rather something that decreases with age (~0.37% NHEJ DRC/year. To investigate the predictive value of pre-aHCT DRC on outcome in patients, we then applied the optimized assays to the analysis of primary lymphocytes from lymphoma patients and found that individuals who later developed t-MDS/AML (cases were indistinguishable in their DRC from controls who never developed t-MDS/AML. However, when DRC was investigated shortly after aHCT in the same individuals (21.6 months later on average, aHCT patients (both cases and controls showed a significant decrease in DSB repair measurements. The average decrease of 6.9% in NHEJ DRC observed among aHCT patients was

  2. Transplante de células-tronco hematopoéticas no diabete melito do tipo I Autologous hematopoietic stem cell transplantation in type I diabetes mellitus

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    Júlio C. Voltarelli

    2004-03-01

    Full Text Available Transplantes autólogos de células-tronco hematopoéticas (TACTH para doenças auto-imunes (DAÍ graves e refratárias à terapia convencional têm sido realizados desde 1996, principalmente dirigidos a doenças reumáticas e neurológicas, com resultados encorajadores. De modo geral, dois terços dos pacientes alcançam remissão duradoura da doença auto-imune, embora a morbimortalidade relacionada ao transplante ou à recidiva e progressão da DAI ainda constituam problemas significativos. Baseados nesses resultados e no efeito benéfico da imunossupressão moderada na evolução do diabete melito do tipo I (DM-I, iniciamos, em dezembro de 2003, um protocolo clínico de TACTH para esta doença, em cooperação com a Universidade Northwestern de Chicago, da Universidade de Miami e do National Institutes of Health. Pacientes com DM-I abaixo de 35 anos, diagnosticados há menos de seis semanas ou na fase assintomática ("lua-de-mel" da doença têm suas CTH mobilizadas com ciclofosfamida (2 g/m² e G-CSF, coletadas do sangue periférico e criopreservadas. Após o condicionamento com ciclofosfamida (200 mg/kg e globulina antitimocitária de coelho (4,5 mg/kg e a infusão das CTH autólogas, os pacientes são seguidos por cinco anos em relação aos aspectos clínicos, endocrinológicos e imunológicos do diabete. Este estudo clínico poderá representar uma importante contribuição científica do transplante de medula óssea brasileiro à moderna era de terapia celular de doenças inflamatórias e degenerativas.Autologous hematopoietic stem cell transplantation (AHSCT for severe and refractory autoimmune diseases has been performed since 1996 with encouraging results. In general, two thirds of the patients achieve durable remissions, although morbidity and mortality related to transplantation or to relapse and progression of autoimmune diseases are still significant. Based on those results and on beneficial effects of moderate immunosuppression

  3. Co-infusion of autologous adipose tissue derived insulin-secreting mesenchymal stem cells and bone marrow derived hematopoietic stem cells: Viable therapy for type III.C. a diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Umang G Thakkar

    2014-12-01

    Full Text Available Transition from acute pancreatitis to insulin-dependent diabetes mellitus (IDDM is a rare manifestation of primary hyperparathyroidism caused by parathyroid adenoma because of impaired glucose tolerance and suppresses insulin secretion. We report the case of a 26-year-old male with pancreatic diabetes caused by parathyroid adenoma induced chronic pancreatitis. He had serum C-peptide 0.12 ng/ml, glutamic acid decarboxylase antibody 5.0 IU/ml, and glycosylated hemoglobin (HbA1C 8.9%, and required 72 IU/day of biphasic-isophane insulin injection for uncontrolled hyperglycemia. We treated him with his own adipose tissue derived insulin-secreting mesenchymal stem-cells (IS-ADMSC along with his bone marrow derived hematopoietic stem cells (BM-HSC. Autologous IS-ADMSC + BM-HSC were infused into subcutaneous tissue, portal and thymic circulation without any conditioning. Over a follow-up of 27 months, the patient is maintaining fasting and postprandial blood sugar levels of 132 and 165 mg/dl, respectively, with HbA1C 6.8% and requiring 36 IU/day of biphasic-isophane insulin. Co-infusion of IS-ADMSC + BM-HSC offers a safe and viable therapy for type III.C.a Diabetes Mellitus.

  4. 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...

  5. Inability of HOXB4 to enhance self-renewal of malignant B cells: favorable profile for the expansion of autologous hematopoietic stem cells.

    Science.gov (United States)

    Fournier, Marilaine; Savoie-Rondeau, Isabelle; Larochelle, Fannie; Hassawi, Mona; Shestakova, Elena A; Roy, Denis Claude; Bijl, Janetta J

    2014-07-01

    Leukemic stem cells share self-renewal properties and slow proliferation with hematopoietic stem cells. Based on expression signatures, it has been suggested that these cells use the same molecular pathways for these processes. However, it is not clear whether leukemic stem cells also respond to factors known to enhance the self-renewal activity of hematopoietic stem cells. The transcription factor homeobox B4 (HOXB4) is known to induce expansion of mouse hematopoietic stem cells. The recombinant TAT-HOXB4 protein also expands human CD34+ cells. In this study we investigated whether overexpression of HOXB4 could increase leukemic initiating cell numbers, an issue that is crucial to its clinical usage. A transgenic mouse model for E2A-PBX1 induced pre-B acute lymphoblastic leukemia was used in combination with HOXB4 transgenic mice to test oncogenic interactions between HOXB4 and E2A-PBX1. The frequency of leukemic initiating cells retrovirally overexpressing HOXB4 was measured by transplantation at limiting dilution and evaluation of leukemia development in recipient mice. Moreover, human B cell lines were evaluated for their colony forming cell potential upon exposure to TAT-HOXB4 protein. Our data with the mouse models show that HOXB4 neither accelerates the generation of E2A-PBX1 B cell leukemia nor expands the number of leukemia initiating cells. Additionally, the growth or colony forming cell proportions of human B cell lines was not changed by HOXB4, suggesting that human B leukemic initiating cells are not affected by HOXB4. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  6. Collection and composition of autologous peripheral blood stem cells graft in patients with acute myeloid leukemia: influence on hematopoietic recovery and outcome.

    Science.gov (United States)

    Raos, Mirela; Nemet, Damir; Bojanić, Ines; Sertić, Dubravka; Batinić, Drago; Dusak, Vesna; Dubravcić, Klara; Mazić, Sanja; Serventi-Seiwerth, Ranka; Mrsić, Mirando; Golubić-Cepulić, Branka; Labar, Boris

    2010-03-01

    Hematopoietic stem cell (HSC) transplantation is a standard approach in the treatment of hematological malignant diseases. For the last 15 years the main source of cells for transplantation have been peripheral blood stem cells (PBSC). With the availability of hematopoietic growth factors and understanding the advantages of treatment with PBSC, the application of bone marrow (BM) was supplanted. The aim of this survey was to explore the success of PBSC collection, the factors which influence the success of PBSC collection, the composition and the quality of graft and their influence on hematopoietic recovery and outcome after transplantation in patients with acute myeloid leukemia (AML). PBSC were collected by the method of leukapheresis after applying a combination of chemotherapy and growth factors or only growth factors. The quality of graft was determined with the clonogenic progenitor cell assay and with the flow cytometry analysis. Of the total 134 patients with AML, who were submitted to HSC mobilization, the collection was successful in 78 (58.2%) patients. The collection was more successful after the first than after the second attempt of HSC mobilization (49% vs. 11%). The criteria for effective mobilization were the number of leukocytes > 3 x 10(9)/L and the concentration of CD34+ cells > 20 x 10(3)/mL in the peripheral blood on the first day of leukapheresis. The number of CD34+ cells infused had the strongest impact on hematopoietic recovery. We noted significantly faster hematological recovery of neutrophils and platelets, fewer number of transfused units of red blood cells and platelets, shorter duration of the tranfusion support, shorter treatment with intravenous antibiotic therapy and shorter hospitalization after PBSC compared to BM transplantation. These advantages could provide their standard application in the treatment of patients with AML.

  7. Oral complications in hematopoietic stem cell recipients: the role of inflammation

    NARCIS (Netherlands)

    Haverman, T. M.; Raber-Durlacher, J. E.; Rademacher, W. M. H.; Vokurka, S.; Epstein, J. B.; Huisman, C.; Hazenberg, M. D.; de Soet, J. J.; de Lange, J.; Rozema, F. R.

    2014-01-01

    Hematopoietic stem cell transplantation (HSCT) is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT

  8. 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

  9. A nationwide survey of the use of plerixafor in patients with lymphoid malignancies who mobilize poorly demonstrates the predominant use of the "on-demand" scheme of administration at French autologous hematopoietic stem cell transplant programs.

    Science.gov (United States)

    Chabannon, Christian; Bijou, Fontanet; Miclea, Jean-Michel; Milpied, Noel; Grouin, Jean-Marie; Mohty, Mohamad

    2015-09-01

    High-dose chemotherapy supported with autologous stem cell transplantation is a standard therapeutic option for a subset of patients with lymphoid malignancies. Cell procurement is nowadays done almost exclusively through cytapheresis, after mobilization of hematopoietic stem and progenitor cells (HSPCs) from the marrow to peripheral blood (PB). The egress of HSPCs out of hematopoietic niches occurs in various physiologic or nonhomeostatic situations; pharmacologic approaches include the administration of acutely myelosuppressive agents or hematopoietic growth factors such as recombinant human granulocyte-colony-stimulating factor (rHuG-CSF). The introduction of plerixafor, a first-of-its-class molecule that reversibly inhibits the interaction between the chemokine CXCL-12 (also known as SDF-1) and its receptor CXCR-4, has offered new opportunities for the so-called "poor mobilizers" who achieve insufficient mobilization and/or collection with conventional approaches. Because of the lack of consensus on a definition for poor mobilizers and the relatively high cost of plerixafor, French competent authorities have mandated a postmarketing survey on its use in routine practice. We report here the results of this nationwide survey that confirms the clinical efficacy of plerixafor, even in the subset of patients who barely increased PB CD34+ cell count in response to rHuG-CSF-containing mobilization regimen. Furthermore, analysis of this registry showed that despite heterogeneity in medical practices, the early-"on-demand" or "preemptive"-introduction of plerixafor was widely used and did not result in an excess of prescriptions, beyond its expected use at the time when marketing authorization was granted. © 2015 AABB.

  10. Hematopoietic stem cells under pressure.

    Science.gov (United States)

    Ganuza, Miguel; McKinney-Freeman, Shannon

    2017-07-01

    Hematopoietic stem cells (HSCs) and progenitors are tasked with maintaining hematopoietic homeostasis in the face of numerous insults and challenges, including infection, inflammation, and exsanguination. HSCs possess the remarkable ability to reconstitute the entire hematopoietic system of an organism whose own hematopoietic system has been ablated. This ability is exploited routinely in the clinic via HSC transplantation (HSCT). Here, we focus on the physiological and molecular bottlenecks overcome by HSCs during transplantation. During transplantation, HSCs encounter a damaged bone marrow niche, characterized molecularly by increases in oxygen concentrations and an altered cytokine milieu. New mechanisms and pathways have been recently implicated during HSCT, including transplanted HSC-dependent secretion of conditioning molecules that facilitate engraftment and pathways that protect HSCs from perturbed organelle homeostasis. Better understanding the molecular processes HSCs employ to withstand the stress of transplant will illuminate novel targets for further improving conditioning regimens and engraftment during HSCT.

  11. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn's Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD-Low Intensity Therapy Evaluation Study Investigators.

    Science.gov (United States)

    Pockley, Alan Graham; Lindsay, James O; Foulds, Gemma A; Rutella, Sergio; Gribben, John G; Alexander, Tobias; Snowden, John A

    2018-01-01

    Patients with treatment refractory Crohn's disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD-Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.

  12. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn’s Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD—Low Intensity Therapy Evaluation Study Investigators

    Science.gov (United States)

    Pockley, Alan Graham; Lindsay, James O.; Foulds, Gemma A.; Rutella, Sergio; Gribben, John G.; Alexander, Tobias; Snowden, John A.

    2018-01-01

    Patients with treatment refractory Crohn’s disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.

  13. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn’s Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD—Low Intensity Therapy Evaluation Study Investigators

    Directory of Open Access Journals (Sweden)

    Alan Graham Pockley

    2018-04-01

    Full Text Available Patients with treatment refractory Crohn’s disease (CD suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs. Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.

  14. Efficacy and safety of autologous bone marrow derived hematopoietic stem cell transplantation in patients with type 2 DM: A 15 months follow-up study

    Directory of Open Access Journals (Sweden)

    Anil Bhansali

    2014-01-01

    Full Text Available Background: there are dearths of studies describing the effect of autologous bone marrow derived stem cell transplantation (ABMSCT through targeted approach in Type 2 Diabetes Mellitus.This study reports the efficacy and safety of super-selective injection of ABMSCT in T2DM. Materials and Methods: Ten patients (8 men and 2 women with T2DM, with duration of disease >5 years and with documented triple drug failure receiving insulin (0.7 U/Kg/day, metformin and pioglitazone underwent super-selective injection of stem cells into superior pancreaticoduodenal artery under fluoroscopic guidance. The primary outcome measure was decrease in insulin requirement by ≥50% (defined as responders, while secondary endpoints were improvement in glucagon stimulated C-peptide levels, changes in weight, HbA1c, lipid profile and quality of life (QOL at the end of 15 months. Results: Six patients (60% were ′responders′ at 15 months of follow-up showing a reduction in mean insulin requirement by 74% as compared to baseline and one patient was off-insulin till the end of the study. Mean HbA1c reduction in ′responders′ was 1.1% (8.1 ± 0.5% to 7.0 ± 0.6%, P = 0.03, accompanied with a significant improvement in glucagon stimulated C-peptide levels (P = 0.03, Homeostasis Model Assessment -β (P = 0.03 and QOL scores. However, ′non-responders′ did not show any significant alterations in these parameters. No serious adverse events were noted. Conclusion: Our observations indicate that ABMSCT is effective in management of T2DM and its efficacy is maintained over a period of 15 months without any adverse events. However, more number of patients and longer duration of follow-up are required to substantiate these observations.

  15. Autologous hematopoietic stem cell transplantation in combination with immunoablative protocol in secondary progressive multiple sclerosis: A 10-year follow-up of the first transplanted patient

    Directory of Open Access Journals (Sweden)

    Obradović Dragana

    2016-01-01

    Full Text Available Introduction. Multiple sclerosis (MS is an immunemediated disease of the central nervous system that affects young individuals and leads to severe disability. High dose immunoablation followed by autologous hemopoietic stem cell transplantation (AHSCT has been considered in the last 15 years as potentialy effective therapeutic approach for agressive MS. The most recent long-time follow-up results suggest that AHSCT is not only effective for highly aggressive MS, but for relapsing-remitting MS as well, providing long-term remission, or maybe even cure. We presented a 10- year follow-up of the first MS patient being treated by immunoablation therapy and AHSCT. Case report. A 27-year-old male experienced the first symptoms - intermitent numbness and paresthesia of arms and legs of what was treated for two years by psychiatrist as anxiety disorder. After he developed severe paraparesis he was admitted to the Neurology Clinic and diagnosed with MS. Our patient developed aggressive MS with frequent relapses, rapid disability progression and transition to secondary progressive form 6 years after MS onset [the Expanded Disability Status Scale (EDSS 7.0 Ambulation Index (AI 7]. AHSCT was performed, cyclophosphamide was used for hemopoietic stem cell mobilization and the BEAM protocol was used as conditionig regimen. No major adverse events followed the AHSCT. Neurological impairment improved, EDSS 6.5, AI 6 and during a 10-year followup remained unchanged. Brain MRI follow-up showed the absence of gadolinium enhancing lesions and a mild progression of brain atrophy. Conclusion. The patient with rapidly evolving, aggressive, noninflammatory MS initialy improved and remained stable, without disability progression for 10 years, after AHSCT. This kind of treatment should be considered in aggressive MS, or in disease modifying treatment nonresponsive MS patients, since appropriately timed AHSCT treatment may not only prevent disability progression but reduce

  16. Autologous hematopoietic stem cell transplantation in combination with immunoablative protocol in secondary progressive multiple sclerosis--A 10-year follow-up of the first transplanted patient.

    Science.gov (United States)

    Obradović, Dragana; Tukić, Ljiljana; Radovinović-Tasić, Sanja; Petrović, Boris; Elez, Marija; Ostojić, Gordana; Balint, Bela

    2016-05-01

    Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that affects young individuals and leads to severe disability. High dose immunoablation followed by autologous hemopoietic stem cell transplantation (AHSCT) has been considered in the last 15 years as potentialy effective therapeutic approach for aggressive MS. The most recent long-time follow-up results suggest that AHSCT is not only effective for highly-aggressive MS, but for relapsing-remitting MS as well, providing long-term remission, or maybe even cure. We presented a 10-year follow-up of the first MS patient being treated by immunoablation therapy and AHSCT. A 27-year-old male experienced the first symptoms--intermitent numbness and paresthesia of arms and legs of what was treated for two years by psychiatrist as anxiety disorder. After he developed severe paraparesis he was admitted to the Neurology Clinic and diagnosed with MS. Our patient developed aggressive MS with frequent relapses, rapid disability progression and transition to secondary progressive form 6 years after MS onset[the Expanded Disability Status Scale (EDSS) 7.0 Ambulation Index (AI) 7]. AHSCT was performed, cyclophosphamide was used for hemopoietic stem cell mobilization and the BEAM protocol was used as conditionig regimen. No major adverse events followed the AHSCT. Neurological impairment improved, EDSS 6.5, AI 6 and during a 10-year follow-up remained unchanged. Brain MRI follow-up showed the absence of gadolinium enhancing lesions and a mild progression of brain atrophy. The patient with rapidly evolving, aggressive, noninflammatory MS initialy improved and remained stable, without disability progression for 10 years, after AHSCT. This kind of treatment should be considered in aggressive MS, or in disease modifying treatment nonresponsive MS patients, since appropriately timed AHSCT treatment may not only prevent disability progression but reduce the achieved level of disability, as well.

  17. 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

  18. Hematopoietic stem cells and the aging hematopoietic system.

    Science.gov (United States)

    Gazit, Roi; Weissman, Irving L; Rossi, Derrick J

    2008-10-01

    The etiology of the age-associated pathophysiological changes of the hematopoietic system including the onset of anemia, diminished adaptive immune competence, and myelogenous disease development are underwritten by the loss of normal homeostatic control. As tissue and organ homeostasis in adults is primarily mediated by the activity of stem and progenitor cells, it has been suggested that the imbalances accompanying aging of the hematopoietic system may stem from alterations in the prevalence and/or functional capacity of hematopoietic stem cells (HSCs) and progenitors. In this review, we examine evidence implicating a role for stem cells in the aging of the hematopoietic system, and focus on the mechanisms suggested to contribute to stem cell aging.

  19. Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention.

    Science.gov (United States)

    Okada, Naoto; Hanafusa, Takeshi; Abe, Shinji; Sato, Chiemi; Nakamura, Toshimi; Teraoka, Kazuhiko; Abe, Masahiro; Kawazoe, Kazuyoshi; Ishizawa, Keisuke

    2016-09-01

    Dysgeusia is one of the sporadic adverse effects induced by chemotherapy, but it remains poorly understood. The aim of this study was to retrospectively identify the risk factors related with dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation (AHSCT). Forty-eight patients with myeloma or lymphoma undergoing AHSCT were enrolled in this study. Data regarding dysgeusia and symptoms were collected by interviews conducted by medical workers. Patient characteristics and unfavorable effects induced by dysgeusia were obtained from medical records and analyzed. Logistic regression analysis was performed to identify the risk factors related with dysgeusia. Of the 48 patients, 20 (42 %) had dysgeusia after AHSCT. The total period of parenteral nutrition (TPN) administration and period of decreased oral intake in the dysgeusia group were statistically longer than those in the non-dysgeusia group. Multivariate analyses revealed that oral mucositis (odds ratio: 30.3; p cryotherapy was the independent suppressive factor of dysgeusia (odds ratio: 0.14; p cryotherapy was an independent suppressive factor for dysgeusia. Therefore, oral cryotherapy should be implemented into the regimen of supportive care management in patients undergoing AHSCT.

  20. Hematopoietic stem cell expansion : challenges and opportunities

    NARCIS (Netherlands)

    Walasek, Marta A.; van Os, Ronald; de Haan, Gerald; Kanz, L; Fibbe, WE; Lengerke, C; Dick, JE

    2012-01-01

    Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell

  1. 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

    2017-12-01

    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

  2. Prognostic Factors and a New Prognostic Index Model for Children and Adolescents with Hodgkin’s Lymphoma Who Underwent Autologous Hematopoietic Stem Cell Transplantation: A Multicenter Study of the Turkish Pediatric Bone Marrow Transplantation Study

    Directory of Open Access Journals (Sweden)

    Vural Kesik

    2016-12-01

    Full Text Available Objective: The prognostic factors and a new childhood prognostic index after autologous hematopoietic stem cell transplantation (AHSCT in patients with relapsed/refractory Hodgkin’s lymphoma (HL were evaluated. Materials and Methods: The prognostic factors of 61 patients who underwent AHSCT between January 1990 and December 2014 were evaluated. In addition, the Age-Adjusted International Prognostic Index and the Childhood International Prognostic Index (CIPI were evaluated for their impact on prognosis. Results: The median age of the 61 patients was 14.8 years (minimummaximum: 5-20 years at the time of AHSCT. There were single relapses in 28 patients, ≥2 relapses in eight patients, and refractory disease in 25 patients. The chemosensitivity/chemorefractory ratio was 36/25. No pretransplant radiotherapy, no remission at the time of transplantation, posttransplant white blood cell count over 10x103/ μL, posttransplant positron emission tomography positivity at day 100, and serum albumin of <2.5 g/dL at diagnosis were correlated with progression-free survival. No remission at the time of transplantation, bone marrow positivity at diagnosis, and relapse after AHSCT were significant parameters for overall survival. Conclusion: The major factors affecting the progression-free and overall survival were clearly demonstrated. A CIPI that uses a lactate dehydrogenase level of 500 IU/L worked well for estimating the prognosis. We recommend AHSCT at first complete remission for relapsed cases, and it should also be taken into consideration for patients with high prognostic scores at diagnosis.

  3. 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

  4. Co-infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and bone marrow derived hematopoietic stem cells, a viable therapy for post-traumatic brachial plexus injury: A case report

    Directory of Open Access Journals (Sweden)

    Umang G Thakkar

    2014-08-01

    Full Text Available Stem cell therapy is emerging as a viable approach in regenerative medicine. A 31-year-old male with brachial plexus injury had complete sensory-motor loss since 16 years with right pseudo-meningocele at C5-D1 levels and extra-spinal extension up to C7-D1, with avulsion on magnetic resonance imaging and irreversible damage. We generated adipose tissue derived neuronal differentiated mesenchymal stem cells (N-AD-MSC and bone marrow derived hematopoietic stem cells (HSC-BM. Neuronal stem cells expressed β-3 tubulin and glial fibrillary acid protein which was confirmed on immunofluorescence. On day 14, 2.8 ml stem cell inoculum was infused under local anesthesia in right brachial plexus sheath by brachial block technique under ultrasonography guidance with a 1.5-inch-long 23 gauge needle. Nucleated cell count was 2 × 10 4 /μl, CD34+ was 0.06%, and CD45-/90+ and CD45-/73+ were 41.63% and 20.36%, respectively. No untoward effects were noted. He has sustained recovery with re-innervation over a follow-up of 4 years documented on electromyography-nerve conduction velocity study.

  5. The biochemistry of hematopoietic stem cell development

    NARCIS (Netherlands)

    P. Kaimakis (Polynikis); M. Crisan (Mihaela); E.A. Dzierzak (Elaine)

    2013-01-01

    textabstractBackground: The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short

  6. High dose chemotherapy followed by autologous peripheral blood stem cell transplantation or conventional pharmacological treatment for refractory rheumatoid arthritis? A Markov decision analysis

    NARCIS (Netherlands)

    Verburg, R. J.; Sont, J. K.; Vliet Vlieland, T. P.; Landewé, R. B.; Boers, M.; Kievit, J.; van Laar, J. M.

    2001-01-01

    To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). Decision analysis using a

  7. Mobilization of hematopoietic progenitor cells for autologous transportation: consensus recommendations

    Directory of Open Access Journals (Sweden)

    Fernando Barroso Duarte

    Full Text Available SUMMARY Selected patients with certain hematological malignancies and solid tumors have the potential to achieve long-term survival with autologous hematopoietic progenitor cell transplant. The collection of these cells in peripheral blood avoids multiple bone marrow aspirations, results in faster engraftment and allows treatment of patients with infection, fibrosis, or bone marrow hypocellularity. However, for the procedure to be successful, it is essential to mobilize a sufficient number of progenitor cells from the bone marrow into the blood circulation. Therefore, a group of Brazilian experts met in order to develop recommendations for mobilization strategies adapted to the reality of the Brazilian national health system, which could help minimize the risk of failure, reduce toxicity and improve the allocation of financial resources.

  8. Stem cells and the aging hematopoietic system.

    Science.gov (United States)

    Beerman, Isabel; Maloney, William J; Weissmann, Irving L; Rossi, Derrick J

    2010-08-01

    Advancing age is accompanied by a number of clinically significant conditions arising in the hematopoietic system that include: diminution and decreased competence of the adaptive immune system, elevated incidence of certain autoimmune diseases, increased hematological malignancies, and elevated incidence of age-associated anemia. As with most tissues, the aged hematopoietic system also exhibits a reduced capacity to regenerate and return to normal homeostasis after injury or stress. Evidence suggests age-dependent functional alterations within the hematopoietic stem cell compartment significantly contribute to many of these pathophysiologies. Recent developments have shed light on how aging of the hematopoietic stem cell compartment contributes to hematopoietic decline through diverse mechanisms. Copyright 2010 Elsevier Ltd. All rights reserved.

  9. A Method for Reconstruction of Severely Damaged Spinal Cord using Autologous Hematopoietic Stem Cells and Platelet-rich Protein as a Biological Scaffold

    OpenAIRE

    Ammar, Ahmed Sabry; Osman, Yasser; Hendam, Ahmed Taher; Hasen, Mohammed Ahmed; Al Rubaish, Fatma Abdullah; Al Nujaidi, Danya Yaagoub; Al Abbas, Faisal Mishal

    2017-01-01

    Introduction: There have been attempts to alter the prognosis of severe spinal cord injury in different centers, but none of which have reliably altered the outcome. Some trials use stem cells (SCs) that produced widely differing results. We hereby add our experience in our center of a surgical reconstruction of the damaged spinal cord using a mixture of SCs and Platelet-Rich Protein (PRP) with fibrin coated as a biological scaffold. Materials and Methods: Four cases of severely damaged spina...

  10. 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

  11. Hematopoietic stem cell transplantation in Europe 2014 : more than 40 000 transplants annually

    NARCIS (Netherlands)

    Passweg, J. R.; Baldomero, H.; Bader, P.; Bonini, C.; Cesaro, S.; Dreger, P.; Duarte, R. F.; Dufour, C.; Kuball, J.; Farge-Bancel, D.; Gennery, A.; Kröger, N.; Lanza, F.; Nagler, A.; Sureda, A.; Mohty, M.

    2016-01-01

    A record number of 40 829 hematopoietic stem cell transplantation (HSCT) in 36 469 patients (15 765 allogeneic (43%), 20 704 autologous (57%)) were reported by 656 centers in 47 countries to the 2014 survey. Trends include: continued growth in transplant activity, more so in Eastern European

  12. 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.

  13. 70th Birthday symposium of Prof. Dr. Riederer: autologous adult stem cells in ischemic and traumatic CNS disorders

    NARCIS (Netherlands)

    de Munter, J.P.J.M.; Wolters, E.C.

    2013-01-01

    Ischemic and traumatic insults of the central nervous system both result in definite chronic disability, only to some extent responsive to rehabilitation. Recently, the application of autologous stem cells (fresh bone marrow-derived mononuclear cells including mesenchymal and hematopoietic stem

  14. O transplante autólogo de células-tronco hematopoéticas no tratamento do Mieloma Múltiplo Autologous hematopoietic stem cell transplant for Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Angelo Maiolino

    2007-03-01

    Full Text Available A quimioterapia em altas doses seguida de transplante autólogo de células-tronco hematopoéticas vem se constituindo ao longo das últimas décadas em um importante instrumento terapêutico, devendo fazer parte da estratégia de tratamento da maior parte dos pacientes com mieloma múltiplo, particularmente daqueles com idade inferior a 65 anos. Pelo menos dois importantes estudos randomizados mostraram vantagens para esta estratégia quando comparadas à quimioterapia convencional. No entanto, a quase totalidade destes pacientes irá recair, necessitando de algum tratamento adicional. A utilização de um segundo transplante, manutenção com talidomida e a introdução de novas drogas como o bortezomibe poderão representar um avanço, melhorando os resultados da estratégia de tratamento do mieloma múltiplo.High dose chemotherapy followed by autologous stem cell transplantation has been recognized as an important step in the treatment of multiple myeloma. At least two well designed randomized studies showed better outcomes in patients treated with high doses compared to those treated with conventional chemotherapy. Nowadays, autologous stem cell transplantation should be considered for all under 65-year-old patients. Although autologous stem cell transplantation has modified the prognosis of myeloma, almost all patients still relapse some time after a single transplant, and then another therapeutic approach becomes necessary. With the aim of improving the results in the treatment of myeloma, new approaches including tandem stem cell transplantation, maintenance with thalidomide and new drugs such as bortezomib are being tested. Strategies including these approaches and autologous stem cell transplantation may improve the results of the treatment of myeloma in the future.

  15. 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

  16. 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...

  17. 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.

  18. 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...... in the context of stem cell tracking in vivo. This review concludes with a section on the unexpected potential of bone marrow-derived stem cells to contribute to the repair of damaged tissues. The contribution of cell fusion to explain the latter phenomenon is discussed. SUMMARY: Because of exciting discoveries...... 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...

  19. Autologous Stem Cell Transplant for AL Amyloidosis

    OpenAIRE

    Roy, Vivek

    2012-01-01

    AL amyloidosis is caused by clonal plasma cells that produce immunoglobulin light chains which misfold and get deposited as amyloid fibrils. Therapy directed against the plasma cell clone leads to clinical benefit. Melphalan and corticosteroids have been the mainstay of treatment for a number of years and the recent availability of other effective agents (IMiDs and proteasome inhibitors) has increased treatment options. Autologous stem cell transplant (ASCT) has been used in the treatment of ...

  20. Sleep disruption among cancer patients following autologous hematopoietic cell transplantation.

    Science.gov (United States)

    Nelson, Ashley M; Jim, Heather S L; Small, Brent J; Nishihori, Taiga; Gonzalez, Brian D; Cessna, Julie M; Hyland, Kelly A; Rumble, Meredith E; Jacobsen, Paul B

    2018-03-01

    Despite a high prevalence of sleep disruption among hematopoietic cell transplant (HCT) recipients, relatively little research has investigated its relationships with modifiable cognitive or behavioral factors or used actigraphy to characterize sleep disruption in this population. Autologous HCT recipients who were 6-18 months post transplant completed self-report measures of cancer-related distress, fear of cancer recurrence, dysfunctional sleep cognitions, and inhibitory sleep behaviors upon enrollment. Patients then wore an actigraph for 7 days and completed a self-report measure of sleep disruption on day 7 of the study. Among the 84 participants (age M = 60, 45% female), 41% reported clinically relevant sleep disruption. Examination of actigraph data confirmed that, on average, sleep was disrupted (wake after sleep onset M = 66 min) and sleep efficiency was less than recommended (sleep efficiency M = 78%). Cancer-related distress, fear of recurrence, dysfunctional sleep cognitions, and inhibitory sleep behaviors were related to self-reported sleep disruption (p valuesdisruption after transplant. Cancer-related distress, fear of recurrence, dysfunctional sleep cognitions, and maladaptive sleep behaviors are related to self-reported sleep disruption and should be considered targets for cognitive behavioral intervention in this population.

  1. Fever and neutropenia in pediatric hematopoietic stem cell transplant patients.

    Science.gov (United States)

    Mullen, C A; Nair, J; Sandesh, S; Chan, K W

    2000-01-01

    The objective of this study was to identify patterns of fever and neutropenia in pediatric patients undergoing initial hospitalization for hematopoietic stem cell transplantation. A retrospective review of 75 HSCTs over a 4-year period at a single institution was performed, of which 68% were allogeneic and 32% were autologous. Stem cell sources included bone marrow (29%), PBSC (52%) and umbilical cord blood (16%). Fever occurred in 74 (98%) of the episodes. Unexplained fever (FUO) occurred in 43%. Bacteremia without an anatomic focus occurred in 29%, while CVC associated infections occurred in 17%. In 49% of transplants at least one blood culture was positive. The incidence of bacteremia was higher in allogeneic HSCTs (58%) than in autologous transplants (29%). Gram-positive bacteria accounted for 71% of the isolates. Lower rates of bacteremia were observed in patients receiving oral fluoroquinolone prophylaxis. The median duration of fever was 12.5 days and time to engraftment 14 days. Regression analysis demonstrated that duration of fever was strongly associated with time to engraftment, and that time to engraftment was associated with source of cells and number of CD34+ cells/kg administered. Recipients of autologous PBSC had the shortest durations of fever and time to engraftment, while recipients of allogeneic umbilical cord blood had the longest. Bone Marrow Transplantation (2000) 25, 59-65.

  2. Rescuing Self: Transient Isolation and Autologous Transplantation of Bone Marrow Mitigates Radiation-Induced Hematopoietic Syndrome and Mortality in Mice.

    Science.gov (United States)

    Ghosh, Subhajit; Indracanti, Namita; Joshi, Jayadev; Indraganti, Prem Kumar

    2017-01-01

    The inflamed bone marrow niche shortly after total body irradiation (TBI) is known to contribute to loss of hematopoietic stem cells in terms of their number and function. In this study, autologous bone marrow transfer (AL-BMT) was evaluated as a strategy for mitigating hematopoietic form of the acute radiation syndrome by timing the collection phase (2 h after irradiation) and reinfusion (24 h after irradiation) using mice as a model system. Collection of bone marrow (BM) cells (0.5 × 10 6 total marrow cells) 2 h after lethal TBI rescued different subclasses of hematopoietic stem and progenitor cells (HSPCs) from the detrimental inflammatory and damaging milieu in vivo . Cryopreservation of collected graft and its reinfusion 24 h after TBI significantly rescued mice from lethal effects of irradiation (65% survival against 0% in TBI group on day 30th) and hematopoietic depression. Transient hypometabolic state (HMS) induced 2 h after TBI effectively preserved the functional status of HSPCs and improved hematopoietic recovery even when BM was collected 8 h after TBI. Homing studies suggested that AL-BMT yielded similar percentages for different subsets of HSPCs when compared to syngeneic bone marrow transfer. The results suggest that the timing of collection, and reinfusion of graft is crucial for the success of AL-BMT.

  3. 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

  4. 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

  5. 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.

  6. Hematopoietic Stem Cell Approaches to Cancer.

    Science.gov (United States)

    Adair, Jennifer E; Kubek, Sara P; Kiem, Hans-Peter

    2017-10-01

    Hematopoietic stem cells (HSCs) are unique in their ability to self-renew and generate all blood lineages for the entire life. HSC modification affects red blood cells, platelets, lymphocytes, and myeloid cells. Chemotherapy can result in myelosuppression, limiting effective chemotherapy administration. For diseases like glioblastoma, high expression of methlylguanine methyltransferase can inactivate alkylating agent chemotherapy. Here we discuss how HSCs can be modified to overcome this resistance, permitting sensitization of tumors to chemotherapy while simultaneously protecting the hematopoietic system. We also discuss how HSCs can be harnessed to produce powerful tumor killing T cells, potentially benefitting and complementing T-cell-based immunotherapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. 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....../progenitor cells (HSPCs, Lin(neg)Sca-1(+)c-Kit(+)) or myeloid committed precursors (Lin(neg)Sca-1(-)c-Kit(+)). By employing stable isotope dimethyl labeling and high-resolution mass spectrometry, more than 5,000 proteins were quantified. From biological triplicate experiments subjected to rigorous statistical...

  8. Transplante de células-tronco hematopoéticas para tumores sólidos: recomendações do Consenso Brasileiro de Transplante de Medula Óssea Autologous hematopoietic stem cell transplantation in solid tumors: the Brazilian Consensus on Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Décio Lerner

    2010-05-01

    Full Text Available O transplante de células-tronco hematopoéticas autólogo permite o escalonamento de dose de drogas quimioterápicas e é uma estratégia atraente para tratamento de tumores sólidos, principalmente em doenças recaídas. Não há, no entanto, estudos randomizados fase III que demonstrem benefício deste procedimento em tumor sólido. Em tumor germinativo de testículo, há estudos fase II com excelentes resultados, proporcionando cura para doentes refratários a platina ou que estão em terceira linha de quimioterapia. Com base nisto, o transplante de células-tronco hematopoéticas autólogo é considerado tratamento padrão para tumor germinativo recaído. Para câncer de mama, o papel desta modalidade de tratamento permanece controverso apesar dos vinte anos de experiência. Ainda é utilizado em ensaios clínicos e talvez exista algum subgrupo que se beneficie. O procedimento não oferece benefício para câncer de ovário, pulmão ou tumor cerebral. O transplante alogeneico de células-tronco hematopoéticas para tumores sólidos se baseia no efeito enxerto-contra-tumor, que é observado para algumas doenças: câncer mamário, colorretal, ovariano, pancreático e, finalmente, renal, em que há a maior experiência. Porém, o tratamento ainda é considerado experimental.Autologous hematopoietic stem cell transplantation, which allows chemotherapy dose-escalonation, is an attractive strategy for solid tumors treatment, specially relapsed diseases. However, there are no phase III trials showing benefits. There are phase II trials showing excellent results for germ cell tumors, including cure for platinrefractory and heavily pretreated patients. Because of this, autologous stem cell transplantation is considered standard of care for relapsed germ cell tumor. The role of this treatment remains controversial for breast cancer despite twenty years of experience. It’s still done in clinical trials and it may benefit a subgroup of patients. The

  9. COST OF HEMATOPOIETIC STEM CELL TRANSPLANTATION IN INDIA

    Directory of Open Access Journals (Sweden)

    Sanjeev Kumar Sharma

    2014-06-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is the definite cure for many hematological diseases. With the increasing indications for HSCT and its relatively low cost in Indian subcontinent, an increasing number of patients are opting for this procedure. We retrospectively analyzed the cost of one hundred sixty two HSCTs done at our center in the last three years. The median cost of autologous transplant was INR 7,52,294 (USD, $ 12,500 (range INR 6,19,850-14,17,212 and the median cost of allogenic transplant was INR 10,74,881 ($18,000 (range INR 6,49,944-23,82,227. The cost of HSCT is cheaper here compared to that in developed countries and success rates are nearly equivalent. The major factors contributing to the cost are related to the complications post-transplant mainly infections and graft versus host disease, which are also the reasons for the increased stay in the hospital.

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

    Science.gov (United States)

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

    2013-12-01

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

  11. [National care logbook for patients undergoing autologous hematopoietic cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    Science.gov (United States)

    Porcheron, Sophie; Balcaen, Sandie; Cardinael, Nathalie; Courbon, Corinne; Dendoncker, Caroline; Faivre-Lescat, Hélène; François, Ghislaine; Gilis, Lila; Guiraud, Myriam; Schmitt, Stéphanie; Vercasson, Marlene; Adam, Catherine; Yakoub-Agha, Ibrahim

    2017-12-01

    In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its seventh annual workshop series in September 2016 in Lille. This event brought together practitioners from across the country. Our workshop discusses the creation of a patient care logbook for patients undergoing autologous hematopoietic cell transplantation. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  12. Autologous Stem Cell Transplant for AL Amyloidosis

    Directory of Open Access Journals (Sweden)

    Vivek Roy

    2012-01-01

    Full Text Available AL amyloidosis is caused by clonal plasma cells that produce immunoglobulin light chains which misfold and get deposited as amyloid fibrils. Therapy directed against the plasma cell clone leads to clinical benefit. Melphalan and corticosteroids have been the mainstay of treatment for a number of years and the recent availability of other effective agents (IMiDs and proteasome inhibitors has increased treatment options. Autologous stem cell transplant (ASCT has been used in the treatment of AL amyloidosis for many years. It is associated with high rates of hematologic response and improvement in organ function. However, transplant carries considerable risks. Careful patient selection is important to minimize transplant related morbidity and mortality and ensure optimal patient outcomes. As newer more affective therapies become available the role and timing of ASCT in the overall treatment strategy of AL amyloidosis will need to be continually reassessed.

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  17. Clinical analysis of hematopoiesis reconstruction after total body irradiation in hematopoietic stem cell transplantation

    International Nuclear Information System (INIS)

    Fang Tong; Gao Hong; Sun Baojing; Chen Li

    2008-01-01

    Objective: To analyze the clinical outcome of total body irradiation in hematopoiesis reconstruction after autologous and allogeneic hematopoietic stem cell transplantation. Methods: 35 patients received autologous hematopoietic stem cell transplantation (ASCT group) and 35 patients received allogeneic hematopoietic stem cell transplantation (Allo-HSCT group) were enrolled in this study. And their hematopoiesis reconstruction were observed and analyzed. Results: The recovery time of ANC were 14 and 16 d, respectively, and the recovery time of PLT were 23 and 27 d, respectively, the difference were not significant (P>0.05) in ASCT group and Allo-HSCT group. But for both group, hematopoiesis reconstruction were faster in peripheral blood stem cell transplant than those in bone marrow transplant (P<0.05). The recovery time of PLT with the patients of total body irradiation dose ≥ 10 Gy were longer than those of < 10 Gy. Conclusions: At the same doses, the clinical outcome of hematopoiesis reconstruction of ASCT is similar to that of Allo-HSCT. But the recovery time in peripheral blood stem cell transplantation is faster than that in bone marrow transplant. The recovery time of PLT has relation with the irradiation dose. (authors)

  18. Prostaglandin E2 regulates hematopoietic stem cell

    International Nuclear Information System (INIS)

    Wang Yingying; Zhou Daohong; Meng Aimin

    2013-01-01

    Prostaglandin E2 (PGE2) is a bioactive lipid molecule produced by cyclooxygenase (COX), which plays an important role on hematopoiesis. While it can block differentiation of myeloid progenitors but enhance proliferation of erythroid progenitors. Recent research found that PGE2 have the effects on hematopoietic stem cell (HSC) function and these effects were independent from effects on progenitor cells. Exposure of HSC cells to PGE2 in vitro can increase homing efficiency of HSC to the murine bone marrow compartment and decrease HSC apoptosis, meanwhile increase long-term stem cell engraftment. In-vivo treatment with PGE2 expands short-term HSC and engraftment in murine bone marrow but not long-term HSC.In addition, PGE2 increases HSC survival after radiation injury and enhance hematopoietic recovery, resulting maintains hematopoietic homeostasis. PGE2 regulates HSC homeostasis by reactive oxygen species and Wnt pathway. Clinical beneficial of 16, 16-dimethyl-prostaglandin E2 treatment to enhance engraftment of umbilical cord blood suggest important improvements to therapeutic strategies. (authors)

  19. Epigenetic regulation of hematopoietic stem cell aging

    International Nuclear Information System (INIS)

    Beerman, Isabel; Rossi, Derrick J.

    2014-01-01

    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

  20. 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.

  1. Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells.

    Directory of Open Access Journals (Sweden)

    Yulan Qing

    Full Text Available Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs, creating a preleukemic stem cell (PLSC. Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC. Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM, but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.

  2. [Autologous stem cell transplantation for autoimmune diseases: recommendations from the SFGM-TC].

    Science.gov (United States)

    Farge, D; Terriou, L; Badoglio, M; Cras, A; Desreumaux, P; Hadj-Khelifa, S; Marjanovic, Z; Moisan, A; Dulery, R; Faucher, C; Hij, A; Martin, T; Vermersch, P; Yakoub-Agha, I

    2014-08-01

    Autologous hematopoietic stem cell transplantation is a valid alternative to immunosuppressive treatment in patients with auto-immune disease; however, the role of this approach remains subject to debate. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. In this article we give an overview regarding the indications of autologous stem cell transplantation in auto-immune diseases as well as recommendations regarding post-transplant follow-up of patients. Copyright © 2014. Published by Elsevier SAS.

  3. 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.

  4. Genetic Modification of Hematopoietic Stem Cells as a Therapy for HIV/AIDS

    Directory of Open Access Journals (Sweden)

    Patrick Younan

    2013-11-01

    Full Text Available 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.

  5. Complications of allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

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

    2014-08-01

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

  6. Mechanism of hematopoietic stem cell homing

    International Nuclear Information System (INIS)

    Jiang Fuquan

    2000-01-01

    The clinical transplantation of hematopoietic stem cell (HSC) originating from many sources such as bone marrow, peripheral blood and cord blood has been widely applied in recent years. At the same time, the development of the study on the mechanism of HSC homing which involves multi-procedures has been achieved. And a lot of molecular and cytokines on the surface or in the microenvironment of HSC are functioning in homing. The purpose of is to review those molecular and cytokines on which more studies have been focused in the past

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

    Science.gov (United States)

    Ramzi, Mani; Vojdani, Reza; Haghighinejad, Hourvash

    2018-01-02

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

  8. Autologous Mesenchymal Stem Cells in Chronic Stroke

    Directory of Open Access Journals (Sweden)

    Ashu Bhasin

    2011-12-01

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

  9. Impact of autologous hematopoietic stem cell transplantation on the quality of life of type 1 diabetes mellitus patients Impacto do transplante de células-tronco hematopoéticas sobre a qualidade de vida de pacientes com diabetes mellitus tipo 1

    Directory of Open Access Journals (Sweden)

    Manoel Antônio dos Santos

    2011-01-01

    Full Text Available The present study aimed at assessing the health-related quality of life (HRQoL of patients with type 1 diabetes mellitus (DM1 submitted to autologous hematopoietic stem cell transplantation (HSCT. This study is part of a pioneering research protocol which tests the applicability of autologous hematopoietic stem cell transplantation as a new therapeutic approach to DM1. The study was conducted on 14 patients admitted to the ward of the Bone Marrow Transplantation Unit of a university hospital during the period from October 2006 to December 2007. The patients were evaluated at admission and on the occasion of the ambulatory return visit 100 days after transplantation. They answered the SF-36 quality of life questionnaire and the data were analyzed according to literature recommendations. The results showed that 100 days after transplantation the value of the patients' quality of life was higher compared to the pre-HSCT value, with significant differences in the Physical Domains (Role Limitations due to Physical Problems (p = .009, Vitality (p = .02 and Mental Health (p = .04, demonstrating significant appreciation of those domains after the procedure. The results indicate an improvement in HRQoL after HSCT. The SF-36 proved to be a useful instrument for the assessment of quality of life in patients with DM1 submitted to HSCT.Este estudo teve como objetivo avaliar a qualidade de vida relacionada à saúde (QVRS de pacientes com diabetes mellitus tipo 1 (DM1 submetidos ao Transplante de Células-Tronco Hematopoéticas (TCTH. O estudo é parte de um protocolo de pesquisa pioneiro no mundo, que testa a aplicabilidade do TCTH como nova abordagem terapêutica no DM1. Foram investigados 14 pacientes, que constituíram a população de pessoas internadas na enfermaria da Unidade de Transplante de Medula Óssea de um hospital universitário, no período de outubro de 2006 a dezembro de 2007. Os pacientes foram avaliados na admissão e no retorno

  10. Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

    Science.gov (United States)

    2016-10-01

    mouse hematopoietic stem cells ex vivo by reprogramming cellular metabolism. Blood. 2015;125(10):1562-1565. 54. Nath N, Khan M, Paintlia MK, Singh I...Award Number: W81XWH-14-1-0297 TITLE: Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells PRINCIPAL INVESTIGATOR: Raymond J...Molecule Protection of Bone Marrow Hematopoietic Stem Cells Stem Cells ’ 5a. CONTRACT NUMBER W81XWH-14-1-0297 W81XWH-14-1-0297 W81XWH-14-1-0297 5b

  11. Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells.

    Science.gov (United States)

    Slukvin, Igor I

    2013-12-12

    Significant advances in cellular reprogramming technologies and hematopoietic differentiation from human pluripotent stem cells (hPSCs) have already enabled the routine production of multiple lineages of blood cells in vitro and opened novel opportunities to study hematopoietic development, model genetic blood diseases, and manufacture immunologically matched cells for transfusion and cancer immunotherapy. However, the generation of hematopoietic cells with robust and sustained multilineage engraftment has not been achieved. Here, we highlight the recent advances in understanding the molecular and cellular pathways leading to blood development from hPSCs and discuss potential approaches that can be taken to facilitate the development of technologies for de novo production of hematopoietic stem cells.

  12. Inflammatory signals regulate hematopoietic stem cells.

    Science.gov (United States)

    Baldridge, Megan T; King, Katherine Y; Goodell, Margaret A

    2011-02-01

    Hematopoietic stem cells (HSCs) are the progenitors of all blood and immune cells, yet their role in immunity is not well understood. Most studies have focused on the ability of committed lymphoid and myeloid precursors to replenish immune cells during infection. Recent studies, however, have indicated that HSCs also proliferate in response to systemic infection and replenish effector immune cells. Inflammatory signaling molecules including interferons, tumor necrosis factor-α and Toll-like receptors are essential to the HSC response. Observing the biology of HSCs through the lens of infection and inflammation has led to the discovery of an array of immune-mediators that serve crucial roles in HSC regulation and function. Copyright © 2010 Elsevier Ltd. All rights reserved.

  13. [Treatment of relapsed Hodgkin lymphoma after autologous stem cell transplantation].

    Science.gov (United States)

    Illés, Árpád; Simon, Zsófia; Udvardy, Miklós; Magyari, Ferenc; Jóna, Ádám; Miltényi, Zsófia

    2017-08-01

    Approximately 10-30% of Hodgkin lymphoma patients relapses or experience refractory disease after first line treatment. Nowadays, autologous stem cell transplantation can successfully salvage half of these patients, median overall survival is only 2-2.5 years. Several prognostic factors determine success of autologous stem cell transplantation. Result of transplantation can be improved considering these factors and using consolidation treatment, if necessary. Patients who relapse after autologous transplantation had worse prognosis, treatment of this patient population is unmet clinical need. Several new treatment options became available in the recent years (brentuximab vedotin and immuncheckpoint inhibitors). These new treatment options offer more chance for cure in relapsed/refractory Hodgkin patients. Outcome of allogenic stem cell transplantation can be improved by using haploidentical donors. New therapeutic options will be discussed in this review. Orv Hetil. 2017; 158(34): 1338-1345.

  14. Intensive care outcomes in adult hematopoietic stem cell transplantation patients.

    Science.gov (United States)

    Bayraktar, Ulas D; Nates, Joseph L

    2016-02-10

    Although outcomes of intensive care for patients undergoing hematopoietic stem cell transplantation (HSCT) have improved in the last two decades, the short-term mortality still remains above 50% among allogeneic HSCT patients. Better selection of HSCT patients for intensive care, and consequently reduction of non-beneficial care, may reduce financial costs and alleviate patient suffering. We reviewed the studies on intensive care outcomes of patients undergoing HSCT published since 2000. The risk factors for intensive care unit (ICU) admission identified in this report were primarily patient and transplant related: HSCT type (autologous vs allogeneic), conditioning intensity, HLA mismatch, and graft-versus-host disease (GVHD). At the same time, most of the factors associated with ICU outcomes reported were related to the patients' functional status upon development of critical illness and interventions in ICU. Among the many possible interventions, the initiation of mechanical ventilation was the most consistently reported factor affecting ICU survival. As a consequence, our current ability to assess the benefit or futility of intensive care is limited. Until better ICU or hospital mortality prediction models are available, based on the available evidence, we recommend practitioners to base their ICU admission decisions on: Patient pre-transplant comorbidities, underlying disease status, GVHD diagnosis/grade, and patients' functional status at the time of critical illness.

  15. 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.

  16. The optimal time for autologous hematopoietic progenitor cell transplantation during treatment of Hodgkin's lymphoma. Foreign recommendations and russian experience

    Directory of Open Access Journals (Sweden)

    N. V. Zhukov

    2014-01-01

    Full Text Available Autologous hematopoietic stem cell transplantation (HSCT is the standard treatment for patients with relapsed and primary refractoryHodgkin's lymphoma (HL. According to current recommendations HSCT must be performed in first relapse or after registration of primary resistance disease. However, the HSCT in optimal time for all patients with HL who need it is impossible, due to insufficient capacity of national transplant centers. Analysis of the HSCT results from 369 HL patients treated in Russia and other CIS countries clinics showed that intensive long-term standard chemotherapy prior to transplantation is a poor prognostic factor regarding to mobilization efficacy, hematopoiesis recovery and late HSCT results. In this regard, to achieve best results HSCT must be performed no later than the second relapse or immediately after registrationof primary resistance disease. Treatment results in patients received a lot of chemotherapy before transplantation is worse. But they stillhave a chance for a cure and should be considered as potential candidates to HSCT if obtained sufficient graft quality and hematopoietic response to induction chemotherapy is achieved.

  17. The optimal time for autologous hematopoietic progenitor cell transplantation during treatment of Hodgkin's lymphoma. Foreign recommendations and russian experience

    Directory of Open Access Journals (Sweden)

    N. V. Zhukov

    2014-09-01

    Full Text Available Autologous hematopoietic stem cell transplantation (HSCT is the standard treatment for patients with relapsed and primary refractoryHodgkin's lymphoma (HL. According to current recommendations HSCT must be performed in first relapse or after registration of primary resistance disease. However, the HSCT in optimal time for all patients with HL who need it is impossible, due to insufficient capacity of national transplant centers. Analysis of the HSCT results from 369 HL patients treated in Russia and other CIS countries clinics showed that intensive long-term standard chemotherapy prior to transplantation is a poor prognostic factor regarding to mobilization efficacy, hematopoiesis recovery and late HSCT results. In this regard, to achieve best results HSCT must be performed no later than the second relapse or immediately after registrationof primary resistance disease. Treatment results in patients received a lot of chemotherapy before transplantation is worse. But they stillhave a chance for a cure and should be considered as potential candidates to HSCT if obtained sufficient graft quality and hematopoietic response to induction chemotherapy is achieved.

  18. Therapeutic Potential of Autologous Stem Cell Transplantation for Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Chaitanya Purandare

    2012-01-01

    Full Text Available Background. Cerebral palsy (CP is a severe disabling disease with worldwide incidence being 2 to 3 per 1000 live births. CP was considered as a noncurable, nonreparative disorder, but stem cell therapy offers a potential treatment for CP. Objective. The present study evaluates the safety and efficacy of autologous bone-marrow-derived mononuclear cell (BMMNCs transplantation in CP patient. Material and Methods. In the present study, five infusions of autologous stem cells were injected intrathecally. Changes in neurological deficits and improvements in function were assessed using Gross Motor Function Classification System (GMFCS-E&R scale. Results. Significant motor, sensory, cognitive, and speech improvements were observed. Bowel and bladder control has been achieved. On the GMFCS-E&R level, the patient was promoted from grade III to I. Conclusion. In this study, we report that intrathecal infusion of autologous BMMNCs seems to be feasible, effective, and safe with encouraging functional outcome improvements in CP patient.

  19. Retroviral transduction of murine and human hematopoietic progenitors and stem cells.

    Science.gov (United States)

    Ciuculescu, Marioara F; Brendel, Christian; Harris, Chad E; Williams, David A

    2014-01-01

    Genetic modification of cells using retroviral vectors is the method of choice when the cell population is difficult to transfect and/or requires persistent transgene expression in progeny cells. There are innumerable potential applications for these procedures in laboratory research and clinical therapeutic interventions. One paradigmatic example is the genetic modification of hematopoietic stem and progenitor cells (HSPCs). These are rare nucleated cells which reside in a specialized microenvironment within the bone marrow, and have the potential to self-renew and/or differentiate into all hematopoietic lineages. Due to their enormous regenerative capacity in steady state or under stress conditions these cells are routinely used in allogeneic bone marrow transplantation to reconstitute the hematopoietic system in patients with metabolic, inflammatory, malignant, and other hematologic disorders. For patients lacking a matched bone marrow donor, gene therapy of autologous hematopoietic stem cells has proven to be an alternative as highlighted recently by several successful gene therapy trials. Genetic modification of HSPCs using retrovirus vectors requires ex vivo manipulation to efficiently introduce the new genetic material into cells (transduction). Optimal culture conditions are essential to facilitate this process while preserving the stemness of the cells. The most frequently used retroviral vector systems for the genetic modifications of HSPCs are derived either from Moloney murine leukemia-virus (Mo-MLV) or the human immunodeficiency virus-1 (HIV-1) and are generally termed according to their genus gamma-retroviral (γ-RV) or lentiviral vectors (LV), respectively. This chapter describes in a step-by-step fashion some techniques used to produce research grade vector supernatants and to obtain purified murine or human hematopoietic stem cells for transduction, as well as follow-up methods for analysis of transduced cell populations.

  20. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma

    DEFF Research Database (Denmark)

    Mellqvist, Ulf-Henrik; Gimsing, Peter; Hjertner, Oyvind

    2013-01-01

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370...

  1. Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Mgbemena, Victoria E; Signer, Robert A J; Wijayatunge, Ranjula; Laxson, Travis; Morrison, Sean J; Ross, Theodora S

    2017-01-24

    BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1 F22-24/F22-24 ) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1 BRCA1/BRCA1 ) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1 F22-24/5382insC ) had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  2. Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function

    Directory of Open Access Journals (Sweden)

    Victoria E. Mgbemena

    2017-01-01

    Full Text Available BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1F22–24/F22–24 developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs. Although mice homozygous for a huBRCA1 knockin allele (Brca1BRCA1/BRCA1 were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1F22–24/5382insC had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction.

  3. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    OpenAIRE

    Kosan, Christian; Godmann, Maren

    2015-01-01

    All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several trans...

  4. Dynamic changes in mouse hematopoietic stem cell numbers during aging

    NARCIS (Netherlands)

    de Haan, G; Van Zant, G

    1999-01-01

    To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The

  5. 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

  6. Comparison of Two Apheresis Systems of COBE and Optia for Autologous Peripheral Blood Stem Cell Collection.

    Science.gov (United States)

    Lee, Se Na; Sohn, Ji Yeon; Kong, Jung Hee; Eom, Hyeon Seok; Lee, Hyewon; Kong, Sun Young

    2017-07-01

    Peripheral blood stem cell (PBSC) transplantation following myeloablative therapy is a mainstay of treatment for various types of malignancies. This study aimed to evaluate the differences between the Optia MNC and COBE Spectra MNC systems (Terumo BCT, Japan) according to apheresis procedures and the parameters of apheresis, products, and collection. The clinical data of 74 patients who underwent autologous PBSC collection from July 2012 to July 2015 were reviewed retrospectively. The patients comprised 48 (65%) men and 26 (35%) women with a median age of 56 yr (range, 23-66 yr). Of 216 procedures, 111 (51%) and 105 (49%) were processed by using COBE and Optia MNC, respectively. PBSC collection rates, throughput, numbers of stem cells retrieved, collection efficacy, and platelet loss were compared. There were no significant differences in the median CD34+ cell counts of collected products (0.61×10⁸ vs 0.94×10⁸), CD34 collection efficiency (43.5% vs 42.1%), and loss of platelets (40.1% vs 44.7%). The Spectra Optia MNC apheresis system was comparable to the COBE Spectra system in collecting autologous CD34+ hematopoietic stem cells and retention of platelets. © The Korean Society for Laboratory Medicine.

  7. Quality of life (QOL), supportive care, and spirituality in hematopoietic stem cell transplant (HSCT) patients.

    Science.gov (United States)

    Sirilla, Janet; Overcash, Janine

    2013-04-01

    For many patients, a hematopoietic stem cell transplant (HSCT) can be challenging to physical and emotional health. Supportive care needs can be overwhelming for many patients and families. The purpose of this study was to evaluate the effect of quality of life (QOL), spiritual well-being, and supportive care resources post-HSCT. This descriptive, repeated-measures study included people over the age of 18 years undergoing HSCT for any cancer diagnosis. The Functional Assessment in Cancer Therapy--Bone Marrow Transplant scale, the Functional Assessment of Chronic Illness Therapy--Spiritual--12 scale, and a resource questionnaire were administered prior to HSCT and following HSCT at 30, 60, 90, and 180 days. Three groups of HSCT patients were examined: allogeneic, autologous, and overall. Data analysis included descriptive statistics and correlations. In the sample (n = 159), the autologous HSCT group reported the highest QOL scores. Spirituality scores increased for the autologous HSCT group at 90 days, but decreased for the overall and allogeneic groups. The type of supportive care resources most used were information from the physician and nurse, the Leukemia and Lymphoma Society Support as the most used form of support group, and Faith, Prayer and Spiritual Healing. QOL and spiritual well-being scores correlated best at 180 days (6 months) for autologous and allogeneic patients.

  8. 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

  9. 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

  10. The aging hematopoietic stem cell niche: Phenotypic and functional changes and mechanisms that contribute to hematopoietic aging.

    Science.gov (United States)

    Latchney, Sarah E; Calvi, Laura M

    2017-01-01

    The hematopoietic system has the remarkable ability to provide a lifelong supply of mature cells that make up the entire blood and immune system. However, similar to other adult stem cell niches, the hematopoietic system is vulnerable to the detrimental effects of aging. This is a substantial health concern as the trend for population aging continues to increase. Identifying mechanisms that underlie hematopoietic aging is vital for understanding hematopoietic-related diseases. In this review, we first discuss the cellular hierarchy of the hematopoietic system and the components that make up the surrounding hematopoietic niche. We then provide an overview of the major phenotypes associated with hematopoietic aging and discuss recent research investigating cell-intrinsic and cell-extrinsic mechanisms of hematopoietic stem cell (HSCs) aging. We end by discussing the exciting new concept of possibly reversing the HSC aging process along with outstanding questions that remain to be answered. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. 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.

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  20. Hematopoietic stem cell transplant candidate and designated proxy distress levels prior to hematopoietic stem cell transplantation.

    Science.gov (United States)

    Duckworth, Katharine E; Forti, Allison M; Russell, Gregory B; Naik, Seema; Hurd, David D; McQuellon, Richard P

    2014-12-01

    Hematopoietic stem cell transplantation (HCT) is associated with a high risk of morbidity, making advance care planning (ACP) essential. The purpose of this study was to assess and compare proxy and HCT candidate distress levels (Distress Thermometer) before (T1) and after (T2) ACP question completion. 79 participants (40 HCT candidates, 39 proxies) rated their distress. The T1, T2 mean distress scores (SD) for HCT candidates were 3.13(2.27), 2.96(2.10); 43% and 38% endorsed clinically significant distress (≥4). Proxies reported 4.21(2.48), 4.33 (2.46); 62% endorsed significant distress at T1, T2. The majority of proxies endorsed distress levels that were clinically significant and comparatively higher (T1 (p = 0.047) and T2 (p = 0.009)) than their paired HCT recipients. Responding to questions about ACP did not increase overall distress ratings. © The Author(s) 2013.

  1. Clinical use of plerixafor in combination with granulocyte-colony stimulating factor in hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Cedar J Fowler

    2010-05-01

    Full Text Available Cedar J Fowler1, Richard T Maziarz21Laboratory of Clinical Infectious Diseases – NIAID, National Institutes of Health, Bethesda, MD, USA; 2Adult Blood and Marrow Stem Cell Transplant Program, Oregon Health and Science University, Portland, OR, USAAbstract: Plerixafor is a CXC4:CXCL12 antagonist that has an expanding role in the stem cell mobilization phase of the hematopoietic stem cell transplant procedure. The drug is currently licensed by the FDA to be used in combination with granulocyte colony stimulating factor (G-CSF to mobilize hematopoietic stem cells into the peripheral blood for collection and subsequent autologous transplantations in patients with non-Hodgkin’s lymphoma and multiple myeloma. Plerixafor is particularly useful in patients who have been heavily pretreated or as effective therapy for frontline salvage of poor peripheral blood stem cells mobilizers. In conjunction with G-CSF, plerixafor can be successful in decreasing the number of apheresis days and therefore the associated additional risks and cost of more apheresis procedures. Patients taking plerixafor, when compared to the side effect profile of G-CSF alone, do not report significantly more side effects.Keywords: plerixafor, AMD3100, autologous stem cell mobilization, non-Hodgkin’s lymphoma, multiple myeloma, CXCR4, CXCL12

  2. Hematopoietic (stem) cell development - how divergent are the roads taken?

    Science.gov (United States)

    Kauts, Mari-Liis; Vink, Chris S; Dzierzak, Elaine

    2016-11-01

    The 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 generation. In contrast to HSCs in the adult, which differentiate via intermediate progenitor populations to produce functional blood cells, the generation of hematopoietic cells in the embryo prior to HSC generation occurs in the early waves by producing blood cells without intermediate progenitors (such as the 'primitive' hematopoietic cells). The lineage relationship between the early hematopoietic cells and the cells giving rise to HSCs, the genetic networks controlling their emergence, and the precise temporal determination of HSC fate remain topics of intense research and debate. This Review article discusses the current knowledge on the step-wise embryonic establishment of the adult hematopoietic system, examines the roles of pivotal intrinsic regulators in this process, and raises questions concerning the temporal onset of HSC fate determination. © 2016 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  3. Engraftment Syndrome following Autologous Stem Cell Transplantation – an Update Unifying the Definition and Management Approach

    Science.gov (United States)

    Cornell, Robert Frank; Hari, Parameswaran; Drobyski, William R.

    2015-01-01

    Engraftment syndrome encompasses a continuum of peri-engraftment complications after autologous hematopoietic stem cell transplantation. ES may include non-infectious fever; skin rash; diarrhea; hepatic dysfunction; renal dysfunction; transient encephalopathy; and capillary leak features, such as non-cardiogenic pulmonary infiltrates, hypoxia, and weight gain with no alternative etiologic basis other than engraftment. Given its pleiotropic clinical presentation, the transplant field has struggled to clearly define ES and related syndromes. Here, we present a comprehensive review of ES in all documented disease settings. Furthermore, we discuss the proposed risk factors, etiology, and clinical relevance of ES. Finally, our current approach to ES is included along with a proposed treatment algorithm for the management of this complication. PMID:26327628

  4. Hematopoietic Stem Cell Niche in Health and Disease.

    Science.gov (United States)

    Hoggatt, Jonathan; Kfoury, Youmna; Scadden, David T

    2016-05-23

    Regulation of stem cells in adult tissues is a key determinant of how well an organism can respond to the stresses of physiological challenge and disease. This is particularly true of the hematopoietic system, where demands on host defenses can call for an acute increase in cell production. Hematopoietic stem cells receive the regulatory signals for cell production in adult mammals in the bone marrow, a tissue with higher-order architectural and functional organization than previously appreciated. Here, we review the data defining particular structural components and heterologous cells in the bone marrow that participate in hematopoietic stem cell function. Further, we explore the case for stromal-hematopoietic cell interactions contributing to neoplastic myeloid disease. As the hematopoietic regulatory networks in the bone marrow are revealed, it is anticipated that strategies will emerge for how to enhance or inhibit production of specific blood cells. In that way, the control of hematopoiesis will enter the domain of therapies to modulate broad aspects of hematopoiesis, both normal and malignant.

  5. Autologous stem cell transplantation in myelodysplastic syndromes.

    NARCIS (Netherlands)

    Witte, T.J.M. de; Suciu, S.; Brand, R.; Muus, P.; Kroger, N.

    2007-01-01

    Allogeneic stem cell transplantation (SCT) is the treatment of choice for the majority of young patients with myelodysplasia (MDS) who have a histocompatible donor (sibling or unrelated donor). For some patients lacking a human leukocyte antigen (HLA)-compatible donor, chemotherapy followed by

  6. [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.

  7. Hematopoietic Niche - Exploring Biomimetic Cues to Improve the Functionality of Hematopoietic Stem/Progenitor Cells.

    Science.gov (United States)

    Costa, Marta H G; de Soure, António M; Cabral, Joaquim M S; Ferreira, Frederico Castelo; da Silva, Cláudia L

    2018-02-01

    The adult bone marrow (BM) niche is a complex entity where a homeostatic hematopoietic system is maintained through a dynamic crosstalk between different cellular and non-cellular players. Signaling mechanisms triggered by cell-cell, cell-extracellular matrix (ECM), cell-cytokine interactions, and local microenvironment parameters are involved in controlling quiescence, self-renewal, differentiation, and migration of hematopoietic stem/progenitor cells (HSPC). A promising strategy to more efficiently expand HSPC numbers and tune their properties ex vivo is to mimic the hematopoietic niche through integration of adjuvant stromal cells, soluble cues, and/or biomaterial-based approaches in HSPC culture systems. Particularly, mesenchymal stem/stromal cells (MSC), through their paracrine activity or direct contact with HSPC, are thought to be a relevant niche player, positioning HSPC-MSC co-culture as a valuable platform to support the ex vivo expansion of hematopoietic progenitors. To improve the clinical outcome of hematopoietic cell transplantation (HCT), namely when the available HSPC are present in a limited number such is the case of HSPC collected from umbilical cord blood (UCB), ex vivo expansion of HSPC is required without eliminating the long-term repopulating capacity of more primitive HSC. Here, we will focus on depicting the characteristics of co-culture systems, as well as other bioengineering approaches to improve the functionality of HSPC ex vivo. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. Nephrotic Syndrome After Hematopoietic Stem Cell Transplant: Outcomes in Iran.

    Science.gov (United States)

    Saddadi, Fereshteh; Alidadi, Ali; Hakemi, Monir; Bahar, Babak

    2017-02-01

    Patients undergoing hematopoietic stem cell transplant have an elevated incidence of acute renal failure. However, the incidence of nephritic syndrome due to graft-versus-host disease is growing and is independently associated with chronic renal disease after this procedure. We conducted a prospective study to examine the risk of chronic kidney disease in glomerulopathy patients following hematopoietic stem cell transplant with a follow-up of 10 years. In our follow-up of 14 patients (4 men and 10 women) who were diagnosed with nephrotic syndrome after hematopoietic stem cell transplant, in 10 patients (71%), biopsy showed membranous nephropathy associated with graft-versus-host disease. The remaining 4 patients had focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, or minimal change disease. All patients were treated with angiotensin receptor blockers, cyclosporine (Neoral), and prednisolone. During follow-up, 6 patients (43%) had heavy proteinuria and a rise in serum creatinine, and 1 patient (7%) needed hemodialysis. Eleven patients (79%) achieved complete remission of nephrotic syndrome, 5 (36%) remained hypertensive, and 3 (21%) did not respond to therapy.. The early diagnosis of nephrotic syndrome should be considered after hematopoietic stem cell transplant, and therapeutic outcome measures should be in place in advance. If this is done, we found that patients' response to treatment can be optimal, and their renal function and overall survival can improve.

  13. 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

  14. 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

  15. Hematopoietic stem cell transplantation for infantile osteopetrosis

    NARCIS (Netherlands)

    Orchard, Paul J.; Fasth, Anders L.; Le Rademacher, Jennifer L.; He, Wensheng; Boelens, Jaap Jan; Horwitz, Edwin M.; Al-Seraihy, Amal; Ayas, Mouhab; Bonfim, Carmem M.; Boulad, Farid; Lund, Troy; Buchbinder, David K.; Kapoor, Neena; OBrien, Tracey A.; Perez, Miguel A Diaz; Veys, Paul A.; Eapen, Mary

    2015-01-01

    We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from

  16. Bussulfano e melfalano como regime de condicionamento para o transplante autogênico de células-tronco hematopoéticas na leucemia mielóide aguda em primeira remissão completa Busulfan and melphalan as conditioning regimen for autologous hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    Directory of Open Access Journals (Sweden)

    Nadjanara D. Bueno

    2008-10-01

    Full Text Available Vinte e dois pacientes consecutivos portadores de leucemia mielóide aguda (LMA em primeira remissão completa (1ªRC submetidos a transplante de células-tronco hematopoéticas autogênico (TCTH Auto condicionados com bussulfano e melfalano (Bu/Mel foram selecionados entre 1993 e 2006. A probabilidade de sobrevida global (SG pelo método de Kaplan-Meier foi de 57,5% após 36 meses, com "plateau" aos 20 meses após o transplante. Fatores como sexo, classificação Franco-Americana-Britânica (FAB da LMA, tratamento de indução, consolidação intensiva, remissão após o primeiro ciclo de indução e fonte de células não tiveram impacto na sobrevida. Pela análise citogenética, um paciente de mau prognóstico submetido ao procedimento, foi a óbito um ano após o transplante. Nove pacientes foram a óbito, oito por recidiva e um por hemorragia. Morte antes dos 100 dias ocorreu em dois pacientes, um por recidiva e outro por hemorragia decorrente da plaquetopenia refratária, relacionada ao procedimento. Concluímos que o regime de condicionamento Bu/Mel é opção válida ao uso de outros regimes de condicionamento, apresentando excelente taxa da sobrevida.Twenty-two consecutive patients with acute myeloid leukemia in first complete remission submitted to autologous hematopoietic stem cells transplantation conditioned with busulfan and melphalan were evaluated between 1993 and 2006. The overall survival, according to the Kaplan-Meier curve, was 57.5% at 36 months, with a "plateau" at 20 months after transplant. Factors such as gender, French-American-British (FAB classification of acute myeloid leukemia, induction therapy, intensive consolidation, remission after the first cycle of induction and source of cells had no impact on survival. One patient with poor prognosis before the procedure died a year after transplantation. Nine patients died, eight by relapse and one because of bleeding. Death before 100 days occurred for two patients, one

  17. Symptoms after hospital discharge following hematopoietic stem cell transplantation

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    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.

  18. Long-term disease-free survival in patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.

    OpenAIRE

    Schetelig, Johannes; Fetscher, Sebastian; Reichle, Albrecht; Berdel, Wolfgang E; Beguin, Yves; Brunet, Salut; Caballero, Dolores; Majolino, Ignazio; Hagberg, Hans; Johnsen, Hans E; Kimby, Eva; Montserrat, Emilio; Stewart, Douglas; Copplestone, Adrian; Rosler, Wolf

    2003-01-01

    BACKGROUND AND OBJECTIVES: Patients with angioimmunoblastic T-cell lymphoma (AIL) have a poor prognosis with conventional treatment. DESIGN AND METHODS: We initiated an EBMT-based survey studying the impact of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation in patients with AIL. Data on 29 patients, who were transplanted between 1992 and 1998 in 16 transplant centers, were collected on standardized documentation forms. RESULTS: The median age at transplant...

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

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    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.

  20. Angiopoietin-like protein 3 promotes preservation of stemness during ex vivo expansion of murine hematopoietic stem cells.

    Science.gov (United States)

    Farahbakhshian, Elnaz; Verstegen, Monique M; Visser, Trudi P; Kheradmandkia, Sima; Geerts, Dirk; Arshad, Shazia; Riaz, Noveen; Grosveld, Frank; van Til, Niek P; Meijerink, Jules P P

    2014-01-01

    Allogeneic hematopoietic stem cell (HSC) transplantations from umbilical cord blood or autologous HSCs for gene therapy purposes are hampered by limited number of stem cells. To test the ability to expand HSCs in vitro prior to transplantation, two growth factor cocktails containing stem cell factor, thrombopoietin, fms-related tyrosine kinase-3 ligand (STF) or stem cell factor, thrombopoietin, insulin-like growth factor-2, fibroblast growth factor-1 (STIF) either with or without the addition of angiopoietin-like protein-3 (Angptl3) were used. Culturing HSCs in STF and STIF media for 7 days expanded long-term repopulating stem cells content in vivo by ∼6-fold and ∼10-fold compared to freshly isolated stem cells. Addition of Angptl3 resulted in increased expansion of these populations by ∼17-fold and ∼32-fold, respectively, and was further supported by enforced expression of Angptl3 in HSCs through lentiviral transduction that also promoted HSC expansion. As expansion of highly purified lineage-negative, Sca-1+, c-Kit+ HSCs was less efficient than less pure lineage-negative HSCs, Angptl3 may have a direct effect on HCS but also an indirect effect on accessory cells that support HSC expansion. No evidence for leukemia or toxicity was found during long-term follow up of mice transplanted with ex vivo expanded HSCs or manipulated HSC populations that expressed Angptl3. We conclude that the cytokine combinations used in this study to expand HSCs ex vivo enhances the engraftment in vivo. This has important implications for allogeneic umbilical cord-blood derived HSC transplantations and autologous HSC applications including gene therapy.

  1. Transplante autólogo de células-tronco hematopoéticas como tratamento do mieloma múltiplo: experiência da Unidade de Transplante de Medula Óssea da Bahia Autologous hematopoietic stem cell transplantation in the treatment of multiple myeloma: the Portuguese Hospital Bone Marrow Transplant Unit in Bahia experience

    Directory of Open Access Journals (Sweden)

    Ronald Pallotta

    2007-06-01

    Full Text Available O mieloma múltiplo (MM é uma doença maligna de células plasmáticas incurável. O transplante de células-tronco hematopoéticas (TCTH faz parte da estratégia terapêutica para a maioria dos pacientes. Devido à distribuição heterogênea dos centros de transplante no nosso país, os autores têm por objetivo descrever a experiência de um centro nordestino no tratamento desta entidade. De fevereiro de 2000 a dezembro de 2005 foram realizados e analisados de maneira prospectiva 21 TCTH autólogos para pacientes com MM no Hospital Português da Bahia. Epidemiologicamente houve predomínio do sexo feminino (1,6:1 e uma predominância de caucasianos (61,9%. A mediana de idade ao diagnóstico foi de 58 anos, sendo a maioria secretores de IgG (71,4% que se apresentavam com estágio clínico IIIA (90,5%. A indicação para o procedimento foi a consolidação da remissão (RC obtida inicialmente pela quimioterapia (52,4% ou o resgate de uma doença refratária (47,6%. A taxa de sobrevida global (SG foi de 74,7%, a taxa de sobrevida livre de doença (SLD foi de 61,9% e a taxa de mortalidade (TM foi de 5% nos primeiros cem dias. Quando avaliamos os pacientes transplantados em relação à fase da doença no momento do procedimento, observamos que aqueles transplantados em RC tiveram SG e SLD superiores àqueles não transplantados em RC (90,9% vs 64% e 68,2% vs 56%. Embora com uma epidemiologia peculiar, os resultados se mostraram semelhantes aos da literatura mundial, reforçando o fato de que o TCTH autólogo é fundamental na estratégia terapêutica contra o MM e está disponível no nordeste brasileiro.Multiple myeloma (MM continues to be an incurable plasma cell malignancy. Autologous hematopoietic stem cell transplantation (HSCT is part of the treatment strategy for the majority of patients. Based on the heterogeneous distribution of the transplantation centers in Brazil, the authors describe their experience treating this disease in a

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  14. Complexity of bone marrow hematopoietic stem cell niche.

    Science.gov (United States)

    Asada, Noboru; Takeishi, Shoichiro; Frenette, Paul S

    2017-07-01

    Hematopoietic stem cells (HSCs) that produce a variety of hematopoietic lineage cells throughout the life reside in specialized microenvironment called "niche" in the bone marrow (BM) where they are tightly regulated. With the recent advances in experimental technologies enabling the selective deletion of molecules, various types of cells in the BM have been proposed to contribute to HSC niche activity. Among these are stromal cells closely associated with the vasculature. In this review, we provide an overview of recent advances in HSC niche research, and focus on the studies describing the functional roles of perivascular cells for HSC maintenance and mobilization. Not only for physiologic state, we also discuss the recent evidences suggesting the importance of microenvironment for emergence of malignant hematopoietic diseases.

  15. EXERCISE in pediatric autologous stem cell transplant patients: a randomized controlled trial protocol

    Directory of Open Access Journals (Sweden)

    Chamorro-Viña Carolina

    2012-09-01

    Full Text Available Abstract Background Hematopoietic stem cell transplantation is an intensive therapy used to improve survivorship and cure various oncologic diseases. However, this therapy is associated with high mortality rates and numerous negative side-effects. The recovery of the immune system is a special concern and plays a key role in the success of this treatment. In healthy populations it is known that exercise plays an important role in immune system regulation, but little is known about the role of exercise in the hematological and immunological recovery of children undergoing hematopoietic stem cell transplant. The primary objective of this randomized-controlled trial (RCT is to study the effect of an exercise program (in- and outpatient on immune cell recovery in patients undergoing an autologous stem cell transplantation. The secondary objective is to determine if an exercise intervention diminishes the usual deterioration in quality of life, physical fitness, and the acquisition of a sedentary lifestyle. Methods This RCT has received approval from The Conjoint Health Research Ethics Board (CHREB of the University of Calgary (Ethics ID # E-24476. Twenty-four participants treated for a malignancy with autologous stem cell transplant (5 to 18 years in the Alberta Children’s Hospital will be randomly assigned to an exercise or control group. The exercise group will participate in a two-phase exercise intervention (in- and outpatient from hospitalization until 10 weeks after discharge. The exercise program includes strength, flexibility and aerobic exercise. During the inpatient phase this program will be performed 5 times/week and will be supervised. The outpatient phase will combine a supervised session with two home-based exercise sessions with the use of the Wii device. The control group will follow the standard protocol without any specific exercise program. A range of outcomes, including quantitative and functional recovery of immune system

  16. Feasibility and toxicity of hematopoietic stem cell transplant in multiple sclerosis.

    Science.gov (United States)

    Kuan, Thomas Low Tat; Amini, Farahnaz; Seghayat, Marjan Sadat

    2017-07-01

    Multiple sclerosis is a debilitating disease of the central nervous system. It affects people of all ages but is more prevalent among 20-40 year olds. Patients with MS can be presented with potentially any neurological symptom depending on the location of the lesion. A quarter of patients with MS suffer from bilateral lower limb spasticity among other symptoms. These devastating effects can be detrimental to the patient's quality of life. Hematopoietic stem cells (HSCs) have been used as a treatment for MS over the past 2 decades but their safety and efficacy has are undetermined. The objective of this study is to evaluate the feasibility and toxicity of autologous HSCs transplantation in MS. A literature search was done from 1997 to 2016 using different keywords. A total of 9 articles, which met the inclusion and exclusion criteria, were included in this review. The type of conditioning regimen and technique of stem cell mobilization are summarized and compared in this study. All studies reported high-dose immunosuppressive therapy with autologous HSCs transplantation being an effective treatment option for severe cases of multiple sclerosis. Fever, sepsis, and immunosuppression side effects were the most observed adverse effects that were reported in the selected studies. HSCs is a feasible treatment for patients with MS; nevertheless the safety is still a concern due to chemo toxicity.

  17. Feasibility and toxicity of hematopoietic stem cell transplant in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Thomas Low Tat Kuan

    2017-07-01

    Full Text Available Multiple sclerosis is a debilitating disease of the central nervous system. It affects people of all ages but is more prevalent among 20-40 year olds. Patients with MS can be presented with potentially any neurological symptom depending on the location of the lesion. A quarter of patients with MS suffer from bilateral lower limb spasticity among other symptoms. These devastating effects can be detrimental to the patient's quality of life. Hematopoietic stem cells (HSCs have been used as a treatment for MS over the past 2 decades but their safety and efficacy has are undetermined. The objective of this study is to evaluate the feasibility and toxicity of autologous HSCs transplantation in MS. A literature search was done from 1997 to 2016 using different keywords. A total of 9 articles, which met the inclusion and exclusion criteria, were included in this review. The type of conditioning regimen and technique of stem cell mobilization are summarized and compared in this study. All studies reported high-dose immunosuppressive therapy with autologous HSCs transplantation being an effective treatment option for severe cases of multiple sclerosis. Fever, sepsis, and immunosuppression side effects were the most observed adverse effects that were reported in the selected studies. HSCs is a feasible treatment for patients with MS; nevertheless the safety is still a concern due to chemo toxicity.

  18. Hematopoietic stem cell transplantation for people with sickle cell disease.

    Science.gov (United States)

    Oringanje, Chioma; Nemecek, Eneida; Oniyangi, Oluseyi

    2016-05-19

    Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review. To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE.Unpublished work was identified by searching the abstract books of major conference proceedings and we conducted a search of the website: www.ClinicalTrials.gov.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 06 October 2015. Randomized controlled and quasi-randomized studies that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting. No relevant trials were identified. Ten trials were identified by the initial search and none for the update. None of these trials were suitable for inclusion in this review. Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell

  19. HLA-mismatched hematopoietic stem cell tranplantation for pediatric solid tumors

    Directory of Open Access Journals (Sweden)

    Andrea Pession

    2011-06-01

    Full Text Available Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing’s sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT allows chemotherapy dose intensification beyond marrow tolerance and has become a fundamental tool in the multimodal therapeutical approach of these patients. Anyway this procedure does not allow to these children an eventfree survival approaching more than 50% at 5 years. New concepts of allogeneic HSCT and in particular HLA-mismatched HSCT for high risk solid tumors do not rely on escalation of chemo therapy intensity and tumor load reduction but rather on a graft-versus-tumor effect. We here report an experimental study design of HLA-mismatched HSCT for the treatment of pediatric solid tumors and the inherent preliminary results.

  20. Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation

    Directory of Open Access Journals (Sweden)

    T. M. Haverman

    2014-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis.

  1. 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...... immunosuppression. FINDINGS: Median age at treatment was 27 (range 9-34) years, MS duration 26 (4-100) months, and annualized relapse rate 10 (4-12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5-8.0). Median follow-up time April 2008 is 29 (23-47) months. Median EDSS...... months. CONCLUSION: This small series of patients with "malignant" relapsing-remitting MS suggests HSCT to be an effective treatment option for this relatively rare disease course. It further suggests that future criteria for HSCT in MS should be close to the present ones Udgivelsesdato: 2009/2...

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

    Directory of Open Access Journals (Sweden)

    Michael M. B. Green

    2016-08-01

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

  3. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3

    Science.gov (United States)

    Rimmelé, Pauline; Liang, Raymond; Bigarella, Carolina L; Kocabas, Fatih; Xie, Jingjing; Serasinghe, Madhavika N; Chipuk, Jerry; Sadek, Hesham; Zhang, Cheng Cheng; Ghaffari, Saghi

    2015-01-01

    Hematopoietic stem cells (HSC) are primarily dormant but have the potential to become highly active on demand to reconstitute blood. This requires a swift metabolic switch from glycolysis to mitochondrial oxidative phosphorylation. Maintenance of low levels of reactive oxygen species (ROS), a by-product of mitochondrial metabolism, is also necessary for sustaining HSC dormancy. Little is known about mechanisms that integrate energy metabolism with hematopoietic stem cell homeostasis. Here, we identify the transcription factor FOXO3 as a new regulator of metabolic adaptation of HSC. ROS are elevated in Foxo3−/− HSC that are defective in their activity. We show that Foxo3−/− HSC are impaired in mitochondrial metabolism independent of ROS levels. These defects are associated with altered expression of mitochondrial/metabolic genes in Foxo3−/− hematopoietic stem and progenitor cells (HSPC). We further show that defects of Foxo3−/− HSC long-term repopulation activity are independent of ROS or mTOR signaling. Our results point to FOXO3 as a potential node that couples mitochondrial metabolism with HSC homeostasis. These findings have critical implications for mechanisms that promote malignant transformation and aging of blood stem and progenitor cells. PMID:26209246

  4. Pulmonary heart valve replacement using stabilized acellular xenogeneic scaffolds; effects of seeding with autologous stem cells

    Directory of Open Access Journals (Sweden)

    Harpa Marius Mihai

    2015-12-01

    Full Text Available Background: We hypothesized that an ideal heart valve replacement would be acellular valve root scaffolds seeded with autologous stem cells. To test this hypothesis, we prepared porcine acellular pulmonary valves, seeded them with autologous adipose derived stem cells (ADSCs and implanted them in sheep and compared them to acellular valves.

  5. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

    Science.gov (United States)

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T.; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R.; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D.; Lutz, Christoph

    2017-01-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. PMID:28550184

  6. Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Israel Henig

    2014-10-01

    Full Text Available Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

  7. Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  8. Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation

    International Nuclear Information System (INIS)

    Server, Andres; Bargallo, Nuria; Floeisand, Yngvar; Sponheim, Jon; Graus, Francesc; Hald, John K.

    2017-01-01

    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.)

  9. DNA Damage Response in Hematopoietic Stem Cell Ageing.

    Science.gov (United States)

    Li, Tangliang; Zhou, Zhong-Wei; Ju, Zhenyu; Wang, Zhao-Qi

    2016-06-01

    Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

  10. Imaging of complications from hematopoietic stem cell transplant

    International Nuclear Information System (INIS)

    Pandey, Tarun; Maximin, Suresh; Bhargava, Puneet

    2014-01-01

    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. 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.

  12. Mitophagy in hematopoietic stem cells: the case for exploration.

    Science.gov (United States)

    Joshi, Aashish; Kundu, Mondira

    2013-11-01

    Hematopoietic stem cells (HSCs) are inherently quiescent and self-renewing, yet can differentiate and commit to multiple blood cell types. Intracellular mitochondrial content is dynamic, and there is an increase in mitochondrial content during differentiation and lineage commitment in HSCs. HSCs reside in a hypoxic niche within the bone marrow and rely heavily on glycolysis, while differentiated and committed progenitors rely on oxidative phosphorylation. Increased oxidative phosphorylation during differentiation and commitment is not only due to increased mitochondrial content but also due to changes in mitochondrial cytosolic distribution and efficiency. These changes in the intracellular mitochondrial landscape contribute signals toward regulating differentiation and commitment. Thus, a functional relationship exists between the mitochondria in HSCs and the state of the HSCs (i.e., stemness vs. differentiated). This review focuses on how autophagy-mediated mitochondrial clearance (i.e., mitophagy) may affect HSC mitochondrial content, thereby influencing the fate of HSCs and maintenance of hematopoietic homeostasis.

  13. Osteoblastic activation in the hematopoietic stem cell niche.

    Science.gov (United States)

    Calvi, Laura M

    2006-04-01

    Hematopoietic stem cells (HSC) are rare primitive cells capable of reconstituting all blood cell lineages throughout the life of an individual. The microenvironment in which stem cells reside is essential for their survival, self-renewal, and differentiation. This microenvironment, or HSC niche, has been difficult to define in bone and bone marrow, but recent studies from our laboratory and others have shown that osteoblasts, the bone-forming cells, are an essential regulatory component of this complex cellular network. We established that parathyroid hormone (PTH), through activation of the PTH/PTHrP receptor (PTH1R) in osteoblastic cells, could alter the HSC niche resulting in HSC expansion in vivo and in vitro and improving dramatically the survival of mice receiving bone marrow transplants. These findings are of great clinical appeal, because they suggest that a strategy aimed at modifying supportive cells in a stem cell niche can expand HSC. While a number of molecules have been found to be important for hematopoietic/osteoblastic interactions, we have focused on the Jagged1/Notch signaling pathway, which was necessary for the PTH-dependent HSC expansion. Since the Jagged1/Notch signaling pathway has been implicated in the microenvironmental control of stem cell self-renewal in several organ systems, definition of Jagged1 modulation, which is currently poorly understood, should provide additional molecular targets for stem cell regulation and advance the understanding of stem cell-microenvironmental interactions.

  14. Nursing care in a hematopoietic stem cells transplantation unit

    OpenAIRE

    Lima,Kaoana; Bernardino,Elizabeth

    2014-01-01

    In hematopoietic stem cell transplantation units, nursing care is different from other services. The objective in this descriptive study with a qualitative approach was to identify the care activities of nurses at a transplantation unit, classified according to the framework of nurses' functions. The data were collected through systematic observation and treated through content analysis. Three functions were identified for nurses: clinical nurse, management nurse and visit nurse, the first ha...

  15. Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins

    NARCIS (Netherlands)

    Hira, Vashendriya V. V.; Wormer, Jill R.; Kakar, Hala; Breznik, Barbara; van der Swaan, Britt; Hulsbos, Renske; Tigchelaar, Wikky; Tonar, Zbynek; Khurshed, Mohammed; Molenaar, Remco J.; van Noorden, Cornelis J. F.

    2018-01-01

    In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell-derived factor-1α (SDF-1α),

  16. Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Matsuyama, Takaharu; Kato, Koji [Nagoya First Red Cross Hospital (Japan). Children' s Medical Center; Hanada, Ryoji [Saitama Children' s Medical Center, Iwatsuki (Japan)] [and others

    2002-07-01

    A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 {mu}g/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

  17. Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

    International Nuclear Information System (INIS)

    Matsuyama, Takaharu; Kato, Koji

    2002-01-01

    A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 μg/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

  18. SCA-1 Expression Level Identifies Quiescent Hematopoietic Stem and Progenitor Cells

    NARCIS (Netherlands)

    Morcos, Mina N.F.; Schoedel, Kristina B.; Hoppe, Anja; Behrendt, Rayk; Basak, Onur; Clevers, Hans C.; Roers, Axel; Gerbaulet, Alexander

    2017-01-01

    Blood cell generation depends on continuous cellular output by the sequential hierarchy of hematopoietic stem cell (HSC) and progenitor populations that all contain quiescent and actively cycling cells. Hematopoietic stem and progenitor cells (HSPCs) express the surface molecule Stem cell antigen 1

  19. Human induced pluripotent stem cells on autologous feeders.

    Directory of Open Access Journals (Sweden)

    Kazutoshi Takahashi

    Full Text Available BACKGROUND: For therapeutic usage of induced Pluripotent Stem (iPS cells, to accomplish xeno-free culture is critical. Previous reports have shown that human embryonic stem (ES cells can be maintained in feeder-free condition. However, absence of feeder cells can be a hostile environment for pluripotent cells and often results in karyotype abnormalities. Instead of animal feeders, human fibroblasts can be used as feeder cells of human ES cells. However, one still has to be concerned about the existence of unidentified pathogens, such as viruses and prions in these non-autologous feeders. METHODOLOGY/PRINCIPAL FINDINGS: This report demonstrates that human induced Pluripotent Stem (iPS cells can be established and maintained on isogenic parental feeder cells. We tested four independent human skin fibroblasts for the potential to maintain self-renewal of iPS cells. All the fibroblasts tested, as well as their conditioned medium, were capable of maintaining the undifferentiated state and normal karyotypes of iPS cells. Furthermore, human iPS cells can be generated on isogenic parental fibroblasts as feeders. These iPS cells carried on proliferation over 19 passages with undifferentiated morphologies. They expressed undifferentiated pluripotent cell markers, and could differentiate into all three germ layers via embryoid body and teratoma formation. CONCLUSIONS/SIGNIFICANCE: These results suggest that autologous fibroblasts can be not only a source for iPS cells but also be feeder layers. Our results provide a possibility to solve the dilemma by using isogenic fibroblasts as feeder layers of iPS cells. This is an important step toward the establishment of clinical grade iPS cells.

  20. Enrichment of human hematopoietic stem/progenitor cells facilitates transduction for stem cell gene therapy.

    Science.gov (United States)

    Baldwin, Kismet; Urbinati, Fabrizia; Romero, Zulema; Campo-Fernandez, Beatriz; Kaufman, Michael L; Cooper, Aaron R; Masiuk, Katelyn; Hollis, Roger P; Kohn, Donald B

    2015-05-01

    Autologous hematopoietic stem cell (HSC) gene therapy for sickle cell disease has the potential to treat this illness without the major immunological complications associated with allogeneic transplantation. However, transduction efficiency by β-globin lentiviral vectors using CD34-enriched cell populations is suboptimal and large vector production batches may be needed for clinical trials. Transducing a cell population more enriched for HSC could greatly reduce vector needs and, potentially, increase transduction efficiency. CD34(+) /CD38(-) cells, comprising ∼1%-3% of all CD34(+) cells, were isolated from healthy cord blood CD34(+) cells by fluorescence-activated cell sorting and transduced with a lentiviral vector expressing an antisickling form of beta-globin (CCL-β(AS3) -FB). Isolated CD34(+) /CD38(-) cells were able to generate progeny over an extended period of long-term culture (LTC) compared to the CD34(+) cells and required up to 40-fold less vector for transduction compared to bulk CD34(+) preparations containing an equivalent number of CD34(+) /CD38(-) cells. Transduction of isolated CD34(+) /CD38(-) cells was comparable to CD34(+) cells measured by quantitative PCR at day 14 with reduced vector needs, and average vector copy/cell remained higher over time for LTC initiated from CD34(+) /38(-) cells. Following in vitro erythroid differentiation, HBBAS3 mRNA expression was similar in cultures derived from CD34(+) /CD38(-) cells or unfractionated CD34(+) cells. In vivo studies showed equivalent engraftment of transduced CD34(+) /CD38(-) cells when transplanted in competition with 100-fold more CD34(+) /CD38(+) cells. This work provides initial evidence for the beneficial effects from isolating human CD34(+) /CD38(-) cells to use significantly less vector and potentially improve transduction for HSC gene therapy. © 2015 AlphaMed Press.

  1. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    Science.gov (United States)

    Kosan, Christian; Godmann, Maren

    2016-01-01

    All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC) have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several transcription factors and epigenetic modifiers are involved in this process. These create modifications that regulate the cell fate in a more or less reversible and dynamic way and contribute to HSC homeostasis. In addition, HSC respond in a unique way to DNA damage. These mechanisms also contribute to the regulation of HSC function and are essential to ensure viability after DNA damage. How HSC maintain their quiescent stage during the entire life is still matter of ongoing research. Here we will focus on the molecular mechanisms that regulate HSC function. PMID:26798358

  2. Hepatic Sinusoidal-obstruction Syndrome and Busulfan-induced Lung Injury in a Post-autologous Stem Cell Transplant Recipient.

    Science.gov (United States)

    Jain, Richa; Gupta, Kirti; Bhatia, Anmol; Bansal, Arun; Bansal, Deepak

    2017-09-15

    Veno-occlusive disease of the liver is mostly encountered as a complication of hematopoietic stem cell transplantation with myeloablative regimens with an incidence estimated to be 13.7%. It is clinically characterized by tender hepatomegaly, jaundice, weight gain and ascites. Strong clinical suspicion and an early recognition of clinical signs are essential to establish the diagnosis and institute effective regimen. Another complication of cytotoxic drugs given for cancers, is development of busulfan-induced lung injury. A strong index of suspicion is needed for its diagnosis, especially in setting where opportunistic fungal and viral infections manifest similarly. We illustrate the clinical and autopsy finings in a 2½-year-old boy who received autologous stem-cell transplantation following resection of stage IV neuroblastoma. He subsequently developed both hepatic veno-occlusive disease and busulfan-induced lung injury. The autopsy findings are remarkable for their rarity.

  3. 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

  4. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation.

    Science.gov (United States)

    Kanda, Junya

    2016-01-01

    The Transplant Registry Unified Management Program (TRUMP) made it possible for members of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) to analyze large sets of national registry data on autologous and allogeneic hematopoietic stem cell transplantation. However, as the processes used to collect transplantation information are complex and differed over time, the background of these processes should be understood when using TRUMP data. Previously, information on the HLA locus of patients and donors had been collected using a questionnaire-based free-description method, resulting in some input errors. To correct minor but significant errors and provide accurate HLA matching data, the use of a Stata or EZR/R script offered by the JSHCT is strongly recommended when analyzing HLA data in the TRUMP dataset. The HLA mismatch direction, mismatch counting method, and different impacts of HLA mismatches by stem cell source are other important factors in the analysis of HLA data. Additionally, researchers should understand the statistical analyses specific for hematopoietic stem cell transplantation, such as competing risk, landmark analysis, and time-dependent analysis, to correctly analyze transplant data. The data center of the JSHCT can be contacted if statistical assistance is required.

  5. Aging of hematopoietic stem cells: DNA damage and mutations?

    Science.gov (United States)

    Moehrle, Bettina M; Geiger, Hartmut

    2016-10-01

    Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  6. 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.

  7. The allure and peril of hematopoietic stem cell transplantation: overcoming immune challenges to improve success.

    Science.gov (United States)

    Newman, Robert G; Ross, Duncan B; Barreras, Henry; Herretes, Samantha; Podack, Eckhard R; Komanduri, Krishna V; Perez, Victor L; Levy, Robert B

    2013-12-01

    Since its inception in the mid-twentieth century, the complication limiting the application and utility of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat patients with hematopoietic cancer is the development of graft-versus-host disease (GVHD). Ironically, GVHD is induced by the cells (T lymphocytes) transplanted for the purpose of eliminating the malignancy. Damage ensuing to multiple tissues, e.g., skin, GI, liver, and others including the eye, provides the challenge of regulating systemic and organ-specific GVH responses. Because the immune system is also targeted by GVHD, this both: (a) impairs reconstitution of immunity post-transplant resulting in patient susceptibility to lethal infection and (b) markedly diminishes the individual's capacity to generate anti-cancer immunity--the raison d'etre for undergoing allo-HSCT. We hypothesize that deleting alloreactive T cells ex vivo using a new strategy involving antigen stimulation and alkylation will prevent systemic GVHD thereby providing a platform for the generation of anti-tumor immunity. Relapse also remains the major complication following autologous HSCT (auto-HSCT). While GVHD does not complicate auto-HSCT, its absence removes significant grant anti-tumor responses (GVL) and raises the challenge of generating rapid and effective anti-tumor immunity early post-transplant prior to immune reconstitution. We hypothesize that effective vaccine usage to stimulate tumor-specific T cells followed by their amplification using targeted IL-2 can be effective in both the autologous and allogeneic HSCT setting. Lastly, our findings support the notion that the ocular compartment can be locally targeted to regulate visual complications of GVHD which may involve both alloreactive and self-reactive (i.e., autoimmune) responses.

  8. Differentiation of embryonic stem cells towards hematopoietic cells: progress and pitfalls.

    Science.gov (United States)

    Tian, Xinghui; Kaufman, Dan S

    2008-07-01

    Hematopoietic development from embryonic stem cells has been one of the most productive areas of stem cell biology. Recent studies have progressed from work with mouse to human embryonic stem cells. Strategies to produce defined blood cell populations can be used to better understand normal and abnormal hematopoiesis, as well as potentially improve the generation of hematopoietic cells with therapeutic potential. Molecular profiling, phenotypic and functional analyses have all been utilized to demonstrate that hematopoietic cells derived from embryonic stem cells most closely represent a stage of hematopoiesis that occurs at embryonic/fetal developmental stages. Generation of hematopoietic stem/progenitor cells comparable to hematopoietic stem cells found in the adult sources, such as bone marrow and cord blood, still remains challenging. However, genetic manipulation of intrinsic factors during hematopoietic differentiation has proven a suitable approach to induce adult definitive hematopoiesis from embryonic stem cells. Concrete evidence has shown that embryonic stem cells provide a powerful approach to study the early stage of hematopoiesis. Multiple hematopoietic lineages can be generated from embryonic stem cells, although most of the evidence suggests that hematopoietic development from embryonic stem cells mimics an embryonic/fetal stage of hematopoiesis.

  9. Rebooting autoimmunity with autologous HSCT.

    Science.gov (United States)

    Snowden, John A

    2016-01-07

    Autologous hematopoietic stem cell transplantation (HSCT) is increasingly used for severe autoimmune and inflammatory diseases, but the mechanisms involved have yet to be elucidated. In this issue of Blood, Delemarre et al report their findings in both animal and human models which provide insights into restoration of functionality and diversity within the regulatory T-cell (Treg) compartment following HSCT.

  10. 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.

  11. Aging, Clonality and Rejuvenation of Hematopoietic Stem Cells

    Science.gov (United States)

    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 epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as 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. PMID:27380967

  12. The many faces of hematopoietic stem cell heterogeneity

    Science.gov (United States)

    2016-01-01

    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. PMID:27965438

  13. 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

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

    Science.gov (United States)

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

    2013-01-01

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

  15. A method to enrich mouse hematopoietic stem cells

    International Nuclear Information System (INIS)

    Barker, J.E.; McFarland, E.C.

    1983-01-01

    Hematopoietic stem cells form colonies in the spleens of lethally irradiated mice. The number of colonies is indicative of the number of stem cells present in the inoculum. In this article, a technique is presented for effecting a seven-fold enrichment of spleen colony-forming cells. Bone marrow cells are first segregated into ''red'' and ''white'' cell populations by centrifugation on Ficoll-Paque. Centrifugation of the ''white'' cell fraction in 75% Percoll concentrates the colony-forming cells in the top one-third of the gradient. The ability of these cells to repopulate and to cure the anemia of WBB6F1-W/Wv mice indicates that long-term functional pluripotent stem cells have not been destroyed or lost during the fractionation procedures. The segregation procedures enrich the colony-forming cell population from thalassemic as well as from normal mice

  16. Tritium contamination of hematopoietic stem cells alters long-term hematopoietic reconstitution

    International Nuclear Information System (INIS)

    Di Giacomo, F.; Barroca, V.; Laurent, D.; Lewandowski, D.; Saintigny, Y.; Romeo, P.H.; Granotier, Ch.; Boussin, F.D.

    2011-01-01

    Purpose: In vivo effects of tritium contamination are poorly documented. Here, we study the effects of tritiated Thymidine ([ 3 H] Thymidine) or tritiated water (HTO) contamination on the biological properties of hematopoietic stem cells (HSC). Materials and methods: Mouse HSC were contaminated with concentrations of [ 3 H] Thymidine ranging from 0.37-37.03 kBq/ml or of HTO ranging from 5-50 kBq/ml. The biological properties of contaminated HSC were studied in vitro after HTO contamination and in vitro and in vivo after [ 3 H] Thymidine contamination. Results: Proliferation, viability and double-strand breaks were dependent on [ 3 H] Thymidine or HTO concentrations used for contamination but in vitro myeloid differentiation of HSC was not affected by [ 3 H] Thymidine contamination. [ 3 H] Thymidine contaminated HSC showed a compromised long-term capacity of hematopoietic reconstitution and competition experiments showed an up to two-fold decreased capacity of contaminated HSC to reconstitute hematopoiesis. These defects were not due to impaired homing in bone marrow but to an initial decreased proliferation rate of HSC. Conclusion: These results indicate that contaminations of HSC with doses of tritium that do not result in cell death, induce short-term effects on proliferation and cell cycle and long-term effects on hematopoietic reconstitution capacity of contaminated HSC. (authors)

  17. Combined Analysis of Endothelial, Hematopoietic, and Mesenchymal Stem Cell Compartments Shows Simultaneous but Independent Effects of Age and Heart Disease

    Directory of Open Access Journals (Sweden)

    Carine Ghem

    2017-01-01

    Full Text Available Clinical trials using stem cell therapy for heart diseases have not reproduced the initial positive results obtained with animal models. This might be explained by a decreased regenerative capacity of stem cells collected from the patients. This work aimed at the simultaneous investigation of endothelial stem/progenitor cells (EPCs, mesenchymal stem/progenitor cells (MSCs, and hematopoietic stem/progenitor cells (HSCs in sternal bone marrow samples of patients with ischemic or valvular heart disease, using flow cytometry and colony assays. The study included 36 patients referred for coronary artery bypass grafting or valve replacement surgery. A decreased frequency of stem cells was observed in both groups of patients. Left ventricular dysfunction, diabetes, and intermediate risk in EuroSCORE and SYNTAX score were associated with lower EPCs frequency, and the use of aspirin and β-blockers correlated with a higher frequency of HSCs and EPCs, respectively. Most importantly, the distribution of frequencies in the three stem cell compartments showed independent patterns. The combined investigation of the three stem cell compartments in patients with cardiovascular diseases showed that they are independently affected by the disease, suggesting the investigation of prognostic factors that may be used to determine when autologous stem cells may be used in cell therapy.

  18. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases.

    Science.gov (United States)

    Snowden, John A; Badoglio, Manuela; Labopin, Myriam; Giebel, Sebastian; McGrath, Eoin; Marjanovic, Zora; Burman, Joachim; Moore, John; Rovira, Montserrat; Wulffraat, Nico M; Kazmi, Majid; Greco, Raffaella; Snarski, Emilian; Kozak, Tomas; Kirgizov, Kirill; Alexander, Tobias; Bader, Peter; Saccardi, Riccardo; Farge, Dominique

    2017-12-26

    Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index ( P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10 -5 ), relapse/progression ( P < 10 -5 ), and nonrelapse mortality ( P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (≥23 transplants for AD, P = .001), learning (time from first HSCT for AD ≥6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status ( P = .02). Despite improved survival over time ( P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.

  19. 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.

  20. Oxidative stress in normal hematopoietic stem cells and leukemia.

    Science.gov (United States)

    Samimi, Azin; Kalantari, Heybatullah; Lorestani, Marzieh Zeinvand; Shirzad, Reza; Saki, Najmaldin

    2018-04-01

    Leukemia is developed following the abnormal proliferation of immature hematopoietic cells in the blood when hematopoietic stem cells lose the ability to turn into mature cells at different stages of maturation and differentiation. Leukemia initiating cells are specifically dependent upon the suppression of oxidative stress in the hypoglycemic bone marrow (BM) environment to be able to start their activities. Relevant literature was identified by a PubMed search (2000-2017) of English-language literature using the terms 'oxidative stress,' 'reactive oxygen species,' 'hematopoietic stem cell,' and 'leukemia.' The generation and degradation of free radicals is a main component of the metabolism in aerobic organisms. A certain level of ROS is required for proper cellular function, but values outside this range will result in oxidative stress (OS). Long-term overactivity of reactive oxygen species (ROS) has harmful effects on the function of cells and their vital macromolecules, including the transformation of proteins into autoantigens and increased degradation of protein/DNA, which eventually leads to the change in pathways involved in the development of cancer and several other disorders. According to the metabolic disorders of cancer, the relationship between OS changes, the viability of cancer cells, and their response to chemotherapeutic agents affecting this pathway are undeniable. Recently, studies have been conducted to determine the effect of herbal agents and cancer chemotherapy drugs on oxidative stress pathways. By emphasizing the role of oxidative stress on stem cells in the incidence of leukemia, this paper attempts to state and summarize this subject. © 2018 APMIS. Published by John Wiley & Sons Ltd.

  1. Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation.

    Science.gov (United States)

    Mortensen, Monika; Watson, Alexander Scarth; Simon, Anna Katharina

    2011-09-01

    The regulated lysosomal degradation pathway of autophagy prevents cellular damage and thus protects from malignant transformation. Autophagy is also required for the maturation of various hematopoietic lineages, namely the erythroid and lymphoid ones, yet its role in adult hematopoietic stem cells (HSCs) remained unexplored. While normal HSCs sustain life-long hematopoiesis, malignant transformation of HSCs or early progenitors leads to leukemia. Mechanisms protecting HSCs from cellular damage are therefore essential to prevent hematopoietic malignancies. By conditionally deleting the essential autophagy gene Atg7 in the hematopoietic system, we found that autophagy is required for the maintenance of true HSCs and therefore also of downstream hematopoietic progenitors. Loss of autophagy in HSCs leads to the expansion of a progenitor cell population in the bone marrow, giving rise to a severe, invasive myeloproliferation, which strongly resembles human acute myeloid leukemia (AML).

  2. 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......) and 5 years (n=45) after HSCT. Depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS). Detailed medical and demographic information was collected. Prevalence rates were compared with an age- and gender-matched control group drawn from a large representative sample (n...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  4. 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).

  5. Age-associated changes in human hematopoietic stem cells.

    Science.gov (United States)

    Pang, Wendy W; Schrier, Stanley L; Weissman, Irving L

    2017-01-01

    Aging has a broad impact on the function of the human hematopoietic system. This review will focus primarily on the effect of aging on the human hematopoietic stem cell (HSC) population. With age, even though human HSCs increase in number, they have decreased self-renewal capacity and reconstitution potential upon transplantation. As a population, human HSCs become more myeloid-biased in their differentiation potential. This is likely due to the human HSC population becoming more clonal with age, selecting for myeloid-biased HSC clones. The HSC clones that come to predominate with age may also contain disease-causing genetic and epigenetic changes that confer an increased risk of developing into an age-associated clonal hematopoietic disease, such as myelodysplastic syndrome, myeloproliferative disorders, or leukemia. The selection of these aged human HSC clones may be in part due to changes in the aging bone marrow microenvironment. While there have been significant advances in the understanding of the effect of aging on mouse hematopoiesis and mouse HSCs, we have comparatively less detailed analyses of the effect of aging on human HSCs. Continued evaluation of human HSCs in the context of aging will be important to determine how applicable the findings in mice and other model organisms are to the human clinical setting. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Ionizing radiation induces apoptosis in hematopoietic stem and progenitor cells

    International Nuclear Information System (INIS)

    Meng, A.; Zhou, D.; Geiger, H.; Zant, G.V.

    2003-01-01

    The aims of this study was to determine if ionizing radiation (IR) induces apoptosis in hematopoietic stem (HSC) and progenitor cells. Lin-cells were isolated from mouse bone marrow (BM) and pretreated with vehicle or 100 μM z-VAD 1 h prior to exposure to 4 Gy IR. The apoptotic and/or necrotic responses of these cells to IR were analyzed by measuring the annexin V and/or 7-AAD staining in HSC and progenitor populations using flow cytometry, and hematopoietic function of these cells was determined by CAFC assay. Exposure of Lin-cells to IR selectively decreased the numbers of HSC and progenitors in association with an increase in apoptosis in a time-dependent manner. Pretreatment of Lin- cells with z-VAD significantly inhibited IR-induced apoptosis and the decrease in the numbers of HSC and progenitors. However, IR alone or in combination with z-VAD did not lead to a significant increase in necrotic cell death in either HSC or progenitors. In addition, pretreatment of BM cells with z-VAD significantly attenuated IR-induced reduction in the frequencies of day-7, -28 and -35 CAFC. Exposure of HSC and progenitors to IR induces apoptosis. The induction of HSC and progenitor apoptosis contributes to IR-induced suppression of their hematopoietic function

  7. Autologous stem cell transplantation in the treatment of Hodgkin's disease

    Directory of Open Access Journals (Sweden)

    Tarabar Olivera

    2009-01-01

    Full Text Available Background/Aim. High-dose chemotherapy with autologous stem cell transplantacion (ASCT has shown to produce long-term disease-free survival in patients with chemotherapysensitive Hodgkin disease. The aim of the study was to evaluate efficacy of ASCT in the treatment of Hodgkin's disease. Methods. Between May 1997 and September 2008, 34 patients with Hodgkin's disease in median age of 25 (range 16-60 years, underwent ASCT. Autologous SCT were performed as consolidation therapy in one poor-risk patients with complete response (CR and in 10 patients in partial remission (PR after induction chemotherapy (32.5%, for chemosensitive relapse (CSR 1 and CSR 2 in 47% patients and in 20.5% patients with chemoresistant disease (CRD. All except one patient were in stage III/IV, extranodal site of disease had 24 patients and bulky disease had l0 patients. All the patients received a uniform preparatory regimen (BEAM. Results. An overall response was achieved in 30 of 32 evaluated patients, with 62.5% in CR and 31.25% in PR. After applying radiotherapy, two patients with PR after ASCT reached CR. Median follow-up was 15.5 months (range 3-133 months. The probability of overall survival (OS and progression-free survival (PFS at a 3-year period for all patients was 51.9 % and 48.9%, respectively. For 22 patients in CR after ASCT, a 3-year DFS was 66.5%. Estimates of 2.5-year survival were 14.3%, 61.9% and 100% for CRD, CSR and for patients with CR/PR, respectively (p < 0.01. However, when patients undergoing consolidation were analyzed separately from those in CSR, no significant difference in OS and PFS was observed according to the disease status at ASCT. In univariate analysis for OS, PFS i DFS, extranodal site of disease and disease bulk had no predictive value. Twelve patients died. The main cause of death was Hodgkin's disease. Transplant-related mortality was 3.1%. One patient with CRD developed secondary acute myeloid leukemia and died 28 months after the

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  8. Autologous peripheral blood stem cell harvest: Collection efficiency and factors affecting it

    Directory of Open Access Journals (Sweden)

    Aseem K Tiwari

    2016-01-01

    Full Text Available Background: Harvest of hematopoietic progenitor cells via leukapheresis is being used increasingly for transplants in India. Adequate yield of cells per kilogram body weight of recipient is required for successful engraftment. Collection efficiency (CE is an objective quality parameter used to assess the quality of leukapheresis program. In this study, we calculated the CE of the ComTec cell separator (Fresenius Kabi, Germany using two different formulae (CE1 and CE2 and analyzed various patient and procedural factors, which may affect it. Materials and Methods: One hundred and one consecutive procedures in 77 autologous donors carried out over 3 years period were retrospectively reviewed. Various characteristics like gender, age, weight, disease status, hematocrit, preprocedure total leukocyte count, preprocedure CD34 positive (CD34+ cells count, preprocedure absolute CD34+ cell count and processed apheresis volume effect on CE were compared. CE for each procedure was calculated using two different formulae, and results were compared using statistical correlation and regression analysis. Results: The mean CE1 and CE2 was 41.2 and 49.1, respectively. CE2 appeared to be more accurate indicator of overall CE as it considered the impact of continued mobilization of stem cells during apheresis procedure, itself. Of all the factors affecting CE, preprocedure absolute CD34+ was the only independent factor affecting CE. Conclusion: The only factor affecting CE was preprocedure absolute CD34+ cells. Though the mean CE2 was higher than CE1, it was not statistically significant.

  9. Assessment of Myocardial Function in Children before and after Autologous Peripheral Blood Stem Cell Transplantation.

    Science.gov (United States)

    ElMarsafawy, Hala; Matter, Mohamed; Sarhan, Mohamed; El-Ashry, Rasha; Al-Tonbary, Youssef

    2016-01-01

    Increased interest is focused on the long-term adverse effects of bone marrow transplantation. Subclinical cardiac involvement appears common in adults, but only a few reports have examined pediatric patients. A prospective case-control study of 19 children with normal cardiac function undergoing autologous hematopoietic stem cell transplantation (HSCT) was performed. Tissue Doppler imaging (TDI) and echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography before and 3 months after HSCT. Lateral mitral annulus before HSCT showed significant reduced mitral systolic annular velocity (P ICT) (P = 0.003) and IRT (P = 0.002) after HSCT, were observed. Investigation of lateral tricuspid annulus showed nearly similar results as the lateral mitral annulus. LV and RV Tei indices were higher before HSCT compared with control and remained high after HSCT. TDI detected subtle abnormalities in systolic and diastolic functions before and after HSCT, which suggests that a conditioning regimen may affect cardiac function. © 2015, Wiley Periodicals, Inc.

  10. 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

  11. 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.

  12. 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

  13. Mitigation of radiation induced hematopoietic injury via regulation of Nrf-2 and increasing hematopoietic stem cells

    International Nuclear Information System (INIS)

    Patwardhan, R.S.; Sharma, Deepak; Checker, Rahul; Santosh Kumar, S.

    2014-01-01

    Therapeutic doses of ionizing radiation (IR) that can be delivered to tumors are restricted due to radiation induced damage to surrounding normal tissues thereby limiting the effectiveness of radiotherapy. Strategies to develop agents that selectively protect normal cells yielded limited success in the past. There is pressing need to develop safe, syndrome specific and effective radiation countermeasures to prevent or mitigate the harmful consequences of radiation exposure. Survival of bone marrow stem cells (HSCs) play a key role in protecting against IR induced hematopoietic injury. Many studies have shown manipulation of HSC frequency and/or survival as principal mechanism of radioprotection. It is known that, Nrf-2 plays crucial role in HSC survival and maintenance under oxidative stress conditions. In the present study, we have investigated the radioprotective ability of a flavonoid baicalein (5,6,7-trihydroxyflavone), extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. There are numerous reports showing anti-inflammatory, anti-apoptotic, anti-oxidant, anti-cancer, anti-microbial, anti-mutagenic and neuroprotective properties of baicalein. Based on these reports, we have investigated the ability of baicalein to protect against radiation induced hematopoietic injury. Baicalein administration to mice protected against WBI induced mortality. Interestingly, the stem cell frequency increased in bone marrow cells obtained from baicalein administered mice as compared to vehicle treated mice. Baicalein treatment led to increased phospho-Nrf-2 levels in lineage negative BM-MNC. Administration of mice with Nrf-2 inhibitor prior to baicalein treatment led to significant abrogation of radioprotective ability of baicalein. This result suggests that, Nrf-2 may be playing a key role in baicalein mediated radioprotection. Here, we have shown that baicalein administration augments stem cell frequency, induces

  14. Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Ljungman, Per; de la Camara, Rafael; Perez-Bercoff, Lena; Abecasis, Manuel; Nieto Campuzano, Jose Bartolo; Cannata-Ortiz, M Jimena; Cordonnier, Catherine; Einsele, Hermann; Gonzalez-Vicent, Marta; Espigado, Ildefonso; Halter, Jörg; Martino, Rodrigo; Mohty, Bilal; Sucak, Gülsan; Ullmann, Andrew J; Vázquez, Lourdes; Ward, Katherine N; Engelhard, Dan

    2011-08-01

    During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01-1.04; P=0.002) and lymphopenia (OR 2.49; 1.33-4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients.

  15. What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

    Science.gov (United States)

    Korkmaz, Serdal; Altuntas, Fevzi

    2017-12-01

    Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Optimized patient-trajectory for patients undergoing treatment with high-dose chemotherapy and autologous stem cell transplantation

    DEFF Research Database (Denmark)

    Bartels, Frederik Reith; Smith, Nicholas Simon; Gørløv, Jette Sønderskov

    2015-01-01

    was reported by using a patient diary, weekly questionnaire and count of daily attendance in supervised sessions during hospital stay. Data collection was scheduled shortly after diagnosis, admission, discharge and eight weeks after discharge. Success criteria were: no severe adverse events in relation......PURPOSE: Before, during and after autologous hematopoietic stem cell transplantation (HD-ASCT) patients suffer from significant loss of physical function, and experience multiple complications during and after hospitalization. Studies regarding safety and feasibility of physical exercise...... interventions for patients undergoing treatment with HD-ASCT are missing. METHODS: Forty patients referred to HD-ASCT treatment, suffering from multiple myeloma, lymphoma or amyloidosis aged 23-70 years were enrolled in a prospective longitudinal study. The study consisted of a home-based exercise program...

  17. 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....

  18. Autologous Intravenous Mononuclear Stem Cell Therapy in Chronic Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Bhasin A

    2012-01-01

    Full Text Available Background: The regenerative potential of brain has led to emerging therapies that can cure clinico-motor deficits after neurological diseases. Bone marrow mononuclear cell therapy is a great hope to mankind as these cells are feasible, multipotent and aid in neurofunctional gains in Stroke patients. Aims: This study evaluates safety, feasibility and efficacy of autologous mononuclear (MNC stem cell transplantation in patients with chronic ischemic stroke (CIS using clinical scores and functional imaging (fMRI and DTI. Design: Non randomised controlled observational study Study: Twenty four (n=24 CIS patients were recruited with the inclusion criteria as: 3 months–2years of stroke onset, hand muscle power (MRC grade at least 2; Brunnstrom stage of recovery: II-IV; NIHSS of 4-15, comprehendible. Fugl Meyer, modified Barthel Index (mBI and functional imaging parameters were used for assessment at baseline, 8 weeks and at 24 weeks. Twelve patients were administered with mean 54.6 million cells intravenously followed by 8 weeks of physiotherapy. Twelve patients served as controls. All patients were followed up at 24 weeks. Outcomes: The laboratory and radiological outcome measures were within normal limits in MNC group. Only mBI showed statistically significant improvement at 24 weeks (p<0.05 whereas the mean FM, MRC, Ashworth tone scores in the MNC group were high as compared to control group. There was an increased number of cluster activation of Brodmann areas BA 4, BA 6 post stem cell infusion compared to controls indicating neural plasticity. Cell therapy is safe and feasible which may facilitate restoration of function in CIS.

  19. Genetic and Epigenetic Mechanisms That Maintain Hematopoietic Stem Cell Function

    Directory of Open Access Journals (Sweden)

    Christian Kosan

    2016-01-01

    Full Text Available All hematopoiesis cells develop from multipotent progenitor cells. Hematopoietic stem cells (HSC have the ability to develop into all blood lineages but also maintain their stemness. Different molecular mechanisms have been identified that are crucial for regulating quiescence and self-renewal to maintain the stem cell pool and for inducing proliferation and lineage differentiation. The stem cell niche provides the microenvironment to keep HSC in a quiescent state. Furthermore, several transcription factors and epigenetic modifiers are involved in this process. These create modifications that regulate the cell fate in a more or less reversible and dynamic way and contribute to HSC homeostasis. In addition, HSC respond in a unique way to DNA damage. These mechanisms also contribute to the regulation of HSC function and are essential to ensure viability after DNA damage. How HSC maintain their quiescent stage during the entire life is still matter of ongoing research. Here we will focus on the molecular mechanisms that regulate HSC function.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Alişan Yıldıran

    2017-12-01

    Full Text Available 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.

  2. Deficiency of GRP94 in the hematopoietic system alters proliferation regulators in hematopoietic stem cells.

    Science.gov (United States)

    Luo, Biquan; Tseng, Chun-Chih; Adams, Gregor B; Lee, Amy S

    2013-12-01

    We have previously reported that acute inducible knockout of the endoplasmic reticulum chaperone GRP94 led to an expansion of the hematopoietic stem and progenitor cell pool. Here, we investigated the effectors and mechanisms for this phenomenon. We observed an increase in AKT activation in freshly isolated GRP94-null HSC-enriched Lin(-) Sca-1(+) c-Kit(+) (LSK) cells, corresponding with higher production of PI(3,4,5)P3, indicative of PI3K activation. Treatment of GRP94-null LSK cells with the AKT inhibitor MK2206 compromised cell expansion, suggesting a causal relationship between elevated AKT activation and increased proliferation in GRP94-null HSCs. Microarray analysis demonstrated a 97% reduction in the expression of the hematopoietic cell cycle regulator Ms4a3 in the GRP94-null LSK cells, and real-time quantitative PCR confirmed this down-regulation in the LSK cells but not in the total bone marrow (BM). A further examination comparing freshly isolated BM LSK cells with spleen LSK cells, as well as BM LSK cells cultured in vitro, revealed specific down-regulation of Ms4a3 in freshly isolated BM GRP94-null LSK cells. On examining cell surface proteins that are known to regulate stem cell proliferation, we observed a reduced expression of cell surface connexin 32 (Cx32) plaques in GRP94-null LSK cells. However, suppression of Cx32 hemichannel activity in wild-type LSK cells through mimetic peptides did not lead to increased LSK cell proliferation in vitro. Two other important cell surface proteins that mediate HSC-niche interactions, specifically Tie2 and CXCR4, were not impaired by Grp94 deletion. Collectively, our study uncovers novel and unique roles of GRP94 in regulating HSC proliferation.

  3. Studies of hematopoietic stem cells spared by 5-fluorouracil

    International Nuclear Information System (INIS)

    Van Zant, G.

    1984-01-01

    Mouse marrow cells were exposed to 5-fluorouracil (FU) either in vivo or in vitro and the effects on the hematopoietic stem cell compartment were studied. The drug was highly toxic to bone marrow cells including the spleen colony-forming unit (CFU-S) population. The small population of stem cells surviving FU, however, caused a different pattern of spleen colony growth when injected into lethally irradiated mice. Whereas numbers of spleen colonies caused by normal marrow cells remained constant during an 8-14 d period after transplantation, spleen colonies derived from FU-treated marrow cells increased by as much as 100-fold during this time. This effect on stem cells was dose dependent both in vitro and in vivo. When FU was given in vivo, the day 14/day 8 ratio of colonies was greatest 1 d after injection and, over the next 7 d, returned to a near-normal value, that is, unity. A number of studies have shown that the stem cell compartment is heterogeneous with respect to self-replicative capacity and developmental potential. An age structure for the stem cell compartment has been proposed wherein cells with a short mitotic history are more likely to self-replicate than they are to differentiate; hence they are more primitive. I propose that the delayed spleen colony appearance in normal hosts is the result of developmental maturation of the primitive stem cell compartment that survives FU and is responsible for spleen colonies arising around day 14. This maturation, at least initially, occurs in the marrow and leads to the replenishment of the more differentiated CFU-S subsets ablated by FU, which are normally responsible for spleen colonies appearing earlier after transplantation

  4. Disseminated Fusarium infection in autologous stem cell transplant recipient

    OpenAIRE

    Avelino-Silva, Vivian Iida; Ramos, Jessica Fernandes; Leal, Fabio Eudes; Testagrossa, Leonardo; Novis, Yana Sarkis

    2015-01-01

    Disseminated infection by Fusarium is a rare, frequently lethal condition in severely immunocompromised patients, including bone marrow transplant recipients. However, autologous bone marrow transplant recipients are not expected to be at high risk to develop fusariosis. We report a rare case of lethal disseminated Fusarium infection in an autologous bone marrow transplant recipient during pre-engraftment phase.

  5. Disseminated Fusarium infection in autologous stem cell transplant recipient

    Directory of Open Access Journals (Sweden)

    Vivian Iida Avelino-Silva

    2015-01-01

    Full Text Available Disseminated infection by Fusarium is a rare, frequently lethal condition in severely immunocompromised patients, including bone marrow transplant recipients. However, autologous bone marrow transplant recipients are not expected to be at high risk to develop fusariosis. We report a rare case of lethal disseminated Fusarium infection in an autologous bone marrow transplant recipient during pre-engraftment phase.

  6. Genetically Modified Hematopoietic Stem Cell Transplantation for HIV-1–infected Patients: Can We Achieve a Cure?

    Science.gov (United States)

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

    2014-01-01

    The cure of a human immunodeficiency virus (HIV)-1–infected patient following allogeneic transplantation from a CCR5-null donor and potential cure of two patients transplanted with CCR5 wild-type hematopoietic stem cells (HSC) have provided renewed optimism that a potential alternative to conventional antiretroviral therapy (ART) is forthcoming. While allogeneic grafts have thus far suggested complete eradication of viral reservoirs, it has yet to be observed following autologous HSC transplantation. Development of curative autologous transplantation strategies would significantly increase the number of treatable patients, eliminating the need for matched donors and reducing the risks of adverse events. Recent studies suggest gene therapy may provide a mechanism for developing curative therapies. Expression of cellular/artificial restriction factors or disruption of CCR5 has been shown to limit viral replication and provide protection of genetically modified cells. However, significant obstacles remain with regards to the depletion of established viral reservoirs in an autologous transplantation setting devoid of the “allo-effect”. Here, we discuss results from early-stage clinical trials and recent findings in animal models of gene modified HSC transplantation. Finally, we propose innovative combination therapies that may aid in the reduction and/or elimination of viral reservoirs in HIV-1–infected patients and promote the artificial development of a natural controller phenotype. PMID:24220323

  7. Response of hematopoietic stem cells to ionizing radiation

    International Nuclear Information System (INIS)

    Simonnet, A.

    2008-12-01

    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 SK cells positive for established indicators of HSC presence: CD150 + and CD105 + . 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 -/low Sca-1 + c-Kit + (LSK) stem/progenitor compartment: CD150 + /Flk2 - and CD150 - /Flk2 + LSK cell frequencies are increased and dramatically reduced, respectively. CD150 + LSK cells also show impaired reconstitution capacity, accrued number of γ-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 this effect, and found in a competitive transplant

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

    Full Text Available InP.Bld.10.AllAg.Hematopoietic_Stem_Cells mm9 Input control Blood Hematopoietic Ste...hive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Bld.10.AllAg.Hematopoietic_Stem_Cells.bed ...

  11. Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study

    Directory of Open Access Journals (Sweden)

    Alois Gratwohl

    2015-12-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37% or autologous (N = 65,007; 63% HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p < 0·0001; HR 0·90;0·85–0·90 per 10 years; p < 0·001 and autologous HSCT (HR 0·91;0·87–0·96 per 10 patients; p < 0·001; HR 0·93;0·87–0·99 per 10 years; p = 0·02. The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2 = 18%; for relapse free survival after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.

  12. Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study.

    Science.gov (United States)

    Gratwohl, Alois; Sureda, Anna; Baldomero, Helen; Gratwohl, Michael; Dreger, Peter; Kröger, Nicolaus; Ljungman, Per; McGrath, Eoin; Mohty, Mohamad; Nagler, Arnon; Rambaldi, Alessandro; de Elvira, Carmen Ruiz; Snowden, John A; Passweg, Jakob; Apperley, Jane; Niederwieser, Dietger; Stijnen, Theo; Brand, Ronald

    2015-12-01

    Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84-0·91 per 10 patients; p < 0·0001; HR 0·90;0·85-0·90 per 10 years; p < 0·001) and autologous HSCT (HR 0·91;0·87-0·96 per 10 patients; p < 0·001; HR 0·93;0·87-0·99 per 10 years; p = 0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R(2) = 18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.

  13. 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

  14. 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.

  15. Role of HLA in Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Meerim Park

    2012-01-01

    Full Text Available The selection of hematopoietic stem cell transplantation (HSCT donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.

  16. Analysis of the motivation for hematopoietic stem cell donation.

    Science.gov (United States)

    Aurelio, M T; Aniasi, A; Haworth, S E; Colombo, M B; Dimonopoli, T; Mocellin, M C; Poli, F; Torelli, R; Crespiatico, L; Serafini, M; Scalamogna, M

    2011-05-01

    The Italian Bone Marrow Donor Register is the institutional organization for management of unrelated hematopoietic stem cell donors. The law requires only a donor's clinical history, but not a psychosocial profile for registration. We have studied the donor's motivation for enlistment on the donor registry and the medical staff's need for this information to interact correctly with the donor. For this purpose we distributed a questionnaire to new donors at the 20 centers in the Lombardy Region over a period of 1 year. The analysis of the responses revealed a prevalence of extrinsic motivations that would not ensure continued registration for donation. Therefore, it is necessary that the donor be well informed and better educated about all aspects of donation, in order to produce a shift to an intrinsic motivation. This objective can be facilitated via professional training of health workers in communication. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. 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.

  18. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

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

    2016-01-01

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

  19. ABO blood group mismatched hematopoietic stem cell transplantation.

    Science.gov (United States)

    Tekgündüz, Sibel Akpınar; Özbek, Namık

    2016-02-01

    Apart from solid organ transplantations, use of ABO-blood group mismatched (ABO-mismatched) donors is acceptable in hematopoietic stem cell transplantation (HSCT) patients. About 20-40% of allogeneic HSCT recipients will receive grafts from ABO-mismatched donors. ABO incompatible HSCT procedures are associated with immediate and late consequences, including but not restricted to acute or delayed hemolytic reactions, delayed red blood cell recovery, pure red cell aplasia and graft-versus-host disease. This review summarizes the current knowledge about consequences of ABO-mismatched HSCT in terms of associated complications and will evaluate its impact on important outcome parameters of HSCT. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Montrone, Corinna; Kokkaliaris, Konstantinos D; Loeffler, Dirk; Lechner, Martin; Kastenmüller, Gabi; Schroeder, Timm; Ruepp, Andreas

    2013-01-01

    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.

  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. Rapid deterioration of preexisting renal insufficiency after autologous mesenchymal stem cell therapy

    Directory of Open Access Journals (Sweden)

    Jun-Seop Kim

    2017-06-01

    Full Text Available Administration of autologous mesenchymal stem cells (MSCs has been shown to improve renal function and histological findings in acute kidney injury (AKI models. However, its effects in chronic kidney disease (CKD are unclear, particularly in the clinical setting. Here, we report our experience with a CKD patient who was treated by intravenous infusion of autologous MSCs derived from adipose tissue in an unknown clinic outside of Korea. The renal function of the patient had been stable for several years before MSC administration. One week after the autologous MSC infusion, the preexisting renal insufficiency was rapidly aggravated without any other evidence of AKI. Hemodialysis was started 3 months after MSC administration. Renal biopsy findings at dialysis showed severe interstitial fibrosis and inflammatory cell infiltration, with a few cells expressing CD34 and CD117, 2 surface markers of stem cells. This case highlights the potential nephrotoxicity of autologous MSC therapy in CKD patients.

  3. 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).

  4. Umbilical Cord-Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Yu-Hua Chao

    2012-01-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is becoming an effective therapeutic modality for a variety of diseases. Mesenchymal stem cells (MSCs can be used to enhance hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, prevent and treat graft-versus-host disease, and repair tissue damage in patients receiving HSCT. Till now, most MSCs for human clinical application have been derived from bone marrow. However, acquiring bone-marrow-derived MSCs involves an invasive procedure. Umbilical cord is rich with MSCs. Compared to bone-marrow-derived MSCs, umbilical cord-derived MSCs (UCMSCs are easier to obtain without harm to the donor and can proliferate faster. No severe adverse effects were noted in our previous clinical application of UCMSCs in HSCT. Accordingly, application of UCMSCs in humans appears to be feasible and safe. Further studies are warranted.

  5. 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

  6. The GOD of Hematopoietic Stem Cells: A Clonal Diversity Model of the Stem Cell Compartment

    OpenAIRE

    Muller-Sieburg, C.E.; Sieburg, H.B.

    2006-01-01

    Hematopoietic stem cells (HSC) show heterogeneous behavior even when isolated as phenotypically homogeneous populations. The cellular and molecular mechanisms that control the generation of diversity (GOD) in the HSC compartment are not well understood, but have been the focus of much debate. There is increasing evidence that the most important HSC functions, self-renewal and differentiation, are epigenetically preprogrammed and therefore predictable. Indeed, recent data show that the adult H...

  7. CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells

    NARCIS (Netherlands)

    van Pel, Melissa; Hagoort, Henny; Hamann, Jörg; Fibbe, Willem E.

    2008-01-01

    BACKGROUND: CD97 is a member of the epidermal growth factor-seven transmembrane (EGF-TM7) family of adhesion receptors and is broadly expressed on hematopoietic cells. The aim of this study was to investigate the expression of CD97 on hematopoietic stem- and progenitor cells (HSC/HPC). DESIGN AND

  8. Analysis and manipulation of hematopoietic progenitor and stem cells from murine embryonic tissues

    NARCIS (Netherlands)

    A. Medvinsky (Alexander); S. Taoudi (Samir); S.C. Mendes (Sandra); E.A. Dzierzak (Elaine)

    2008-01-01

    textabstractHematopoietic development begins in several locations in the mammalian embryo: yolk sac, aorta-gonad-mesonephros region (AGM), and the chorio-allantoic placenta. Generation of the most potent cells, adult definitive hematopoietic stem cells (HSCs), occurs within the body of the mouse

  9. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo.

    NARCIS (Netherlands)

    M.F.T.R. de Bruijn (Marella); N.A. Speck; M.C. Peeters (Marian); E.A. Dzierzak (Elaine)

    2000-01-01

    textabstractThe aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site within the mammalian embryo body, and the first place from which hematopoietic stem cells (HSCs) emerge. Within the complex embryonic vascular, excretory and reproductive tissues of the

  10. 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

  11. Trends of Hematopoietic stem cell transplantation in the Eastern Mediterranean region, 1984–2007

    Science.gov (United States)

    Ahmed, S.O.; Ghavamzadeh, A.; Zaidi, S.; Baldomero, H.; Pasquini, M.; Hussain, F.; Alimoghadam, K.; Almohareb, F.; Ayas, M.; Hamidieh, A.; Mahmoud, H.; Elhaddad, A.; Othman, T. Ben; Abdelkefi, A.; Sarhan, M.; Abdel-Rahman, F.; Adil, S.; Alkindi, S.; Bazarbachi, A.; Benchekroun, S.; Niederwieser, D.; Horowitz, M.; Gratwohl, A.; El Solh, H.; Aljurf, M.

    2012-01-01

    Hematopoietic stem cell transplantation (HSCT) activity was surveyed in the 9 countries in the WHO Eastern Mediterranean (EM) region that are reported to carry out transplants. Between the years of 1984 and 2007, 7933 transplants were reported. The total number of HSCT per year has continued to increase, with a plateau in allogeneic HSCT (allo-HSCT) between 2005 and 2007. Overall, a greater proportion of transplants were allogeneic HSCT (allo-HSCT) (n=5761, 77%) compared to autologous HSCT (ASCT) (n=2172, 23% ASCT). Of 5761 allo-HSCT, acute leukemia constituted the main indication (n=2124, 37%). There was a relatively high proportion of allo-HSCT for bone marrow failure (n=1001, 17%) and hemoglobinopathies (n=885, 15%). The rate of unrelated donor transplants remained low, with only 2 non-umbilical cord matched unrelated donor (MUD) allo-HSCT reported. One hundred umbilical cord (UCB) transplants were reported (0.017% of allo- HSCT). Peripheral blood stem cells (PBSC) were the main source of graft in allo-HSCT, and PBSCT increasingly constitutes the main source of stem cells. Reduced intensity conditioning was utilized in 5.7% of allografts over the surveyed period. ASCT numbers continue to increase. There has been a shift in the indication for ASCT from acute leukemia to lymphoproliferative disorders (45%) followed by myeloma (26%). The survey reflects transplantation activity according to the unique health settings of this region. Notable differences in transplant practices as reported to the European Group for Blood and Marrow Transplantation (EBMT) over recent years are addressed. PMID:21440654

  12. DIABETES IMPAIRS HEMATOPOIETIC STEM CELL MOBILIZATION THROUGH ALTERATION OF NICHE FUNCTION

    Science.gov (United States)

    Ferraro, Francesca; Lymperi, Stefania; Méndez-Ferrer, Simón; Saez, Borja; Spencer, Joel A; Yeap, Beow Y; Masselli, Elena; Graiani, Gallia; Prezioso, Lucia; Rizzini, Elisa Lodi; Mangoni, Marcellina; Rizzoli, Vittorio; Sykes, Stephen M; Lin, Charles P.; Frenette, Paul S.; Quaini, Federico; Scadden, David T.

    2013-01-01

    Autologous hematopoietic stem/progenitor cells (HSPC) transplantation success depends upon adequate cell collection after G-CSF-administration that a substantial fraction of patients fails to achieve. Retrospective analysis of patient records demonstrated that diabetes correlated with lower CD34+ cell mobilization. Using mouse models, we found impaired HSPC egress from the bone marrow in either streptozotocin-induced or db/db diabetic animals. HSPC aberrantly localized within the marrow microenvironment of diabetic animals in association with abnormalities in sympathetic neuron number and function. Markedly increased sympathetic neuron density was accompanied by abnormal response to β-adrenergic stimulation and a failure to generate the G-CSF-induced CXCL12 gradient in nestin-expressing mesenchymal cells associated with HSPC mobilization. Alternative mobilization by direct pharmacologic inhibition of CXCL12-CXCR4 interaction rescued the defect. These data reveal diabetes-induced changes in bone marrow physiology and microanatomy and point to a pathophysiologically based approach to overcome HSPC mobilization defects in diabetic patients. PMID:21998408

  13. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    De Ravin, Suk See; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M; Zarember, Kol A; O'Connor, Geraldine; McVicar, Daniel; Kuhns, Douglas; Throm, Robert E; Zhou, Sheng; Notarangelo, Luigi D; Hanson, I Celine; Cowan, Mort J; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T; Sorrentino, Brian P; Malech, Harry L; Kardava, Lela

    2016-04-20

    X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1. Copyright © 2016, American Association for the Advancement of Science.

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

    Science.gov (United States)

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

    2016-11-01

    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 2006 to October 2014. Fourteen of 1449 episodes (1.0%) of bacterial meningitis occurred in patients with a history of HSCT. The incidence of bacterial meningitis in HSCT recipients was 40.4 per 100 000 patients per year (95% confidence interval (CI) 23.9-62.2), which is 30-fold (95% CI 18-51; Pmeningitis were infected with a serotype included in the 23-valent pneumococcal polysaccharide vaccine, of whom four developed meningitis despite vaccination. In conclusion, HSCT recipients have a substantially increased risk compared with the general population of acquiring bacterial meningitis, which is mostly due to S. pneumoniae, and disease is associated with high mortality and morbidity. Vaccination is important to prevent disease although vaccine failures did occur.

  15. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Anderson, Kristina; Porse, Bo T

    2006-01-01

    Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression...

  16. 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.

  17. Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study

    Science.gov (United States)

    Gratwohl, Alois; Baldomero, Helen; Gratwohl, Michael; Aljurf, Mahmoud; Bouzas, Luis Fernando; Horowitz, Mary; Kodera, Yoshihisa; Lipton, Jeff; Iida, Minako; Pasquini, Marcelo C.; Passweg, Jakob; Szer, Jeff; Madrigal, Alejandro; Frauendorfer, Karl; Niederwieser, Dietger

    2013-01-01

    Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006–2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (PTransplant rates were associated with Gross National Income/capita (Ptransplantation activity is increasing worldwide. The preferential increase in high income countries, the widening gap between low and high income countries and the significant regional differences suggest that different strategies are required in individual countries to foster hematopoietic stem cell transplantation

  18. Hematopoietic Stem Cells in Regenerative Medicine: Astray or on the Path?

    Science.gov (United States)

    Müller, Albrecht M; Huppertz, Sascha; Henschler, Reinhard

    2016-07-01

    Hematopoietic stem cells (HSCs) are the best characterized adult stem cells and the only stem cell type in routine clinical use. The concept of stem cell transplantation laid the foundations for the development of novel cell therapies within, and even outside, the hematopoietic system. Here, we report on the history of hematopoietic cell transplantation (HCT) and of HSC isolation, we briefly summarize the capabilities of HSCs to reconstitute the entire hemato/lymphoid cell system, and we assess current indications for HCT. We aim to draw the lines between areas where HCT has been firmly established, areas where HCT can in the future be expected to be of clinical benefit using their regenerative functions, and areas where doubts persist. We further review clinical trials for diverse approaches that are based on HCT. Finally, we highlight the advent of genome editing in HSCs and critically view the use of HSCs in non-hematopoietic tissue regeneration.

  19. 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.

  20. 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

  1. Skin Cancer Risk in Hematopoietic Stem-Cell Transplant Recipients Compared With Background Population and Renal Transplant Recipients

    DEFF Research Database (Denmark)

    Omland, Silje Haukali; Gniadecki, Robert; Hædersdal, Merete

    2016-01-01

    IMPORTANCE: While a high risk of nonmelanoma skin cancer is well recognized in solid-organ transplant recipients, the risk of skin cancer in hematopoietic stem-cell transplant (HSCT) recipients has not been extensively studied. OBJECTIVE: To determine the risk of cutaneous cancer in HSCT recipients...... autologous) from 1999 through 2014, 4789 RTRs from 1976 through 2014, and 10 age- and sex-matched nontransplanted individuals for each of the groups from the background population. Person-years at risk were calculated from the time of study inclusion until first cutaneous cancer. To compare the risk of skin...... cancer between transplant recipients and background population, we used a stratified proportional hazard regression model for hazard ratio (HR) estimations. By use of the cumulative incidence, we estimated 5- and 10-year risks of skin cancers. All RTR and HSCT recipients were treated and followed up...

  2. Gastrocnemius tendon strain in a dog treated with autologous mesenchymal stem cells and a custom orthosis.

    Science.gov (United States)

    Case, J Brad; Palmer, Ross; Valdes-Martinez, Alex; Egger, Erick L; Haussler, Kevin K

    2013-05-01

    To report clinical findings and outcome in a dog with gastrocnemius tendon strain treated with autologous mesenchymal stem cells and a custom orthosis. Clinical report. A 4-year-old spayed female Border Collie. Bone-marrow derived, autologous mesenchymal stem cells were transplanted into the tendon core lesion. A custom, progressive, dynamic orthosis was fit to the tarsus. Serial orthopedic examinations and ultrasonography as well as long-term force-plate gait analysis were utilized for follow up. Lameness subjectively resolved and peak vertical force increased from 43% to 92% of the contralateral pelvic limb. Serial ultrasonographic examinations revealed improved but incomplete restoration of normal linear fiber pattern of the gastrocnemius tendon. Findings suggest that autologous mesenchymal stem cell transplantation with custom, progressive, dynamic orthosis may be a viable, minimally invasive technique for treatment of calcaneal tendon injuries in dogs. © Copyright 2013 by The American College of Veterinary Surgeons.

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

    OpenAIRE

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

    2012-01-01

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

  4. High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Franzius, Ch.; Eckardt, J.; Sciuk, J.; Schober, O. [Dept. of Nuclear Medicine, Univ. Hospital, Muenster (Germany); Bielack, S.; Flege, S.; Juergens, H. [Dept. of Pediatric Hematology and Oncology, Univ. Hospital, Muenster (Germany)

    2001-12-01

    Purpose: Despite highly efficacious chemotherapy, patients with osteosarcomas still have a poor prognosis if adequate surgical control cannot be obtained. These patients may benefit from therapy with radiolabeled phosphonates. Patients and Methods: Six patients (three male, three female; seven to 41 years) with unresectable primary osteosarcoma (n = 3) or unresectable recurrent sites of osteosarcomas (n = 3) were treated with high-activity of Sm-153-EDTMP (150 MBq/kg BW). In all patients autologous peripheral blood stem cells had been collected before Sm-153-EDTMP therapy. Results: No immediate adverse reactions were observed in the patients. In one patient bone pain increased during the first 48 hrs after therapy. Three patients received pain relief. Autologous peripheral blood stem cell reinfusion was performed on day +12 to +27 in all patients to overcome potentially irreversible damage to the hematopoietic stem cells. In three patient external radiotherapy of the primary tumor site was performed after Sm-153-EDTMP therapy and in two of them polychemotherapy was continued. Thirty-six months later one of these patients is still free of progression. Two further patients are still alive. However, they have developed new metastases. The three patients who had no accompanying external radiotherapy, all died of disease progression five to 20 months after therapy. Conclusion: These preliminary results show that high-dose Sm-153-EDTMP therapy is feasible and warrants further evaluation of efficacy. The combination with external radiation and polychemotherapy seems to be most promising. Although osteosarcoma is believed to be relatively radioresistant, the total focal dose achieved may delay local progression or even achieve permanent local tumor control in patients with surgically inaccessible primary or relapsing tumors. (orig.)

  5. ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Worel, Nina

    2016-01-01

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

  6. 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.

  7. 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.

  8. Hematopoietic Stem Cell Transplantation Activity in Pediatric Cancer between 2008 and 2014 in the United States: A Center for International Blood and Marrow Transplant Research Report.

    Science.gov (United States)

    Khandelwal, Pooja; Millard, Heather R; Thiel, Elizabeth; Abdel-Azim, Hisham; Abraham, Allistair A; Auletta, Jeffery J; Boulad, Farid; Brown, Valerie I; Camitta, Bruce M; Chan, Ka Wah; Chaudhury, Sonali; Cowan, Morton J; Angel-Diaz, Miguel; Gadalla, Shahinaz M; Gale, Robert Peter; Hale, Gregory; Kasow, Kimberly A; Keating, Amy K; Kitko, Carrie L; MacMillan, Margaret L; Olsson, Richard F; Page, Kristin M; Seber, Adriana; Smith, Angela R; Warwick, Anne B; Wirk, Baldeep; Mehta, Parinda A

    2017-08-01

    This Center for International Blood and Marrow Transplant Research report describes the use of hematopoietic stem cell transplantation (HSCT) in pediatric patients with cancer, 4408 undergoing allogeneic (allo) and3076 undergoing autologous (auto) HSCT in the United States between 2008 and 2014. In both settings, there was a greater proportion of boys (n = 4327; 57%), children reports of transplant practices in the United States. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Loss of quiescence and impaired function of CD34(+)/CD38(low) cells one year following autologous stem cell transplantation

    NARCIS (Netherlands)

    Woolthuis, Carolien M.; Brouwers-Vos, Annet Z.; Huls, Gerwin; de Wolf, Joost Th. M.; Schuringa, Jan Jacob; Vellenga, Edo

    2013-01-01

    Patients who have undergone autologous stem cell transplantation are subsequently more susceptible to chemotherapy-induced bone marrow toxicity. In the present study, bone marrow primitive progenitor cells were examined one year after autologous stem cell transplantation and compared with normal

  10. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis.

    Science.gov (United States)

    Ustun, Celalettin; Reiter, Andreas; Scott, Bart L; Nakamura, Ryotaro; Damaj, Gandhi; Kreil, Sebastian; Shanley, Ryan; Hogan, William J; Perales, Miguel-Angel; Shore, Tsiporah; Baurmann, Herrad; Stuart, Robert; Gruhn, Bernd; Doubek, Michael; Hsu, Jack W; Tholouli, Eleni; Gromke, Tanja; Godley, Lucy A; Pagano, Livio; Gilman, Andrew; Wagner, Eva Maria; Shwayder, Tor; Bornhäuser, Martin; Papadopoulos, Esperanza B; Böhm, Alexandra; Vercellotti, Gregory; Van Lint, Maria Teresa; Schmid, Christoph; Rabitsch, Werner; Pullarkat, Vinod; Legrand, Faezeh; Yakoub-Agha, Ibrahim; Saber, Wael; Barrett, John; Hermine, Olivier; Hagglund, Hans; Sperr, Wolfgang R; Popat, Uday; Alyea, Edwin P; Devine, Steven; Deeg, H Joachim; Weisdorf, Daniel; Akin, Cem; Valent, Peter

    2014-10-10

    Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown. In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non-mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC). Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response. AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial. © 2014 by American Society of Clinical Oncology.

  11. Regeneration of Cartilage in Human Knee Osteoarthritis with Autologous Adipose Tissue-Derived Stem Cells and Autologous Extracellular Matrix

    Directory of Open Access Journals (Sweden)

    Jaewoo Pak

    2016-08-01

    Full Text Available This clinical case series demonstrates that percutaneous injections of autologous adipose tissue-derived stem cells (ADSCs and homogenized extracellular matrix (ECM in the form of adipose stromal vascular fraction (SVF, along with hyaluronic acid (HA and platelet-rich plasma (PRP activated by calcium chloride, could regenerate cartilage-like tissue in human knee osteoarthritis (OA patients. Autologous lipoaspirates were obtained from adipose tissue of the abdominal origin. Afterward, the lipoaspirates were minced to homogenize the ECM. These homogenized lipoaspirates were then mixed with collagenase and incubated. The resulting mixture of ADSCs and ECM in the form of SVF was injected, along with HA and PRP activated by calcium chloride, into knees of three Korean patients with OA. The same affected knees were reinjected weekly with additional PRP activated by calcium chloride for 3 weeks. Pretreatment and post-treatment magnetic resonance imaging (MRI data, functional rating index, range of motion (ROM, and pain score data were then analyzed. All patients' MRI data showed cartilage-like tissue regeneration. Along with MRI evidence, the measured physical therapy outcomes in terms of ROM, subjective pain, and functional status were all improved. This study demonstrates that percutaneous injection of ADSCs with ECM contained in autologous adipose SVF, in conjunction with HA and PRP activated by calcium chloride, is a safe and potentially effective minimally invasive therapy for OA of human knees.

  12. ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias.

    Science.gov (United States)

    Ishibashi, Tomohiko; Yokota, Takafumi; Tanaka, Hirokazu; Ichii, Michiko; Sudo, Takao; Satoh, Yusuke; Doi, Yukiko; Ueda, Tomoaki; Tanimura, Akira; Hamanaka, Yuri; Ezoe, Sachiko; Shibayama, Hirohiko; Oritani, Kenji; Kanakura, Yuzuru

    2016-04-01

    Reliable markers are essential to increase our understanding of the biological features of human hematopoietic stem cells and to facilitate the application of hematopoietic stem cells in the field of transplantation and regenerative medicine. We previously identified endothelial cell-selective adhesion molecule (ESAM) as a novel functional marker of hematopoietic stem cells in mice. Here, we found that ESAM can also be used to purify human hematopoietic stem cells from all the currently available sources (adult bone marrow, mobilized peripheral blood, and cord blood). Multipotent colony-forming units and long-term hematopoietic-reconstituting cells in immunodeficient mice were found exclusively in the ESAM(High) fraction of CD34(+)CD38(-) cells. The CD34(+)CD38(-) fraction of cord blood and collagenase-treated bone marrow contained cells exhibiting extremely high expression of ESAM; these cells are likely to be related to the endothelial lineage. Leukemia cell lines of erythroid and megakaryocyte origin, but not those of myeloid or lymphoid descent, were ESAM positive. However, high ESAM expression was observed in some primary acute myeloid leukemia cells. Furthermore, KG-1a myeloid leukemia cells switched from ESAM negative to ESAM positive with repeated leukemia reconstitution in vivo. Thus, ESAM is a useful marker for studying both human hematopoietic stem cells and leukemia cells. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  13. Hematopoietic Stem Cell Transplantation Activity and Trends at a Pediatric Transplantation Center in Turkey During 1998-2008

    Directory of Open Access Journals (Sweden)

    Volkan Hazar

    2012-06-01

    Full Text Available OBJECTIVE: The aim of this study was to document hematopoietic stem cell transplantation (HSCT activity and trends at our treatment center. METHODS: Data collected over a 10-year period were retrospectively analyzed, concentrating primarily on types of HSCT, transplant-related mortality (TRM, stem cell sources, indications for HSCT, and causes of death following HSCT. RESULTS: In total, 222 allogeneic (allo-HSCT (87.4% and 32 autologous (auto-HSCT (12.6% procedures were performed between 1998 and 2008. Stem cells obtained from unrelated donors were used in 22.6% (50/222 of the allo- HSCTs. Cord blood was the source of hematopoietic stem cells (HSC in 12.2% of all transplants. The most common indication for allo-HSCT was hemoglobinopathy (43.2%, versus neuroblastoma (53.1% for auto-HSCT. The TRM rate 1 year post transplantation was 18.3% ± 2.5% for all transplants, but differed according to transplantation type (23.5% ± 7.9% for auto-HSCT and 17.5% ± 2.6% for allo-HSCT. The most common cause of death 1 year post HSCT was infection (35.9%. CONCLUSION: The TRM rate in the patients that underwent allo-HSCT was similar to that which has been previously reported; however, the TRM rate in the patients that underwent auto-HSCT was higher than previously reported in developed countries. The selection of these patients to be transplanted must be made attentively.

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

    Science.gov (United States)

    Flach, Johanna; Milyavsky, Michael

    2018-03-01

    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.

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

    Science.gov (United States)

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

    2015-10-01

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

  16. Hematopoietic Stem and Progenitor Cells as Effectors in Innate Immunity

    Directory of Open Access Journals (Sweden)

    Jennifer L. Granick

    2012-01-01

    Full Text Available Recent research has shed light on novel functions of hematopoietic stem and progenitor cells (HSPC. While they are critical for maintenance and replenishment of blood cells in the bone marrow, these cells are not limited to the bone marrow compartment and function beyond their role in hematopoiesis. HSPC can leave bone marrow and circulate in peripheral blood and lymph, a process often manipulated therapeutically for the purpose of transplantation. Additionally, these cells preferentially home to extramedullary sites of inflammation where they can differentiate to more mature effector cells. HSPC are susceptible to various pathogens, though they may participate in the innate immune response without being directly infected. They express pattern recognition receptors for detection of endogenous and exogenous danger-associated molecular patterns and respond not only by the formation of daughter cells but can themselves secrete powerful cytokines. This paper summarizes the functional and phenotypic characterization of HSPC, their niche within and outside of the bone marrow, and what is known regarding their role in the innate immune response.

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

    Science.gov (United States)

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

    2017-03-01

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

  18. [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.

  19. Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science

    Science.gov (United States)

    Choi, Ji Sun; Mahadik, Bhushan P.; Harley, Brendan A. C.

    2016-01-01

    Hematopoietic stem cells (HSCs) play a crucial role in the generation of the body’s blood and immune cells. This process takes place primarily in the bone marrow in specialized ‘niche’ microenvironments, which provide signals responsible for maintaining a balance between HSC quiescence, self-renewal, and lineage specification required for life-long hematopoiesis. While our understanding of these signaling mechanisms continues to improve, our ability to engineer them in vitro for the expansion of clinically relevant HSC populations is still lacking. In this review, we focus on development of biomaterials-based culture platforms for in vitro study of interactions between HSCs and their local microenvironment. The tools and techniques used for both examining HSC-niche interactions as well as applying these findings towards controlled HSC expansion or directed differentiation in 2D and 3D platforms are discussed. These novel techniques hold the potential to push the existing boundaries of HSC cultures towards high-throughput, real-time, and single-cell level biomimetic approaches that enable a more nuanced understanding of HSC regulation and function. Their application in conjunction with innovative biomaterial platforms can pave the way for engineering artificial bone marrow niches for clinical applications as well as elucidating the pathology of blood-related cancers and disorders. PMID:26356030

  20. 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.

  1. Ocular findings after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

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

    2009-09-01

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

  2. Autologous stem cell transplantation in treatment of aggressive non-Hodgkin's lymphoma

    NARCIS (Netherlands)

    Kluin-Nelemans, Hanneke

    2002-01-01

    There is no doubt that autologous stem cell transplantation is useful for patients with relapsed aggressive non-Hodgkin's lymphoma if they are responsive to the chemotherapy given before the transplantation. A small subset of patients with primary refractory disease still profits from this high dose

  3. Hemolytic uremic syndrome after high dose chemotherapy with autologous stem cell support

    NARCIS (Netherlands)

    van der Lelie, H.; Baars, J. W.; Rodenhuis, S.; Van Dijk, M. A.; de Glas-Vos, C. W.; Thomas, B. L.; van Oers, R. H.; von dem Borne, A. E.

    1995-01-01

    BACKGROUND: Chemotherapy intensification may lead to new forms of toxicity such as hemolytic uremic syndrome. METHODS: Three patients are described who developed this complication 4 to 6 months after high dose chemotherapy followed by autologous stem cell support. The literature on this subject is

  4. Severe encephalopathy after high-dose chemotherapy with autologous stem cell support for brain tumours

    NARCIS (Netherlands)

    van den Berkmortel, F.; Gidding, C.; de Kanter, M.; Punt, C. J. A.

    2006-01-01

    Recurrent medulloblastoma carries a poor prognosis. Long-term survival has been obtained with high-dose chemotherapy with autologous stem cell transplantation and secondary irradiation. A 21-year-old woman with recurrent medulloblastoma after previous chemotherapy and radiotherapy is presented. The

  5. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma

    DEFF Research Database (Denmark)

    d'Amore, Francesco; Relander, Thomas; Lauritzsen, Grete F

    2012-01-01

    Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large...

  6. Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy.

    Science.gov (United States)

    Bhartiya, Deepa; Shaikh, Ambreen; Nagvenkar, Punam; Kasiviswanathan, Sandhya; Pethe, Prasad; Pawani, Harsha; Mohanty, Sujata; Rao, S G Ananda; Zaveri, Kusum; Hinduja, Indira

    2012-01-01

    Very small embryonic-like stem cells (VSELs) are possibly lost during cord blood banking and bone marrow (BM) processing for autologus stem cell therapy mainly because of their small size. The present study was conducted on human umbilical cord blood (UCB, n=6) and discarded red blood cells (RBC) fraction obtained after separation of mononuclear cells from human BM (n=6), to test this hypothesis. The results show that VSELs, which are pluripotent stem cells with maximum regenerative potential, settle along with the RBCs during Ficoll-Hypaque density separation. These cells are very small in size (3-5 μm), have high nucleo-cytoplasmic ratio, and express nuclear Oct-4, cell surface protein SSEA-4, and other pluripotent markers such as Nanog, Sox-2, Rex-1, and Tert as indicated by immunolocalization and quantitative polymerase chain reaction (Q-PCR) studies. Interestingly, a distinct population of slightly larger, round hematopoietic stem cells (HSCs) with cytoplasmic Oct-4 were detected in the "buffy" coat, which usually gets banked or used during autologus stem cell therapy. Immunohistochemical studies on the umbilical cord tissue (UCT) sections (n=3) showed the presence of nuclear Oct-4-positive VSELs and many fibroblast-like mesenchymal stem cells (MSCs) with cytoplasmic Oct-4. These VSELs with nuclear Oct-4, detected in UCB, UCT, and discarded RBC fraction obtained after BM processing, may persist throughout life, maintain tissue homeostasis, and undergo asymmetric cell division to self-renew as well as produce larger progenitor stem cells, viz. HSCs or MSCs, which follow differentiation trajectories depending on the somatic niche. Hence, it can be concluded that the true stem cells in adult body tissues are the VSELs, whereas the HSCs and MSCs are actually progenitor stem cells that arise by asymmetric cell division of VSELs. The results of the present study may help explain low efficacy reported during adult autologous stem cell trials, wherein unknowingly

  7. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial

    OpenAIRE

    Chen, Fa-Ming; Gao, Li-Na; Tian, Bei-Min; Zhang, Xi-Yu; Zhang, Yong-Jie; Dong, Guang-Ying; Lu, Hong; Chu, Qing; Xu, Jie; Yu, Yang; Wu, Rui-Xin; Yin, Yuan; Shi, Songtao; Jin, Yan

    2016-01-01

    Background Periodontitis, which progressively destroys tooth-supporting structures, is one of the most widespread infectious diseases and the leading cause of tooth loss in adults. Evidence from preclinical trials and small-scale pilot clinical studies indicates that stem cells derived from periodontal ligament tissues are a promising therapy for the regeneration of lost/damaged periodontal tissue. This study assessed the safety and feasibility of using autologous periodontal ligament stem ce...

  8. Importance of Nongovernmental Organizations for the Establishment of a Successful Hematopoietic Stem-Cell Transplantation Program in a Developing Country

    Directory of Open Access Journals (Sweden)

    Monica M. Rivera Franco

    2018-02-01

    Full Text Available Purpose: In low- and middle-income countries with limited resources, the success of a hematopoietic stem-cell transplantation (HSCT program relies directly on its affordability while obtaining similar outcomes to developed regions. The objective of this study was to describe the experience of a tertiary/referral center in Mexico City performing HSCT with the subsidy of a nongovernmental organization (NGO. Patients and Methods: We performed a retrospective analysis including 146 patients who underwent HSCT at the National Institutes of Health Sciences and Nutrition Salvador Zubiran and were subsidized by the NGO Unidos. Results: Seventy-five patients (51% and 71 patients (49% underwent autologous and allogeneic HSCT, respectively. The median age was 30 years, 56% did not obtain a bachelor’s degree, 79% had a low socioeconomic level, and 75% were unemployed. None had any health coverage. According to the real patient out-of-pocket expense, the subsidy by Unidos corresponded to 88% and 72% in autologous and allogeneic HSCT, respectively. Conclusion: Our results highlight that undergoing an HSCT was feasible for vulnerable patients because of the subsidy of medications and chemotherapy by Unidos. Therefore, creating NGOs in developing countries is important to provide complex medical procedures, such as HSCT, at limited-resource centers to underserved populations while obtaining good outcomes.

  9. Evaluation of engraftment and immunological tolerance after reduced intensity conditioning in a rhesus hematopoietic stem cell gene therapy model.

    Science.gov (United States)

    Uchida, N; Weitzel, R P; Evans, M E; Green, R; Bonifacino, A C; Krouse, A E; Metzger, M E; Hsieh, M M; Donahue, R E; Tisdale, J F

    2014-02-01

    Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) targeted gene therapy; however, RIC may be insufficient for efficient engraftment and inducing immunological tolerance to transgenes. We previously established long-term gene marking in our rhesus macaque autologous HSC transplantation model following 10 Gy total body irradiation (TBI). In this study, we evaluated RIC transplantation with 4 Gy TBI in two rhesus macaques that received equal parts of CD34(+) cells transduced with green fluorescent protein (GFP)-expressing lentiviral vector and empty vector not expressing transgenes. In both animals, equivalently low gene marking between GFP and empty vectors was observed 6 months post-transplantation, even with efficient transduction of CD34(+) cells in vitro. Autologous lymphocyte infusion with GFP marking resulted in an increase of gene marking in lymphocytes in a control animal with GFP tolerance, but not in the two RIC-transplanted animals. In vitro assays revealed strong cellular and humoral immune responses to GFP protein in the two RIC-transplanted animals, but this was not observed in controls. In summary, 4 Gy TBI is insufficient to permit engraftment of genetically modified HSCs and induce immunological tolerance to transgenes. Our findings should help in the design of conditioning regimens in gene therapy trials.

  10. 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.

  11. Nucleofection, an efficient nonviral method to transfer genes into human hematopoietic stem and progenitor cells.

    NARCIS (Netherlands)

    Levetzow, G. von; Spanholtz, J.; Beckmann, J.; Fischer, J.; Kogler, G.; Wernet, P.; Punzel, M.; Giebel, B.

    2006-01-01

    The targeted manipulation of the genetic program of single cells as well as of complete organisms has strongly enhanced our understanding of cellular and developmental processes and should also help to increase our knowledge of primary human stem cells, e.g., hematopoietic stem cells (HSCs), within

  12. 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

  13. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches

    NARCIS (Netherlands)

    Hira, Vashendriya V. V.; van Noorden, Cornelis J. F.; Carraway, Hetty E.; Maciejewski, Jaroslaw P.; Molenaar, Remco J.

    2017-01-01

    Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are

  14. Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects?

    Science.gov (United States)

    Woolthuis, Carolien M; de Haan, Gerald; Huls, Gerwin

    2011-08-01

    During development hematopoietic stem cells (HSCs) expand in number and persist throughout life by undergoing self-renewing divisions. Nevertheless, the hematopoietic system does not escape the negative effects of aging, suggesting that self-renewal is not complete. A fundamental issue in stem cell biology relates to such age-dependent loss of stem cell activity. Both stem cell intrinsic factors and extrinsic factors associated with an aging micro-environment could contribute to aging of the hematopoietic system. Recently, changes in the clonal composition of the HSC compartment during aging have been put forward as a key factor. Here, we discuss these recent developments and speculate how they may be of clinical relevance. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post first and second hematopoietic stem cell transplant

    Science.gov (United States)

    Ahmed, Ibrahim; Teruya, Jun; Murray-Krezan, Cristina; Krance, Robert

    2015-01-01

    The reported incidence of post allogeneic hematopoietic stem cell transplant (HSCT) auto-immune hemolytic anemia (AIHA) was between 4.4% and 6% following a single transplant. Cord blood transplantation, T-cell depletion and chronic GvHD are significantly associated with post-transplant AIHA. During an 11 year period, data for 500 pediatric HSCT recipients were eligible for evaluation of the incidence of AIHA post first and second transplants. Demographic, transplant, and post-transplant related variables were analyzed. Twelve/500 (2.4%) recipients at a median of 273 days and 7/72 (9.7%) recipients at a median of 157 days developed AIHA post first and second HSCT respectively. Post first HSCT, none of the matched related donor recipients developed AIHA (0/175 MRD vs. 12/325 other donors, p=0.04). Four/12 required a second HSCT to control the AIHA. Post the second HSCT, matched unrelated donor was significantly associated with the development of AIHA. No other variables were associated with the post-second transplant AIHA. The incidence of AIHA post first and second HSCT was less than reported. The increased incidence of AIHA among recipients of second HSCT is most likely due to the profound immune dysregulation. A much larger, prospective study would be needed to evaluate the incidence, complications and management of post-transplant AIHA. PMID:25809012

  16. Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Manesia, Javed K; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M

    2017-04-15

    During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

  17. Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells

    International Nuclear Information System (INIS)

    Wilson, J.M.; Danos, O.; Grossman, M.; Raulet, D.H.; Mulligan, R.C.

    1990-01-01

    Recombinant retroviruses encoding human adenosine deaminase have been used to infect murine hematopoietic stem cells. In bone marrow transplant recipients reconstituted with the genetically modified cells, human ADA was detected in peripheral blood mononuclear cells of the recipients for at least 6 months after transplantation. In animals analyzed in detail 4 months after transplantation, human ADA and proviral sequences were detected in all hematopoietic lineages; in several cases, human ADA activity exceeded the endogenous activity. These studies demonstrate the feasibility of introducing a functional human ADA gene into hematopoietic stem cells and obtaining expression in multiple hematopoietic lineages long after transplantation. This approach should be helpful in designing effective gene therapies for severe combined immunodeficiency syndromes in humans

  18. Flow cytometry data analysis of CD34+/CD133+ stem cells in bone marrow and peripheral blood and T, B, and NK cells after hematopoietic grafting

    Directory of Open Access Journals (Sweden)

    José C. Jaime-Pérez

    2016-06-01

    Full Text Available This article provides flow cytometry information regarding levels of expression for hematopoietic stem cell markers CD34 and CD133 obtained simultaneously of the bone marrow and peripheral blood from recipients of allogeneic and autologous transplants of PB hematoprogenitors for treating hematological malignancies and who were clinically healthy after ≥100 days following the procedure. CD34 and CD133 expression is compared regarding type of transplant (autologous vs. allogeneic and sample cell source (bone marrow vs. peripheral blood. Patients were conditioned with a reduced-intensity conditioning regimen. Also shown is the flow cytometry analysis of mononuclear cell and lymphocyte populations in the peripheral blood of both types of recipients, as well as the characterization of immune cells, including T lymphocyte antigenic make up markers CD3, CD4 and CD8, B lymphocytes and NK cells, including total NK, bright and dim subtypes in the peripheral blood of both types of recipients. For further information and discussion regarding interpretation and meaning of post-transplant flow cytometry analysis, please refer to the article “Assessment of immune reconstitution status in recipients of a successful hematopoietic stem cell transplant from peripheral blood after reduced intensity conditioning” [1].

  19. 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.

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

    Science.gov (United States)

    Claude Gorin, Norbert

    2016-04-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome

    Directory of Open Access Journals (Sweden)

    Katharina L. Gössling

    2017-06-01

    Full Text Available Immunodeficiency, centromeric instability, and facial anomaly (ICF syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up-to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen Pneumocystis jirovecii (PJ. Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on.

  3. 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.

  4. IMMUNITY TO INFECTIONS AFTER HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    Franco Aversa

    2016-10-01

    Full Text Available The advantage of using a Human Leukocyte Antigen (HLA-mismatched related donor is that almost every patient who does not have a HLA-identical donor or who urgently needs hematopoietic stem cell transplantation (HSCT has at least one family member with whom shares one haplotype (haploidentical and who is promptly available as a donor. The major challenge of haplo-HSCT is intense bi-directional alloreactivity leading to high incidences of graft rejection and graft-versus-host disease (GVHD. Advances in graft processing and in pharmacologic prophylaxis of GVHD have reduced these risks and have made haplo-HSCT a viable alternative for patients lacking a matched donor. Indeed, the haplo-HSCT  has spread to centers worldwide even though some centers have preferred an approach based on T cell depletion of G-CSF-mobilized peripheral blood progenitor cells (PBPCs, others have focused on new strategies for GvHD prevention, such as G-CSF priming of bone marrow and robust post-transplant immune suppression or post-transplant cyclophosphamide (PTCY. Today, the graft can be a megadose of T-cell depleted PBPCs or standard dose of unmanipulated bone marrow and/or PBPCs.  Although haplo-HSCT modalities are based mainly on high intensity conditioning regimens, recently introduced reduced intensity regimens (RIC   showed promise in decreasing early transplant-related mortality (TRM, and extending the opportunity of HSCT to an elderly population with more comorbidities. Infections are still mostly responsible for toxicity and non-relapse mortality due to prolonged immunosuppression related, or not, to GVHD. Future challenges lie in determining the safest preparative conditioning regimen, minimizing GvHD and promoting rapid and more robust immune reconstitution.

  5. 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.

  6. Establishment of autologous embryonic stem cells derived from preantral follicle culture and oocyte parthenogenesis.

    Science.gov (United States)

    Lee, Seung Tae; Choi, Mun Hwan; Lee, Eun Ju; Gong, Seung Pyo; Jang, Mi; Park, Sang Hyun; Jee, Hyang; Kim, Dae Yong; Han, Jae Yong; Lim, Jeong Mook

    2008-11-01

    To evaluate whether autologous embryonic stem cells can be established without generating clone embryos. Prospective model study. Gamete and stem cell biotechnology laboratory in Seoul National University, Seoul, Korea. F1 hybrid B6D2F1 mice. Preantral follicles were cultured, and oocytes matured in the follicles were parthenogenetically activated. Preimplantation development and stem cell characterization. More intrafollicular oocytes that were retrieved from secondary follicles matured and developed into blastocysts after parthenogenesis than those that were retrieved from primary follicles. Of those 35 blastocysts derived from 193 parthenotes, one line of colony-forming cells was established from the culturing of early secondary follicles. The established cells were positive for embryonic stem cell-specific markers and had normal diploid karyotype and telomerase activity. They differentiated into embryoid bodies in vitro and teratomas in vivo. Inducible differentiation of the established cells into neuronal lineage cells also was possible. Autologous embryonic stem cells can be established by preantral follicle culture and oocyte parthenogenesis. A combined technique of follicle culture and oocyte parthenogenesis that does not use developmentally competent oocytes has the potential to replace somatic cell nuclear transfer for autologous cell therapy.

  7. Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival

    DEFF Research Database (Denmark)

    Kølle, Stig-Frederik Trojahn; Fischer-Nielsen, Anne; Mathiasen, Anders Bruun

    2013-01-01

    Autologous fat grafting is increasingly used in reconstructive surgery. However, resorption rates ranging from 25% to 80% have been reported. Therefore, methods to increase graft viability are needed. Here, we report the results of a triple-blind, placebo-controlled trial to compare the survival ...... of fat grafts enriched with autologous adipose-derived stem cells (ASCs) versus non-enriched fat grafts....

  8. In-vitro chondrogenic potential of synovial stem cells and chondrocytes allocated for autologous chondrocyte implantation

    DEFF Research Database (Denmark)

    Kubosch, Eva Johanna; Heidt, Emanuel; Niemeyer, Philipp

    2017-01-01

    Purpose: The use of passaged chondrocytes is the current standard for autologous chondrocyte implantation (ACI). De-differentiation due to amplification and donor site morbidity are known drawbacks highlighting the need for alternative cell sources. Methods: Via clinically validated flow cytometry...... analysis, we compared the expression of human stem cell and cartilage markers (collagen type 2 (Col2), aggrecan (ACAN), CD44) of chondrocytes (CHDR), passaged chondrocytes for ACI (CellGenix™), bone marrow derived mesenchymal stem cells (BMSC), and synovial derived stem cells (SDSC). Results: Primary...

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

    Science.gov (United States)

    Kitchen, Scott G; Bennett, Michael; Galić, Zoran; Kim, Joanne; Xu, Qing; Young, Alan; Lieberman, Alexis; Joseph, Aviva; Goldstein, Harris; Ng, Hwee; Yang, Otto; Zack, Jerome A

    2009-12-07

    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.

  10. 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.

  11. Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment.

    Science.gov (United States)

    Perlin, Julie R; Sporrij, Audrey; Zon, Leonard I

    2017-08-01

    Cells of the hematopoietic system undergo rapid turnover. Each day, humans require the production of about one hundred billion new blood cells for proper function. Hematopoietic stem cells (HSCs) are rare cells that reside in specialized niches and are required throughout life to produce specific progenitor cells that will replenish all blood lineages. There is, however, an incomplete understanding of the molecular and physical properties that regulate HSC migration, homing, engraftment, and maintenance in the niche. Endothelial cells (ECs) are intimately associated with HSCs throughout the life of the stem cell, from the specialized endothelial cells that give rise to HSCs, to the perivascular niche endothelial cells that regulate HSC homeostasis. Recent studies have dissected the unique molecular and physical properties of the endothelial cells in the HSC vascular niche and their role in HSC biology, which may be manipulated to enhance hematopoietic stem cell transplantation therapies.

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  8. IP3 3-kinase B controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice

    Science.gov (United States)

    Siegemund, Sabine; Rigaud, Stephanie; Conche, Claire; Broaten, Blake; Schaffer, Lana; Westernberg, Luise; Head, Steven Robert

    2015-01-01

    Tight regulation of hematopoietic stem cell (HSC) homeostasis ensures lifelong hematopoiesis and prevents blood cancers. The mechanisms balancing HSC quiescence with expansion and differentiation into hematopoietic progenitors are incompletely understood. Here, we identify Inositol-trisphosphate 3-kinase B (Itpkb) as an essential regulator of HSC homeostasis. Young Itpkb−/− mice accumulated phenotypic HSC, which were less quiescent and proliferated more than wild-type (WT) controls. Itpkb−/− HSC downregulated quiescence and stemness associated, but upregulated activation, oxidative metabolism, protein synthesis, and lineage associated messenger RNAs. Although they had normal-to-elevated viability and no significant homing defects, Itpkb−/− HSC had a severely reduced competitive long-term repopulating potential. Aging Itpkb−/− mice lost hematopoietic stem and progenitor cells and died with severe anemia. WT HSC normally repopulated Itpkb−/− hosts, indicating an HSC-intrinsic Itpkb requirement. Itpkb−/− HSC showed reduced colony-forming activity and increased stem-cell-factor activation of the phosphoinositide-3-kinase (PI3K) effectors Akt/mammalian/mechanistic target of rapamycin (mTOR). This was reversed by treatment with the Itpkb product and PI3K/Akt antagonist IP4. Transcriptome changes and biochemistry support mTOR hyperactivity in Itpkb−/− HSC. Treatment with the mTOR-inhibitor rapamycin reversed the excessive mTOR signaling and hyperproliferation of Itpkb−/− HSC without rescuing colony forming activity. Thus, we propose that Itpkb ensures HSC quiescence and function through limiting cytokine-induced PI3K/mTOR signaling and other mechanisms. PMID:25788703

  9. Autologous stem cell transplantation for primary refractory Hodgkin's disease: results and clinical variables affecting outcome.

    Science.gov (United States)

    Constans, M; Sureda, A; Terol, M J; Arranz, R; Caballero, M D; Iriondo, A; Jarque, I; Carreras, E; Moraleda, J M; Carrera, D; León, A; López, A; Albó, C; Díaz-Mediavilla, J; Fernández-Abellán, P; García-Ruiz, J C; Hernández-Navarro, F; Mataix, R; Petit, J; Pascual, M J; Rifón, J; García-Conde, J; Fernández-Rañada, J M; Mateos, M V; Sierra, J; Conde, E

    2003-05-01

    Patients with primary refractory Hodgkin's disease (PR-HD) have a dismal prognosis when treated with conventional salvage chemotherapy. We analyzed time to treatment failure (TTF), overall survival (OS) and clinical variables influencing the outcome in patients undergoing autologous stem cell transplantation (ASCT) for PR-HD and reported to the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO). Sixty-two patients, 41 males and 21 females with a median age of 27 years (range 13-55) were analyzed. Forty-two patients (68%) had advanced stage at diagnosis, 47 (76%) presented with B symptoms and 29 (47%) with a bulky mediastinal mass. Seventy-five percent of the patients had received more than one line of therapy before ASCT. Thirty-three patients received bone marrow as a source of hematopoietic progenitors, and 29 peripheral blood. Six patients were conditioned with high-dose chemotherapy plus total-body irradiation and 56 received chemotherapy-based protocols. One-year transplantation-related mortality was 14% [95% confidence interval (CI) 6% to 23%]. Response rate at 3 months after ASCT was 52% [complete remission in 21 patients (34%), partial remission in 11 patients (18%)]. Actuarial 5-year TTF and OS were 15% (95% CI 5% to 24%) and 26% (95% CI 13% to 39%), respectively. The presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF [relative risk (RR) 1.75, 95% CI 0.92-3.35, P = 0.08]. The presence of B symptoms at diagnosis (RR 2.08, 95% CI 0.90-4.79, P = 0.08), MOPP-like regimens as first-line therapy (RR 3.84, 95% CI 1.69-9.09, P = 0.001), bulky disease at ASCT (RR 2.79, 95% CI 0.29-6.03, P = 0.009) and two or more lines of therapy before ASCT (RR 2.24, 95% CI 0.95-5.27, P = 0.06) adversely influenced OS. In our experience, although overall results of ASCT in PR-HD patients are poor, one-quarter of the patients remain alive at 5 years. Despite this, other therapeutic strategies should be

  10. 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.

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

    Science.gov (United States)

    Coste, Cécile; Neirinckx, Virginie; Gothot, André; Wislet, Sabine; Rogister, Bernard

    2015-01-01

    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 (CXCL) 12-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-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.

  12. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

    Science.gov (United States)

    Niederwieser, D; Baldomero, H; Szer, J; Gratwohl, M; Aljurf, M; Atsuta, Y; Bouzas, L F; Confer, D; Greinix, H; Horowitz, M; Iida, M; Lipton, J; Mohty, M; Novitzky, N; Nunez, J; Passweg, J; Pasquini, M C; Kodera, Y; Apperley, J; Seber, A; Gratwohl, A

    2016-06-01

    Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

  13. Hematopoietic Stem Cell Transplantation Activity Worldwide in 2012 and a SWOT Analysis of the Worldwide Network for Blood and Marrow Transplantation Group (WBMT) including the global survey

    Science.gov (United States)

    Niederwieser, Dietger; Baldomero, Helen; Szer, Jeff; Gratwohl, Michael; Aljurf, Mahmoud; Atsuta, Yoshiko; Bouzas, Luis Fernando; Confer, Dennis; Greinix, Hildegard; Horowitz, Mary; Iida, Minako; Lipton, Jeff; Mohty, Mohamad; Novitzky, Nicolas; Nunez, José; Passweg, Jakob; Pasquini, Marcelo C.; Kodera, Yoshihisa; Apperley, Jane; Seber, Adriana; Gratwohl, Alois

    2016-01-01

    Data on 68,146 hematopoietic stem cell transplants (HSCT) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCT were registered from unrelated 16,433 than related 15,493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared to 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCT/team). An increase of 67% was noted in mismatched/haploidentical family HSCT. A SWOT analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four WHO regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood. PMID:26901703

  14. Autologous stem cells in neurology: is there a future?

    NARCIS (Netherlands)

    de Munter, J.P.J.M.; Wolters, E.C.

    2013-01-01

    Stem cells seem very promising in the treatment of degenerative neurological diseases for which there are currently no or limited therapeutic strategies. However, their clinical application meets many regulatory hurdles. This article gives an overview of stem cells, their potential healing

  15. Vitamin D deficiency in children and adolescents submitted to hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Denise Johnsson Campos

    2014-04-01

    Full Text Available Background: Sub-optimal levels of vitamin D have been found to be highly prevalent in all age groups, with epidemiologic studies demonstrating a link between vitamin D deficiency and disease susceptibility, such as infection and cancer, and mortality rates. In adult transplant patients, it has been suggested that the immunomodulatory properties of vitamin D may have an important role in the prevention and treatment of graft-versus-host disease. Objective: The objective of this study was to assess serum 25-hydroxyvitamin D levels of children and adolescents submitted to allogeneic hematopoietic stem cell transplantation. Methods: Serum 25-hydroxyvitamin D levels of 66 patients, aged 4-20 years, were assessed at three stages: before hospitalization for hematopoietic stem cell transplantation and at 30 and 180 days after hematopoietic stem cell transplantation. The control group consisted of 25 healthy children. Results: At the pre-hematopoietic stem cell transplantation stage, patients had lower levels of 25-hydroxyvitamin D compared to controls (25.7 ± 12.3 ng/mL vs. 31.9 ± 9.9 ng/mL; p-value = 0.01, and a higher prevalence of 25-hydroxyvitamin D deficiency (32% vs. 8%; p-value = 0.01. Prevalence increased significantly after hematopoietic stem cell transplantation (p-value = 0.01 with half of the patients having vitamin D deficiency at 180 days after transplantation. At this stage, mean serum 25-hydroxyvitamin D levels were 20.9 ± 10.9 ng/mL, a significant decline in relation to baseline (p-value = 0.01. No correlation was found between 25-hydroxyvitamin D levels and vitamin D intake, graft-versus-host disease, corticoid use or survival rates. Conclusion: Low levels of 25-hydroxyvitamin D were detected even before hematopoietic stem cell transplantation and were significantly lower at 180 days after hematopoietic stem cell transplantation, thus recommending vitamin D supplementation for children and adolescents submitted to hematopoietic stem

  16. Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

    International Nuclear Information System (INIS)

    2003-01-01

    Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching

  17. 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

  18. 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...

  19. Outcomes in relapsed Hodgkin's lymphoma treated with autologous and allogeneic hematopoietic cell transplantation at the Pontificia Universidad Católica de Chile

    Directory of Open Access Journals (Sweden)

    Pablo Ramirez

    2015-06-01

    Full Text Available Introduction: Hodgkin's lymphoma is a highly curable disease. Autologous and reduced intensity allogeneic hematopoietic cell transplantations are alternatives to treat relapsed patients. Here, we report on the results of one service using these procedures. Methods: All patients who underwent transplantations in our institution between 1996 and 2014 were retrospectively studied and demographics, toxicities and survival rate were analyzed. Results: This study evaluated 24 autologous and five reduced intensity allogeneic transplantations: the median ages of the patients were 29 and 32 years, respectively. At the time of autologous transplantation, ten patients were in complete remission, nine had chemosensitive disease but were not in complete remission, three had refractory disease and the status of two is unknown. In the allogeneic group, two were in complete remission and three had chemosensitive disease. The 5-year overall survival after autologous transplantation was 42% (66% patients were in complete remission, 37% had chemosensitive disease with incom- plete remission and 0% had refractory disease and 1-year overall survival after allogeneic transplantation was 80%. Transplant-related mortality was 0% in patients conditioned with the ifosfamide/carboplatin/etoposide (ICE, carmustine/etoposide/cyclophosphamide (BEC and carmustine/etoposide/cytarabine/melphalan (BEAM regimens, 37% in patients condi- tioned with busulfan-based regimens and 20% in allogeneic transplantations. Conclusions: Hematopoietic cell transplantation for relapsed Hodgkin's lymphoma is a potentially curative procedure especially in patients in complete remission at the time of autologous transplantations, and possibly after allogeneic transplantations. Further studies are necessary to clarify the role of allogeneic transplantations in the treatment of relapsed Hodgkin's lymphoma.

  20. Hematopoietic stem cells: ex-vivo expansion and therapeutic potential for myocardial ischemia

    Directory of Open Access Journals (Sweden)

    Jingwei Lu

    2010-03-01

    Full Text Available Jingwei Lu, Vincent J Pompili, Hiranmoy DasCardiovascular Stem Cell Research Laboratory, The Dorothy M Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH 43210, USAAbstract: Despite recent advances in cardiovascular medicine, ischemic heart disease remains the major cause of death in the United States and abroad. Cell-based therapy for degenerative diseases like myocardial ischemia using stem cells is currently under serious investigation. Various types of stem cells are being considered to be candidates for cell transplantation in cell-based therapy. Hematopoietic stem cells are one of the most promising cell types as several studies demonstrated their ability to improve ischemic cardiac functions by enhancing neovascularization and by reducing the total size of scar tissue. However, in order to procure sufficient numbers of functional stem cells, ex-vivo expansion technology became critically important. In this review, we focus on the state-of-the-art ex-vivo technology for the expansion of hematopoietic stem cells, and the underlying mechanisms regulating stem cell self-renewal as well as differentiation.Keywords: ischemic heart disease, ex-vivo expansion, hematopoietic stem cells, cytokines, nanofibers

  1. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1

    Science.gov (United States)

    Zhou, Bo O; Ding, Lei; Morrison, Sean J

    2015-01-01

    Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit+ hematopoietic progenitors, megakaryocytes, and Leptin Receptor+ (LepR+) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR+ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR+ stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery. DOI: http://dx.doi.org/10.7554/eLife.05521.001 PMID:25821987

  2. [Pathogenesis and therapy of hydronephrosis after hematopoietic stem cell transplantation].

    Science.gov (United States)

    Yu, Lu-ping; Xu, Tao; Huang, Xiao-bo; Wang, Xiao-feng

    2014-08-18

    To investigate the pathogenesis and therapy of hydronephrosis after hematopoietic stem cell transplantation (HSCT). From March 2004 to March 2014, 23 patients with hydronephrosis after HSCT were identified. With these data, the pathogenesis of hydronephrosis after HSCT were analyzed. According to the surgical intervention of hydronephrosis and ureteral dialation of ureteral stricture, the patients were divided into two groups, rank-sum test and exact probability test were used to evaluate whether there were significant differences in the time of hemorrhagic cystitis (HC) occurred, ureteritis and viremia. HC, ureteritis, ureteral stenosis were all the causes of hydronephrosis after HSCT. In this study, 69.6% (16/23) of the patients suffered from HSCT were cured by conservative treatment, 30.4% (7/23) by surgical intervention, and 13.0% (3/23) by insertion DJ stent or nephrostomy.Of the patients [17.4% (4/23)] who suffered ureteral stenosis, 2 were cured after the balloon dialation of ureter, 1 needed DJ tube long-term insertion, and 1 was still followed-up. rank-sum test and exact probability test results showed that the patients who needed surgical intervention might suffer from HC later than other patients, and their incidences of viremia and ureteritis were higher, but the differences between the two groups were not statistically significant (P = 0.524, P = 0.169, and P = 0.124, respectively). The results also showed that the ureteritis incidences of the patients who suffered from ureteral stricture and needed ureteral dialation were higher than that of the other patients, and the difference between the two groups was statistically significant (P = 0.024). The patients who needed ureteral dialation suffered from HC later and their incidences of viremia was higher, but the differences between the two groups were not statistically significant (P = 0.73 and P = 0.27). HC, ureteritis and ureteral stenosis may cause hydronephrosis after HSCT. Patients may treated by

  3. Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.

    Science.gov (United States)

    Baba, Masaya; Toyama, Hirofumi; Sun, Lei; Takubo, Keiyo; Suh, Hyung-Chan; Hasumi, Hisashi; Nakamura-Ishizu, Ayako; Hasumi, Yukiko; Klarmann, Kimberly D; Nakagata, Naomi; Schmidt, Laura S; Linehan, W Marston; Suda, Toshio; Keller, Jonathan R

    2016-04-01

    Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  4. 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.

  5. Enhanced genetic modification of adult growth factor mobilized peripheral blood hematopoietic stem and progenitor cells with rapamycin.

    Science.gov (United States)

    Li, Lijing; Torres-Coronado, Mónica; Gu, Angel; Rao, Anitha; Gardner, Agnes M; Epps, Elizabeth W; Gonzalez, Nancy; Tran, Chy-Anh; Wu, Xiwei; Wang, Jin-Hui; DiGiusto, David L

    2014-10-01

    Genetic modification of adult human hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors leads to long-term gene expression in the progeny of the HSPCs and has been used to successfully treat several monogenic diseases. In some cases, the gene-modified cells have a selective growth advantage over nonmodified cells and eventually are the dominant engrafted population. However, in disease indications for which the gene-modified cells do not have a selective advantage, optimizing transduction of HSPC is paramount to successful stem cell-based gene therapy. We demonstrate here that transduction of adult CD34+ HSPCs with lentiviral vectors in the presence of rapamycin, a widely used mTORC1 inhibitor, results in an approximately threefold increase in stable gene marking with minimal effects on HSPC growth and differentiation. Using this approach, we have demonstrated that we can enhance the frequency of gene-modified HSPCs that give rise to clonogenic progeny in vitro without excessive increases in the number of vector copies per cell or changes in integration pattern. The genetic marking of HSPCs and expression of transgenes is durable, and transplantation of gene-modified HSPCs into immunodeficient mice results in high levels of gene marking of the lymphoid and myeloid progeny in vivo. The prior safe clinical history of rapamycin in other applications supports the use of this compound to generate gene-modified autologous HSPCs for our HIV gene therapy clinical trials. ©AlphaMed Press.

  6. Cord Blood Banking Standards: Autologous Versus Altruistic

    Science.gov (United States)

    Armitage, Sue

    2016-01-01

    Cord blood (CB) is either donated to public CB banks for use by any patient worldwide for whom it is a match or stored in a private bank for potential autologous or family use. It is a unique cell product that has potential for treating life-threatening diseases. The majority of CB products used today are for hematopoietic stem cell transplantation and are accessed from public banks. CB is still evolving as a hematopoietic stem cell source, developing as a source for cellular immunotherapy products, such as natural killer, dendritic, and T-cells, and fast emerging as a non-hematopoietic stem cell source in the field of regenerative medicine. This review explores the regulations, standards, and accreditation schemes that are currently available nationally and internationally for public and private CB banking. Currently, most of private banking is under regulated as compared to public banking. Regulations and standards were initially developed to address the public arena. Early responses from the medical field regarding private CB banking was that at the present time, because of insufficient scientific data to support autologous banking and given the difficulty of making an accurate estimate of the need for autologous transplantation, private storage of CB as “biological insurance” should be discouraged (1, 2, 3). To ensure success and the true realization of the full potential of CB, whether for autologous or allogeneic use, it is essential that each and every product provided for current and future treatments meets high-quality, international standards. PMID:26779485

  7. Cord Blood Banking Standards: Autologous Versus Altruistic.

    Science.gov (United States)

    Armitage, Sue

    2015-01-01

    Cord blood (CB) is either donated to public CB banks for use by any patient worldwide for whom it is a match or stored in a private bank for potential autologous or family use. It is a unique cell product that has potential for treating life-threatening diseases. The majority of CB products used today are for hematopoietic stem cell transplantation and are accessed from public banks. CB is still evolving as a hematopoietic stem cell source, developing as a source for cellular immunotherapy products, such as natural killer, dendritic, and T-cells, and fast emerging as a non-hematopoietic stem cell source in the field of regenerative medicine. This review explores the regulations, standards, and accreditation schemes that are currently available nationally and internationally for public and private CB banking. Currently, most of private banking is under regulated as compared to public banking. Regulations and standards were initially developed to address the public arena. Early responses from the medical field regarding private CB banking was that at the present time, because of insufficient scientific data to support autologous banking and given the difficulty of making an accurate estimate of the need for autologous transplantation, private storage of CB as "biological insurance" should be discouraged (1, 2, 3). To ensure success and the true realization of the full potential of CB, whether for autologous or allogeneic use, it is essential that each and every product provided for current and future treatments meets high-quality, international standards.

  8. 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.

  9. The effects of proliferation and DNA damage on hematopoietic stem cell function determine aging.

    Science.gov (United States)

    Khurana, Satish

    2016-07-01

    In most of the mammalian tissues, homeostasis as well as injury repair depend upon a small number of resident adult stem cells. The decline in tissue/organ function in aged organisms has been directly linked with poorly functioning stem cells. Altered function of hematopoietic stem cells (HSCs) is at the center of an aging hematopoietic system, a tissue with high cellular turnover. Poorly engrafting, myeloid-biased HSCs with higher levels of DNA damage accumulation are the hallmark features of an aged hematopoietic system. These cells show a higher proliferation rate than their younger counterparts. It was proposed that quiescence of these cells over long period of time leads to accumulation of DNA damage, eventually resulting in poor function/pathological conditions in hematopoietic system. However, various mouse models with premature aging phenotype also show highly proliferative HSCs. This review examines the evidence that links proliferation of HSCs with aging, which leads to functional changes in the hematopoietic system. Developmental Dynamics 245:739-750, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. [Adjunctive reflections on history of hematopoietic stem cell study--editorial].

    Science.gov (United States)

    Tang, Pei-Xian

    2005-10-01

    The article reviews concisely around the history of hematopoietic stem cell research, basic and clinical, since its very beginning after the nuclear explosions at the end of the Second World War, that explains why the stem cell study in the world began with the hematopoietic stem cells and the existence of non-hematopoietic stem cell in vivo had been left out of account for many decades till 21st century. During 50-60s of the last century, it was known from the animal experiments that there must be hematopoietic stem cells existing in vivo and believed that the effective bone marrow transplant is actually the stem cell transplantation. It is reviewed how the basic studies of stem cell interacted with the clinical stem cell transplantation and how great the contribution was given to strongly push forward the development of contemporary stem cell biology and modern hematology from the basic studies especially in the immunological and molecular biological fields, for instance, the applications of HLA technology and monoclonal antibody produced, flow cytometry, and genetic recombinant cytokines, the novel technique for gene cloning, genomics, proteomics, and iRNA as well as bioinformatics. It has lead to the pluralistic cell therapy as a novel trend in stem cell transplantation as to combine immunotherapy and mesenchymal stem cells with the conventional stem cell transplants. This paper looks back in the past several decades, however, on every achievement of stem cell study that were usually accompanied with some idealistic one-sidedness or even errors in design and conclusion of some experiments. Usually it took a period of 2 or even 4 decades to clarify some basic idea, that seemed normal in the science development, for examples, the dividing line between the hematopoietic stem cell and progenitor cells, possibility to expand or clone the real stem cell ex vivo, and whether the majority of leukemias are originated from stem cell level, etc. Towards the end of 20th

  11. Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia: a Single-Centre Experience

    Directory of Open Access Journals (Sweden)

    Kakucs Enikő

    2013-04-01

    Full Text Available Introduction: Autologous haemopoietic stem cell transplantation (SCT is an important treatment modality for patients with acute myeloid leukemia with low and intermediate risk disease. It has served advantages over allogenic transplantation, because it does not need a matched donor, there is no graft versus host disease, there are less complications and a faster immune reconstitution than in the allo-setting. The disadvantage is the lack of the graft versus leukaemia effect.

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

    Science.gov (United States)

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

    2016-03-01

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

  13. Ex Vivo Expansion of Hematopoietic Stem Cells to Improve Engraftment in Stem Cell Transplantation.

    Science.gov (United States)

    Ko, Kap-Hyoun; Nordon, Robert; O'Brien, Tracey A; Symonds, Geoff; Dolnikov, Alla

    2017-01-01

    The efficient use of hematopoietic stem cells (HSC) for transplantation is often limited by the relatively low numbers of HSC collected. The ex vivo expansion of HSC for clinical use is a potentially valuable and safe approach to increase HSC numbers thereby increasing engraftment and reducing the risk of morbidity from infection. Here, we describe a protocol for the robust ex vivo expansion of human CD34(+) HSC isolated from umbilical cord blood. The protocol described can efficiently generate large numbers of HSC. We also describe a flow cytometry-based method using high-resolution division tracking to characterize the kinetics of HSC growth and differentiation. Utilizing the guidelines discussed, it is possible for investigators to use this protocol as presented or to modify it for their specific needs.

  14. Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells.

    NARCIS (Netherlands)

    Tang, L.; Bergevoet, S.M.; Gilissen, C.F.H.A.; Witte, T.J.M. de; Jansen, J.H.; Reijden, B.A. van der; Raymakers, R.A.P.

    2010-01-01

    BACKGROUND: ATP-binding cassette (ABC) transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes. Earlier we showed that many ABC transporters are highly expressed in hematopoietic stem cells (HSCs) compared to more committed progenitor cells. The ABC

  15. Autologous Bone Marrow-Derived Stem Cells in Spinal Cord Injury.

    Science.gov (United States)

    Bansal, Himanshu; Verma, Poonam; Agrawal, Anupama; Leon, Jerry; Sundell, I Birgitta; Koka, Prasad S

    Spinal cord injury is a traumatic neurological condition which makes the patient disable. Its management still remains challenging but advancements in the regenerative medicine have changed the approach of treating this serious debilitating condition of the central nervous system. Cell based therapies can restore function in spinal cord injury by replacing the lost neural tissue. These therapies also rejuvenate the existing intact neurons by facilitating remyelination and by repairing and reducing progressive tissue damage and scarring. Autologous bone marrow stem cells were collected from the patients. 5 ml of the processed sample was injected back into the patients via lumbar puncture at L1/L2 level. The bone marrow harvesting and administration was repeated every 4 weeks 3 times (12 weeks). Significant improvements were noticed following the injections into the patients with the duration of injury less than 6 months. ASIA grade improvements were observed in 6 out of 10 patients. VTC and walking, at least with the support, was restored in eight patients. Bladder control and sexual functions improved in three and five patients respectively. Eight patients exhibited decreased spasticity. We believe that autologous bone marrow stem cells contributed towards the neuroplaticity and/or paracrine effect due to which we observed the considerable improvements in the conditions of the patients. This preliminary proof of patient improvement reinforces the potential of autologous bone marrow stem cell treatment in the patients suffering from Spinal Cord Injury. Although the results are encouraging further studies are needed to substantiate the claims.

  16. Autologous conjunctiva transplantation with stem cells on edge of cornea for recurrent pterygium

    Directory of Open Access Journals (Sweden)

    Yun Wang

    2013-10-01

    Full Text Available AIM: To observe the clinical effectiveness and practicality the autologous conjunctiva transplantation with stem cells on edge of cornea for recurrent pterygium.METHODS: Of the 53 recurrent pterygium patients(57 eyes, after all pathological tissues were removed, underwent the autologous conjunctiva transplantation with stem cells on edge of cornea which were locked above conjunctival transplantation of the operated eye.RESULTS: Postopretive follow-up was 1-12 months for all 57 eyes, of which 3 eyes(5%relapsed. The corneoscleral autolysis was occurred in one eye and surgery treatment was conducted. Corneal wounds were healing and transplantations survived well for the remaining 53 patients without obvious surgical marks. Cure rate was 93%.CONCLUSION: Autologous conjunctiva transplantation with stem cells on edge of cornea for recurrent pterygium can meet the aesthetic requirements of the some patients, with the advantages of obtaining material easily, faster wound healing, lower postoperative recurrence rate, meeting the aesthetic needs of some patients and improving postoperative results. Thus, it is an ideal surgery and is worthy of applying on primary hospital.

  17. Effect of Routine Surveillance Imaging on the Outcomes of Patients With Classical Hodgkin Lymphoma After Autologous Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Kapke, Jonathan T; Epperla, Narendranath; Shah, Namrata; Richardson, Kristin; Carrum, George; Hari, Parameswaran N; Pingali, Sai R; Hamadani, Mehdi; Karmali, Reem; Fenske, Timothy S

    2017-07-01

    Patients with relapsed and refractory classical Hodgkin lymphoma (cHL) are often treated with autologous hematopoietic cell transplantation (auto-HCT). After auto-HCT, most transplant centers implement routine surveillance imaging to monitor for disease relapse; however, there is limited evidence to support this practice. In this multicenter, retrospective study, we identified cHL patients (n = 128) who received auto-HCT, achieved complete remission (CR) after transplantation, and then were followed with routine surveillance imaging. Of these, 29 (23%) relapsed after day 100 after auto-HCT. Relapse was detected clinically in 14 patients and with routine surveillance imaging in 15 patients. When clinically detected relapse was compared with to radiographically detected relapse respectively, the median overall survival (2084 days [range, 225-4161] vs. 2737 days [range, 172-2750]; P = .51), the median time to relapse (247 days [range, 141-3974] vs. 814 days [range, 96-1682]; P = .30) and the median postrelapse survival (674 days [range, 13-1883] vs. 1146 days [range, 4-2548]; P = .52) were not statistically different. In patients who never relapsed after auto-HCT, a median of 4 (range, 1-25) surveillance imaging studies were performed over a median follow-up period of 3.5 years. A minority of patients with cHL who achieve CR after auto-HCT will ultimately relapse. Surveillance imaging detected approximately half of relapses; however, outcomes were similar for those whose relapse was detected using routine surveillance imaging versus detected clinically in between surveillance imaging studies. There appears to be limited utility for routine surveillance imaging in cHL patients who achieve CR after auto-HCT. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Tachykinins and hematopoietic stem cell functions: implications in clinical disorders and tissue regeneration.

    Science.gov (United States)

    Murthy, Raghav G; Reddy, Bobby Y; Ruggiero, Jaclyn E; Rameshwar, Pranela

    2007-05-01

    Hematopoiesis is the process by which a limited number of hematopoietic stem cells (HSCs) maintain a functioning blood and immune system. In adults, hematopoiesis occurs in bone marrow and is supported by the microenvironment. The tachykinin family of peptides regulates hematopoiesis. Tachykinins can be released in bone marrow as neurotransmitters from innervating fibers, and from resident bone marrow cells. The hematopoietic effects by tachykinins involve four tachykinin genes, Tac1-Tac4. The latter is the most recently discovered member and encodes hemokinin-1, endokinin A, endokinin B, and two orphan peptides, endokinin C, and endokinin D. The alteration of normal hematopoietic functions by the tachykinins may result in the development of various pathologies. For example, Tac1 is involved in myelofibrosis and in leukemia, both of which are dysfunction of hematopoietic stem cells. A comprehensive understanding of dysfunctions caused by the tachykinins requires further research since other cells, such as stromal cells and factors including cytokines, chemokines, and endopeptidases, are involved in a network in which the tachykinins have critical roles. Studies into the properties and functions of tachykinins, the biology of their receptors, and related molecules would provide insights into the development of aging disorders, hematopoiesis, other dysfunction, and may also lead to the discovery of novel and effective clinical therapies. Controversies on applications for hematopoietic stem cells in regenerative medicine are discussed. Despite these controversies, a detailed understanding on how the bone marrow microenvironment maintains pluripotency of hematopoietic stem cells would be useful to manipulate the system to acquire specialized cells for tissue repair.

  19. Validation of a single-platform method for hematopoietic CD34+ stem cells enumeration according to accreditation procedure.

    Science.gov (United States)

    Massin, Frédéric; Huili, Cai; Decot, Véronique; Stoltz, Jean-François; Bensoussan, Danièle; Latger-Cannard, Véronique

    2015-01-01

    Stem cells for autologous and allogenic transplantation are obtained from several sources including bone marrow, peripheral blood or cord blood. Accurate enumeration of viable CD34+ hematopoietic stem cells (HSC) is routinely used in clinical settings, especially to monitor progenitor cell mobilization and apheresis. The number of viable CD34+ HSC has also been shown to be the most critical factor in haematopoietic engraftment. The International Society for Cellular Therapy actually recommends the use of single-platform flow cytometry system using 7-AAD as a viability dye. In a way to move routine analysis from a BD FACSCaliburTM instrument to a BD FACSCantoTM II, according to ISO 15189 standard guidelines, we define laboratory performance data of the BDTM Stem Cell Enumeration (SCE) kit on a CE-IVD system including a BD FACSCanto II flow cytometer and the BD FACSCantoTM Clinical Software. InterQCTM software, a real time internet laboratory QC management system developed by VitroTM and distributed by Becton DickinsonTM, was also tested to monitor daily QC data, to define the internal laboratory statistics and to compare them to external laboratories. Precision was evaluated with BDTM Stem Cell Control (high and low) results and the InterQC software, an internet laboratory QC management system by Vitro. This last one drew Levey-Jennings curves and generated numeral statistical parameters allowing detection of potential changes in the system performances as well as interlaboratory comparisons. Repeatability, linearity and lower limits of detection were obtained with routine samples from different origins. Agreement evaluation between BD FACSCanto II system versus BD FACSCalibur system was tested on fresh peripheral blood, freeze-thawed apheresis, fresh bone marrow and fresh cord blood samples. Instrument's measure and staining repeatability clearly evidenced acceptable variability on the different samples tested. Intra- and inter-laboratory CV in CD34+ cell absolute

  20. 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.

  1. 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

  2. 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

  3. Epigenetic control of hematopoietic stem cell aging - The case of Ezh2

    NARCIS (Netherlands)

    de Haan, Gerald; Gerrits, Alice; Kanz, L; Weisel, KC; Dick, JE; Fibbe, WE

    2007-01-01

    Hematopoietic stem cells have potent, but not unlimited, selfrenewal potential. The mechanisms that restrict selfrenewal are likely to play a role during aging. Recent data suggest that the regulation of histone modifications by Polycomb group genes may be of crucial relevance to balance selfrenewal

  4. Age- and stage-specific regulation patterns in the hematopoietic stem cell hierarchy

    NARCIS (Netherlands)

    Geiger, H; True, JM; de Haan, G; Van Zant, G

    2001-01-01

    The molecular mechanisms that regulate self-renewal and differentiation of very primitive hematopoietic stem and progenitor cells in vivo are still poorly understood. Despite the clinical relevance, even less is known about the mechanisms that regulate these cells in old animals. In a forward

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

    NARCIS (Netherlands)

    Gillissen, M.A.

    2018-01-01

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

  6. 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…

  7. 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

    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...

  8. 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...

  9. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients

    NARCIS (Netherlands)

    Laheij, A.M.G.A.; de Soet, J.J.; von dem Borne, P.A.; Kuijper, E.J.; Kraneveld, E.A.; van Loveren, C.; Raber-Durlacher, J.E.

    2012-01-01

    BACKGROUND: Oral mucositis is a serious and debilitating side effect of conditioning regimens for hematopoietic stem cell transplant (HSCT). Through HSCT, the homeostasis in the oral cavity is disrupted. The contribution of the oral microflora to mucositis remains to be clarified. The aim of our

  10. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients

    NARCIS (Netherlands)

    Laheij, Alexa M. G. A.; de Soet, Johannes J.; von dem Borne, Peter A.; Kuijper, Ed J.; Kraneveld, Eefje A.; van Loveren, Cor; Raber-Durlacher, Judith E.

    2012-01-01

    Oral mucositis is a serious and debilitating side effect of conditioning regimens for hematopoietic stem cell transplant (HSCT). Through HSCT, the homeostasis in the oral cavity is disrupted. The contribution of the oral microflora to mucositis remains to be clarified. The aim of our study was to

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

    Directory of Open Access Journals (Sweden)

    Juliana Folloni Fernandes

    2011-06-01

    Full Text Available Objective: To report the experience of a tertiary care hospital withallogeneic hematopoietic stem cell transplantation in children withprimary immunodeficiencies. Methods: Seven patients with primaryimmunodeficiencies (severe combined immunodeficiency: n = 2;combined immunodeficiency: n = 1; chronic granulomatous disease:n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1who underwent eight hematopoietic stem cell transplants (HSCTin a single center, from 2007 to 2010, were studied. Results: Twopatients received transplants from HLA-identical siblings; the othersix transplants were done with unrelated donors (bone marrow: n= 1; cord blood: n = 5. All patients had pre-existing infectionsbefore hematopoietic stem cell transplants. One patient receivedonly anti-thymocyte globulin prior to transplant, three transplantswere done with reduced intensity conditioning regimens and fourtransplants were done after myeloablative therapy. Two patientswere not evaluable for engraftment due to early death. Three patientsengrafted, two had primary graft failure and one received a secondtransplant with posterior engraftment. Two patients died of regimenrelated toxicity (hepatic sinusoidal obstruction syndrome; one patient died of progressive respiratory failure due to Parainfluenza infection diagnosed prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Conclusion: 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.

  12. Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.

    Science.gov (United States)

    Jin, Hao; Sood, Raman; Xu, Jin; Zhen, Fenghua; English, Milton A; Liu, P Paul; Wen, Zilong

    2009-02-01

    One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonad-mesonephros (AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow (BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1(w84x) and vlad tepes (vlt(m651)) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs.

  13. 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...

  14. Interferon-gamma impairs proliferation of hematopoietic stem cells in mice

    NARCIS (Netherlands)

    de Bruin, Alexander M.; Demirel, Özlem; Hooibrink, Berend; Brandts, Christian H.; Nolte, Martijn A.

    2013-01-01

    Balancing the processes of hematopoietic stem cell (HSC) differentiation and self-renewal is critical for maintaining a lifelong supply of blood cells. The bone marrow (BM) produces a stable output of newly generated cells, but immunologic stress conditions inducing leukopenia increase the demand

  15. 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 ...

  16. Regulation of hematopoietic stem cells during mouse development

    NARCIS (Netherlands)

    C. Orelio (Claudia)

    2003-01-01

    textabstractThe hematopoietic system is comprised of many different cell types that fulfill important physiological functions throughout embryonic and adult stages of mouse development. As the mature blood cells have a limited life-span, the pool of blood cells needs constant replenishing. At the

  17. [Information and consent forms for hematopoietic stem cell transplantation donors and recipients: Guidelines from the Franchophone society of bone marrow transplantation and cellular therapy (SFGM-TC)].

    Science.gov (United States)

    Bruno, Bénédicte; Thibert, Jean-Baptiste; Bancillon, Nelly; Desbos, Anna; Fawaz, Abir; Fournier, Isabelle; Genty, Carole; Issarni, Dominique; Leveille, Sandrine; Premel, Christelle; Polomeni, Alice; Renault, Myriam; Tarillon, Sylvie; Wallart, Anne; Yakoub-Agha, Ibrahim; Bordessoule, Dominique

    2016-11-01

    Within the context of the SFGM-TC's 6th workshop series on the harmonization of clinical practices, our workshop proposes a standardization of the informed consent process for hematopoietic stem cell donors and recipients leading up to an autologous or allogenic transplantation. All informed consent was for bone marrow or peripheral stem cell donors, and mononuclear/lymphocyte donors according to usual procedures. The informed consent for autologous and allogenic related or unrelated adults and pediatric transplantation patients have been included. A first step has been conducted for collecting in advance the informed consent forms used routinely in all francophone transplantation centers. In a second step, a comprehensive version has been re-written by a multidisciplinary team. For the purposes of understanding the risks and advantages, language has been carefully considered and streamlined. In the third step, texts were sent to stem cell transplantation experts, experts at the French biomedical agency (agence de la biomédecine [ABM]), law specialists, members of the ethical committee of the French society of hematology and several transplant recipients to be edited and proofread. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  18. Mitigation of radiation-induced hematopoietic injury via regulation of cellular MAPK/phosphatase levels and increasing hematopoietic stem cells.

    Science.gov (United States)

    Patwardhan, R S; Sharma, Deepak; Checker, Rahul; Sandur, Santosh K

    2014-03-01

    Here we describe a novel strategy for mitigation of ionizing radiation-induced hematopoietic syndrome by suppressing the activity of MKP3, resulting in ERK activation and enhanced abundance of hematopoietic stem cells, using the antioxidant flavonoid baicalein (5,6,7-trihydroxyflavone). It offered complete protection to mouse splenic lymphocytes against radiation-induced cell death. Inhibitors of ERK and Nrf-2 could significantly abrogate baicalein-mediated radioprotection in lymphocytes. Baicalein inhibited phosphatase MKP3 and thereby enhanced phosphorylation of ERK and its downstream proteins such as Elk and Nrf-2. It also increased the nuclear levels of Nrf-2 and the mRNA levels of its dependent genes. Importantly, baicalein administration to mice before radiation exposure led to significant recovery of loss of bone marrow cellularity and also inhibited cell death. Administration of baicalein increased the hematopoietic stem cell frequency as measured by side-population assay and also by antibody staining. Further, baicalein offered significant protection against whole-body irradiation (WBI; 7.5Gy)-induced mortality in mice. Interestingly, we found that baicalein works by activating the same target molecules ERK and Nrf-2 both in vitro and in vivo. Finally, administration of all-trans-retinoic acid (inhibitor of Nrf-2) significantly abrogated baicalein-mediated protection against WBI-induced mortality in mice. Thus, in contrast to the generalized conception of antioxidants acting as radioprotectors, we provide a rationale that antioxidants exhibit pleiotropic effects through the activation of multiple cellular signaling pathways. © 2013 Elsevier Inc. All rights reserved.

  19. Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation.

    Science.gov (United States)

    Jones, Morgan; Osawa, Gail; Regal, Joshua A; Weinberg, Daniel N; Taggart, James; Kocak, Hande; Friedman, Ann; Ferguson, David O; Keegan, Catherine E; Maillard, Ivan

    2014-01-01

    The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors.

  20. Differentiation within autologous fibrin scaffolds of porcine dermal cells with the mesenchymal stem cell phenotype

    International Nuclear Information System (INIS)

    Puente, Pilar de la; Ludeña, Dolores; López, Marta; Ramos, Jennifer; Iglesias, Javier

    2013-01-01

    Porcine mesenchymal stem cells (pMSCs) are an attractive source of cells for tissue engineering because their properties are similar to those of human stem cells. pMSCs can be found in different tissues but their dermal origin has not been studied in depth. Additionally, MSCs differentiation in monolayer cultures requires subcultured cells, and these cells are at risk of dedifferentiation when implanting them into living tissue. Following this, we attempted to characterize the MSCs phenotype of porcine dermal cells and to evaluate their cellular proliferation and differentiation in autologous fibrin scaffolds (AFSs). Dermal biopsies and blood samples were obtained from 12 pigs. Dermal cells were characterized by flow cytometry. Frozen autologous plasma was used to prepare AFSs. pMSC differentiation was studied in standard structures (monolayers and pellets) and in AFSs. The pMSCs expressed the CD90 and CD29 markers of the mesenchymal lineage. AFSs afforded adipogenic, osteogenic and chondrogenic differentiation. The porcine dermis can be proposed to be a good source of MSCs with adequate proliferative capacity and a suitable expression of markers. The pMSCs also showed optimal proliferation and differentiation in AFSs, such that these might serve as a promising autologous and implantable material for use in tissue engineering. -- Highlights: ► Low fibrinogen concentration provides a suitable matrix for cell migration and differentiation. ► Autologous fibrin scaffolds is a promising technique in tissue engineering. ► Dermal cells are an easily accessible mesenchymal stem cell source. ► Fibrin scaffolds afforded adipogenic, osteogenic and chondrogenic differentiation.

  1. Differentiation within autologous fibrin scaffolds of porcine dermal cells with the mesenchymal stem cell phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Puente, Pilar de la, E-mail: pilardelapuentegarcia@gmail.com [Tissue Bank, San Francisco Clinic Foundation, Av./Facultad 51, 5°, 24004 León (Spain); Ludeña, Dolores [Pathology Service, University Hospital of Salamanca, P/San Vicente 58-182, 37007 Salamanca (Spain); López, Marta; Ramos, Jennifer; Iglesias, Javier [Tissue Bank, San Francisco Clinic Foundation, Av./Facultad 51, 5°, 24004 León (Spain)

    2013-02-01

    Porcine mesenchymal stem cells (pMSCs) are an attractive source of cells for tissue engineering because their properties are similar to those of human stem cells. pMSCs can be found in different tissues but their dermal origin has not been studied in depth. Additionally, MSCs differentiation in monolayer cultures requires subcultured cells, and these cells are at risk of dedifferentiation when implanting them into living tissue. Following this, we attempted to characterize the MSCs phenotype of porcine dermal cells and to evaluate their cellular proliferation and differentiation in autologous fibrin scaffolds (AFSs). Dermal biopsies and blood samples were obtained from 12 pigs. Dermal cells were characterized by flow cytometry. Frozen autologous plasma was used to prepare AFSs. pMSC differentiation was studied in standard structures (monolayers and pellets) and in AFSs. The pMSCs expressed the CD90 and CD29 markers of the mesenchymal lineage. AFSs afforded adipogenic, osteogenic and chondrogenic differentiation. The porcine dermis can be proposed to be a good source of MSCs with adequate proliferative capacity and a suitable expression of markers. The pMSCs also showed optimal proliferation and differentiation in AFSs, such that these might serve as a promising autologous and implantable material for use in tissue engineering. -- Highlights: ► Low fibrinogen concentration provides a suitable matrix for cell migration and differentiation. ► Autologous fibrin scaffolds is a promising technique in tissue engineering. ► Dermal cells are an easily accessible mesenchymal stem cell source. ► Fibrin scaffolds afforded adipogenic, osteogenic and chondrogenic differentiation.

  2. Open for business: a comparative study of websites selling autologous stem cells in Australia and Japan.

    Science.gov (United States)

    Munsie, Megan; Lysaght, Tamra; Hendl, Tereza; Tan, Hui-Yin Lynn; Kerridge, Ian; Stewart, Cameron

    2017-11-10

    This article examines online marketing practices of Japanese and Australian clinics offering putative autologous stem cell treatments. We conducted google searches for keywords related to stem cell therapy and stem cell clinics in English and Japanese. We identified websites promoting 88 point-of-sale clinics in Japan and 70 in Australia. Our findings provide further evidence of the rapid global growth in clinics offering unproven stem cell interventions. We also show that these clinics adopt strategies to promote their services as though they are consistent with evidentiary and ethical standards of science, research and medicine. Unless addressed, these practices risk harming not only vulnerable patients but also undermining public trust in science and medicine.

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

    Science.gov (United States)

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

    2017-07-01

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

  4. SHIP1-expressing mesenchymal stem cells regulate hematopoietic stem cell homeostasis and lineage commitment during aging.

    Science.gov (United States)

    Iyer, Sonia; Brooks, Robert; Gumbleton, Matthew; Kerr, William G

    2015-05-01

    Hematopoietic stem cell (HSC) self-renewal and lineage choice are subject to intrinsic control. However, this intrinsic regulation is also impacted by external cues provided by niche cells. There are multiple cellular components that participate in HSC support with the mesenchymal stem cell (MSC) playing a pivotal role. We had previously identified a role for SH2 domain-containing inositol 5'-phosphatase-1 (SHIP1) in HSC niche function through analysis of mice with germline or induced SHIP1 deficiency. In this study, we show that the HSC compartment expands significantly when aged in a niche that contains SHIP1-deficient MSC; however, this expanded HSC compartment exhibits a strong bias toward myeloid differentiation. In addition, we show that SHIP1 prevents chronic G-CSF production by the aging MSC compartment. These findings demonstrate that intracellular signaling by SHIP1 in MSC is critical for the control of HSC output and lineage commitment during aging. These studies increase our understanding of how myeloid bias occurs in aging and thus could have implications for the development of myeloproliferative disease in aging.

  5. Preclinical derivation and imaging of autologously transplanted canine induced pluripotent stem cells.

    Science.gov (United States)

    Lee, Andrew S; Xu, Dan; Plews, Jordan R; Nguyen, Patricia K; Nag, Divya; Lyons, Jennifer K; Han, Leng; Hu, Shijun; Lan, Feng; Liu, Junwei; Huang, Mei; Narsinh, Kazim H; Long, Charles T; de Almeida, Patricia E; Levi, Benjamin; Kooreman, Nigel; Bangs, Charles; Pacharinsak, Cholawat; Ikeno, Fumiaki; Yeung, Alan C; Gambhir, Sanjiv S; Robbins, Robert C; Longaker, Michael T; Wu, Joseph C

    2011-09-16

    Derivation of patient-specific induced pluripotent stem cells (iPSCs) opens a new avenue for future applications of regenerative medicine. However, before iPSCs can be used in a clinical setting, it is critical to validate their in vivo fate following autologous transplantation. Thus far, preclinical studies have been limited to small animals and have yet to be conducted in large animals that are physiologically more similar to humans. In this study, we report the first autologous transplantation of iPSCs in a large animal model through the generation of canine iPSCs (ciPSCs) from the canine adipose stromal cells and canine fibroblasts of adult mongrel dogs. We confirmed pluripotency of ciPSCs using the following techniques: (i) immunostaining and quantitative PCR for the presence of pluripotent and germ layer-specific markers in differentiated ciPSCs; (ii) microarray analysis that demonstrates similar gene expression profiles between ciPSCs and canine embryonic stem cells; (iii) teratoma formation assays; and (iv) karyotyping for genomic stability. Fate of ciPSCs autologously transplanted to the canine heart was tracked in vivo using clinical positron emission tomography, computed tomography, and magnetic resonance imaging. To demonstrate clinical potential of ciPSCs to treat models of injury, we generated endothelial cells (ciPSC-ECs) and used these cells to treat immunodeficient murine models of myocardial infarction and hindlimb ischemia.

  6. The use of intravenous antibiotics at the onset of neutropenia in patients receiving outpatient-based hematopoietic stem cell transplants.

    Directory of Open Access Journals (Sweden)

    Aziz Hamadah

    Full Text Available 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.

  7. 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

  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. Importance of mesenchymal stem cells in autologous fat grafting

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  10. Distinguishing autocrine and paracrine signals in hematopoietic stem cell culture using a biofunctional microcavity platform

    Science.gov (United States)

    Müller, Eike; Wang, Weijia; Qiao, Wenlian; Bornhäuser, Martin; Zandstra, Peter W.; Werner, Carsten; Pompe, Tilo

    2016-08-01

    Homeostasis of hematopoietic stem cells (HSC) in the mammalian bone marrow stem cell niche is regulated by signals of the local microenvironment. Besides juxtacrine, endocrine and metabolic cues, paracrine and autocrine signals are involved in controlling quiescence, proliferation and differentiation of HSC with strong implications on expansion and differentiation ex vivo as well as in vivo transplantation. Towards this aim, a cell culture analysis on a polymer microcavity carrier platform was combined with a partial least square analysis of a mechanistic model of cell proliferation. We could demonstrate the discrimination of specific autocrine and paracrine signals from soluble factors as stimulating and inhibitory effectors in hematopoietic stem and progenitor cell culture. From that we hypothesize autocrine signals to be predominantly involved in maintaining the quiescent state of HSC in single-cell niches and advocate our analysis platform as an unprecedented option for untangling convoluted signaling mechanisms in complex cell systems being it of juxtacrine, paracrine or autocrine origin.

  11. The effect of carbon beam on the survival of hematopoietic stem cells in irradiated mice

    International Nuclear Information System (INIS)

    Tsuboi, Atsushi; Kojima, Eiichi; Tanaka, Kaoru

    1993-01-01

    The new cyclotron for heavy ion radiotherapy will be completed in the very near future at NIRS. High LET radiations having different qualities are known to produce differences in biological effectiveness. It is necessary to determine the biological effectiveness of this new radiation source in both normal and tumor tissues. In this paper, the effects of 200 kVp x-rays and a 135 MeV/u carbon 12 beam on hematopoietic stem cells (CFU-S and GM-CFC) are described. The rationale for this experimental approach is that the sensitivity of hematopoietic stem cells and the committed stem cells to radiation is often the treatment limiting-factor for radiotherapy. (author)

  12. Early Prognostic Value of Monitoring Serum Free Light Chain in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

    Science.gov (United States)

    Özkurt, Zübeyde Nur; Sucak, Gülsan Türköz; Akı, Şahika Zeynep; Yağcı, Münci; Haznedar, Rauf

    2017-03-16

    We hypothesized the levels of free light chains obtained before and after autologous stem cell transplantation can be useful in predicting transplantation outcome. We analyzed 70 multiple myeloma patients. Abnormal free light chain ratios before stem cell transplantation were found to be associated early progression, although without any impact on overall survival. At day +30, the normalization of levels of involved free light chain related with early progression. According to these results almost one-third reduction of free light chain levels can predict favorable prognosis after autologous stem cell transplantation.

  13. Psychological and cytokine changes in children and adolescents undergoing hematopoietic stem cell transplantation.

    Science.gov (United States)

    Munitz-Shenkar, Dafna; Krulik, Tamar; Peretz, Chava; Shiloh, Roni; Elhasid, Ronit; Toren, Amos; Weizman, Abraham

    2007-01-01

    Hematopoietic stem cell transplantation is a therapeutic option of a large variety of diseases. It involves several physiological and psychological changes. Investigations of mood changes in patients undergoing hematopoietic stem cell transplantation are common. There are no studies however, on the relationship between changes in mood and physiological changes in hematopoietic stem cell transplantation in children and adolescents. We investigated the correlation between anxiety, depression and serum Interleukin-1beta (IL-1beta), IL-2 and IL-6. Participants, 11 boys and 12 girls, aged 6-18 years, were administered the Children Depression Inventory (CDI) and the Spielberger State Anxiety Inventory for Children (SAIC), at four different points in time: at conditioning time when treatment is initiated (time 1 = T1), on the day of hematopoietic transplantation (T2), on the day of engraftment (T3) and a week after the engraftment (T4). At each of those times serum samples for cytokines determination were collected as well. Up to the time of engraftment depression and anxiety were relatively high but resolved subsequently. Globally, there was a significant time effect for anxiety (p = 0.0082). Namely, scores differ between times. Depression showed a similar trend, though this trend did not reach significance (p = 0.1394). Negative correlation was found between serum IL-1beta, IL-2 and IL-6 levels and anxiety (IL-2 and IL-6) and depression scores (IL-1beta and IL-2) at T4. The complex interaction between cytokines, depression and anxiety in children and adolescents undergoing hematopoietic stem cell transplantation merits further long-term studies under natural conditions and on laboratory models.

  14. Concise review: From greenhouse to garden: the changing soil of the hematopoietic stem cell microenvironment during development.

    Science.gov (United States)

    Mirshekar-Syahkal, Bahar; Fitch, Simon R; Ottersbach, Katrin

    2014-07-01

    The hematopoietic system has been intensely studied for many decades. For this reason, it has become the best understood stem cell-derived system that serves as a paradigm for stem cell biology and has found numerous applications in the clinics. While a lot of progress has recently been made in describing the bone marrow components that maintain and control blood stem cell function in the adult, very little is currently known about the regulatory microenvironment in which the first adult-repopulating hematopoietic stem cells are formed during development. Knowledge of these processes is crucial for understanding the basic regulation of hematopoietic stem cell production and behavior and to allow their in vitro expansion and generation from embryonic stem cells or iPS cells for clinical and research purposes. This review summarizes the recent advances that have been made in defining the cellular components, as well as the soluble and physical factors, that are part of the niche involved in regulating hematopoietic stem cell generation in the embryo. The findings are compared with what is known about the adult bone marrow niche to find common pathways for stem cell regulation, but also to highlight processes uniquely required for de novo hematopoietic stem cell generation, as these are the conditions that will need to be recreated for the successful production of blood stem cells in culture. © 2014 AlphaMed Press.

  15. 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

  16. HEMATOPOIETIC PROGENITOR CELLS AS A PREDICTIVE OF CD34+ ENUMERATION PRIOR TO PERIPHERAL BLOOD STEM CELLS HARVESTING

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    Z. Zulkafli

    2014-09-01

    Full Text Available Background: To date, the CD34+ cell enumeration has relied predominantly on flow cytometry technique. However, flow cytometry is time consuming and operator dependent. The application of the hematopoietic progenitor cells (HPCs channel in Sysmex XE-2100, a fully automated hematology analyzer offers an alternative approach, which is with minimal sample manipulation and less operator dependent. This study evaluates the utility of HPC counts as a predictive of CD34+ enumeration prior to peripheral blood stem cells harvesting. Materials and methods: HPC, CD34+, white blood cell (WBC, reticulocytes (retic, immature platelet fraction (IPF and immature reticulocyte fraction (IRF were determined in 61 samples from 19 patients with hematological malignancies (15 lymphoma and 4 multiple myeloma patients at Hospital Universiti Sains Malaysia (Hospital USM who had received granulocyte-colony stimulating factor (G-CSF and planned for autologous transplantation. Results: CD34+ count showed strong and significant correlation with HPC. The receiver operating characteristics (ROC curve analysis revealed that HPC count > 21.5 x 106 / L can predicts a pre harvest CD34+ count of >20 x 106 / L with sensitivity of 77%, specificity of 64% and area under the curve (AUC of 0.802. Conclusion: We concluded that HPC count can be a useful potential parameter in optimizing timing for CD34+ enumeration prior to leukapheresis.

  17. A Transient Developmental Hematopoietic Stem Cell Gives Rise to Innate-like B and T Cells.

    Science.gov (United States)

    Beaudin, Anna E; Boyer, Scott W; Perez-Cunningham, Jessica; Hernandez, Gloria E; Derderian, S Christopher; Jujjavarapu, Chethan; Aaserude, Eric; MacKenzie, Tippi; Forsberg, E Camilla

    2016-12-01

    The generation of distinct hematopoietic cell types, including tissue-resident immune cells, distinguishes fetal from adult hematopoiesis. However, the mechanisms underlying differential cell production to generate a layered immune system during hematopoietic development are unclear. Using an irreversible lineage-tracing model, we identify a definitive hematopoietic stem cell (HSC) that supports long-term multilineage reconstitution upon transplantation into adult recipients but does not persist into adulthood in situ. These HSCs are fully multipotent, yet they display both higher lymphoid cell production and greater capacity to generate innate-like B and T lymphocytes as compared to coexisting fetal HSCs and adult HSCs. Thus, these developmentally restricted HSCs (drHSCs) define the origin and generation of early lymphoid cells that play essential roles in establishing self-recognition and tolerance, with important implications for understanding autoimmune disease, allergy, and rejection of transplanted organs. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells.

    Science.gov (United States)

    Li, LiQi; Jothi, Raja; Cui, Kairong; Lee, Jan Y; Cohen, Tsadok; Gorivodsky, Marat; Tzchori, Itai; Zhao, Yangu; Hayes, Sandra M; Bresnick, Emery H; Zhao, Keji; Westphal, Heiner; Love, Paul E

    2011-02-01

    The nuclear adaptor Ldb1 functions as a core component of multiprotein transcription complexes that regulate differentiation in diverse cell types. In the hematopoietic lineage, Ldb1 forms a complex with the non-DNA-binding adaptor Lmo2 and the transcription factors E2A, Scl and GATA-1 (or GATA-2). Here we demonstrate a critical and continuous requirement for Ldb1 in the maintenance of both fetal and adult mouse hematopoietic stem cells (HSCs). Deletion of Ldb1 in hematopoietic progenitors resulted in the downregulation of many transcripts required for HSC maintenance. Genome-wide profiling by chromatin immunoprecipitation followed by sequencing (ChIP-Seq) identified Ldb1 complex-binding sites at highly conserved regions in the promoters of genes involved in HSC maintenance. Our results identify a central role for Ldb1 in regulating the transcriptional program responsible for the maintenance of HSCs.

  19. Our Experience with Autologous Bone Marrow Stem Cell Application in Dilated Cardiomyopathy

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    Mukund K

    2009-01-01

    Full Text Available Background - Use of autologous bone marrow stem cell is a newly evolving treatment modality for end stage cardiac failure as reported in the literature. We report our experience with two patients with dilated cardiomyopathy who underwent this treatment after failure of maximal conventional therapy. Methods - A 29 year old Male patient with history of orthopnea and PND, with a diagnosis of dilated cardiomyopathy and echocardiographic evidence of severe LV dysfunction was referred for further treatment. His echo on admission showed EF of 17% and no other abnormal findings except elevated bilirubin levels. He was in NYHA functional class IV. He received intracoronary injection of autologous bone marrow stem cells in January 2009. 254X106 cells were injected with a CD34+ of 0.20%. His clinical condition stabilized and he was discharged home. He received a second injection of 22X106 in vitro expanded stem cells with a CD34+ of 0.72% in Aug 2009. He is now in NYHA class II-III with EF 24%. A 31year old Male patient with history of increasing shortness of breath, severe over the past 3-4 days was admitted for evaluation and treatment. His echo on admission showed EF of 20% and was in NYHA functional class IV. Coronary angiogram was normal and he was stabilized on maximal anti failure measures. He received intracoronary autologous bone marrow stem cell injection of 56X106 with a CD34+ of 0.53% in August 2009. His clinical condition stabilized over the next 10 days and he was discharged home. Conclusions - In our experience of two cases of dilated cardiomyopathy, safety of intracoronary injection of autologous bone marrow stem cells both isolated and in vitro expanded has been proven in both the cases with efficacy proven in one of the cases. Long term follow-up of these two cases and inclusion of more number of similar cases where all available conventional therapies have not resulted in significant improvement for such studies are planned.

  20. Total body irradiation in hematopoietic stem cell transplantation

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    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. 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.; 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

  2. Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells

    NARCIS (Netherlands)

    T.B. van Dijk (Thamar); M. Parren-Van Amelsvoort (Martine); H. Mano; M.M. von Lindern (Marieke); B. Löwenberg (Bob); E. van den Akker (Emile)

    2000-01-01

    textabstractStem cell factor (SCF) has an important role in the proliferation, differentiation, survival, and migration of hematopoietic cells. SCF exerts its effects by binding to cKit, a receptor with intrinsic tyrosine kinase activity. Activation of

  3. [Protective effects of amifostine on hematopoietic stem/progenitor cells against chemotherapeutic damage].

    Science.gov (United States)

    Chen, Bao-An; Li, Cui-Ping; Zhou, Min; Gao, Chong; Ding, Jia-Hua

    2004-12-01

    The aim was to study the protective effects of amifostine (AMF) on normal hematopoietic stem/progenitor cells against the chemotherapeutic damage from etoposide (VP-16). The cord blood mononuclear cells (CBMNC), fresh and frozen peripheral blood stem cells (PBSC), and HL-60 cells were divided into AMF, AMF + VP-16, VP-16 and control groups, each group cell viability was determined by using trypan blue exclusion test, the CFU-GM culture was used to count cells, the apoptosis was detected by flow cytometry. The results showed that in CBMNC, fresh and frozen PBSC samples, cell viability and the number of CFU-GM in AMF + VP-16 group were all significantly higher than those in VP-16 group (P GFU-GM life in AMF + VP-16 group was also longer than that of latter, in CBMNC samples, the number of CFU-GM in AMF groups was higher than that in control group, but there was no statistical significance between the two groups (P > 0.05), in HL-60 cell apoptotic rate in AMF + VP-16 group was little higher than that in VP-16 group, but no statistical significance between these two groups (P > 0.05). It is concluded that AMF can significantly protect normal hematopoietic stem/progenitor cells against the damage from VP-16. Moreover, AMF does not affect cytotoxity of VP-16 on HL-60 cells, and can not stimulate the growth and differentiation of cord hematopoietic stem/progenitor cells directly.

  4. Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells.

    Science.gov (United States)

    Ishida, Takashi; Suzuki, Sachie; Lai, Chen-Yi; Yamazaki, Satoshi; Kakuta, Shigeru; Iwakura, Yoichiro; Nojima, Masanori; Takeuchi, Yasuo; Higashihara, Masaaki; Nakauchi, Hiromitsu; Otsu, Makoto

    2017-04-01

    Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre-conditioning to maximize anti-tumor effects and donor-HSC engraftment. While this induces bone marrow (BM)-localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor-HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF-α plays a role in HSC damage: TNF-α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow-cytometry-sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short-term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant N-acetyl-L-cysteine (NAC) prevents TNF-α-mediated ROS accumulation in HSCs. Importantly, pre-transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft-HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft-HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM. Stem Cells 2017;35:989-1002. © 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  5. Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche.

    Science.gov (United States)

    Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal; Kourtzelis, Ioannis; Economopoulou, Matina; Kajikawa, Tetsuhiro; Troullinaki, Maria; Ziogas, Athanasios; Ruppova, Klara; Hosur, Kavita; Maekawa, Tomoki; Wang, Baomei; Subramanian, Pallavi; Tonn, Torsten; Verginis, Panayotis; von Bonin, Malte; Wobus, Manja; Bornhäuser, Martin; Grinenko, Tatyana; Di Scala, Marianna; Hidalgo, Andres; Wielockx, Ben; Hajishengallis, George; Chavakis, Triantafyllos

    2017-10-02

    Hematopoietic stem cells (HSCs) remain mostly quiescent under steady-state conditions but switch to a proliferative state following hematopoietic stress, e.g., bone marrow (BM) injury, transplantation, or systemic infection and inflammation. The homeostatic balance between quiescence, self-renewal, and differentiation of HSCs is strongly dependent on their interactions with cells that constitute a specialized microanatomical environment in the BM known as the HSC niche. Here, we identified the secreted extracellular matrix protein Del-1 as a component and regulator of the HSC niche. Specifically, we found that Del-1 was expressed by several cellular components of the HSC niche, including arteriolar endothelial cells, CXCL12-abundant reticular (CAR) cells, and cells of the osteoblastic lineage. Del-1 promoted critical functions of the HSC niche, as it regulated long-term HSC (LT-HSC) proliferation and differentiation toward the myeloid lineage. Del-1 deficiency in mice resulted in reduced LT-HSC proliferation and infringed preferentially upon myelopoiesis under both steady-state and stressful conditions, such as hematopoietic cell transplantation and G-CSF- or inflammation-induced stress myelopoiesis. Del-1-induced HSC proliferation and myeloid lineage commitment were mediated by β3 integrin on hematopoietic progenitors. This hitherto unknown Del-1 function in the HSC niche represents a juxtacrine homeostatic adaptation of the hematopoietic system in stress myelopoiesis.

  6. Reengineering autologous bone grafts with the stem cell activator WNT3A.

    Science.gov (United States)

    Jing, Wei; Smith, Andrew A; Liu, Bo; Li, Jingtao; Hunter, Daniel J; Dhamdhere, Girija; Salmon, Benjamin; Jiang, Jie; Cheng, Du; Johnson, Chelsey A; Chen, Serafine; Lee, Katherine; Singh, Gurpreet; Helms, Jill A

    2015-04-01

    Autologous bone grafting represents the standard of care for treating bone defects but this biomaterial is unreliable in older patients. The efficacy of an autograft can be traced back to multipotent stem cells residing within the bone graft. Aging attenuates the viability and function of these stem cells, leading to inconsistent rates of bony union. We show that age-related changes in autograft efficacy are caused by a loss in endogenous Wnt signaling. Blocking this endogenous Wnt signal using Dkk1 abrogates autograft efficacy whereas providing a Wnt signal in the form of liposome-reconstituted WNT3A protein (L-WNT3A) restores bone forming potential to autografts from aged animals. The bioengineered autograft exhibits significantly better survival in the hosting site. Mesenchymal and skeletal stem cell populations in the autograft are activated by L-WNT3A and mitotic activity and osteogenic differentiation are significantly enhanced. In a spinal fusion model, aged autografts treated with L-WNT3A demonstrate superior bone forming capacity compared to the standard of care. Thus, a brief incubation in L-WNT3A reliably improves autologous bone grafting efficacy, which has the potential to significantly improve patient care in the elderly. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Cytomegalovirus viremia, viruria and disease after autologous peripheral blood stem cell transplantation: no need for surveillance.

    Science.gov (United States)

    Bilgrami, S; Aslanzadeh, J; Feingold, J M; Bona, R D; Clive, J; Dorsky, D; Edwards, R L; Tutschka, P J

    1999-07-01

    A retrospective evaluation of 200 consecutive recipients of autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence, risk factors, clinical features, complications, and outcome of cytomegalovirus (CMV) infection. A total of 26 patients (13%) developed CMV viremia (n = 5), DNAemia (n = 3), viruria (n = 18) and/or disease (n = 3) at a median of 45 days following stem cell infusion. None of the patients underwent surveillance testing for CMV. A diagnosis was established by culture and polymerase chain reaction of blood, urine or other tissue samples submitted when patients exhibited clinical features suggestive of CMV infection. Cytomegalovirus seropositivity prior to transplantation was the only statistically significant risk factor predicting subsequent identification of CMV (P < 0.001). The symptoms were severe enough in 23 patients to warrant treatment with intravenous ganciclovir. Three patients developed CMV disease; two developed fatal CMV pneumonia and one developed CMV gastritis which responded to antiviral treatment. Clinical signs and symptoms as well as viremia and viruria resolved with (20 patients) and without (three patients) treatment in the remaining individuals. All instances of CMV viremia, DNAemia, viruria and disease occurred within 3 months of stem cell infusion. These results demonstrate that CMV is a common pathogen after autologous PBSCT and may result in fatality in rare instances. Surveillance programs appear to be neither useful nor cost-effective. Diagnostic evaluation should be performed only in patients exhibiting suspicious clinical features and antiviral chemotherapy should be administered for persistent and severe signs and symptoms.

  8. Bone marrow laminins influence hematopoietic stem and progenitor cell cycling and homing to the bone marrow.

    Science.gov (United States)

    Susek, Katharina Helene; Korpos, Eva; Huppert, Jula; Wu, Chuan; Savelyeva, Irina; Rosenbauer, Frank; Müller-Tidow, Carsten; Koschmieder, Steffen; Sorokin, Lydia

    2018-01-31

    Hematopoietic stem and progenitor cell (HSPC) functions are regulated by a specialized microenvironment in the bone marrow - the hematopoietic stem cell niche - of which the extracellular matrix (ECM) is an integral component. We describe here the localization of ECM molecules, in particular the laminin α4, α3 and α5 containing isoforms in the bone marrow. Laminin 421 (composed of laminin α4, β2, γ1 chains) is identified as a major component of the bone marrow ECM, occurring abundantly surrounding venous sinuses and in a specialized reticular fiber network of the intersinusoidal spaces of murine bone marrow (BM) in close association with HSPC. Bone marrow from Lama4 -/- mice is significantly less efficient in reconstituting the hematopoietic system of irradiated wildtype (WT) recipients in competitive bone marrow transplantation assays and shows reduced colony formation in vitro. This is partially due to retention of Lin - c-kit + Sca-1 + CD48 - long-term and short-term hematopoietic stem cells (LT-HSC/ST-HSC) in the G0 phase of the cell cycle in Lama4 -/- bone marrow and hence a more quiescent phenotype. In addition, the extravasation of WT BM cells into Lama4 -/- bone marrow is impaired, influencing the recirculation of HSPC. Our data suggest that these effects are mediated by a compensatory expression of laminin α5 containing isoforms (laminin 521/522) in Lama4 -/- bone marrow. Collectively, these intrinsic and extrinsic effects lead to reduced HSPC numbers in Lama4 -/- bone marrow and reduced hematopoietic potential. Copyright © 2018 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  9. Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta-adrenergic stimulation.

    Science.gov (United States)

    Köse, Sevil; Aerts-Kaya, Fatima; Köprü, Çağla Zübeyde; Nemutlu, Emirhan; Kuşkonmaz, Barış; Karaosmanoğlu, Beren; Taşkıran, Ekim Zihni; Altun, Belgin; Uçkan Çetinkaya, Duygu; Korkusuz, Petek

    2018-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a well-known hematopoietic stem cell (HSC)-mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize a sufficient number of cells. New mobilization agents are therefore needed. Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors CB1 and CB2. We suggest that eCBs may act as mobilizers of HSCs from the bone marrow (BM) under stress conditions as beta-adrenergic receptors (Adrβ). This study demonstrates that BM mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF-treated group compared with BM plasma. BM mononuclear cells (MNCs) and CD34 + HSCs express CB1, CB2, and Adrβ subtypes. CD34 + HSCs had higher CB1 and CB2 receptor expression in G-CSF-untreated and G-CSF-treated groups compared with MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry. AEA- and 2-AG-stimulated HSC migration was blocked by eCB receptor antagonists in an in vitro migration assay. In conclusion, components of the eCB system and their interaction with Adrβ subtypes were demonstrated on HSCs and MSCs of G-CSF-treated and G-CSF-untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting. Copyright © 2018 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  10. 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.

  11. A question of ethics: selling autologous stem cell therapies flaunts professional standards.

    Science.gov (United States)

    Munsie, Megan; Hyun, Insoo

    2014-11-01

    The idea that the body's own stem cells could act as a repair kit for many conditions, including cardiac repair, underpins regenerative medicine. While progress is being made, with hundreds of clinical trials underway to evaluate possible autologous cell-based therapies, some patients and physicians are not prepared to wait and are pursuing treatments without evidence that the proposed treatments are effective, or even safe. This article explores the inherent tension between patients, practitioners and the need to regulate the development and commercialization of new cellular therapies--even when the cells come from the patient. Copyright © 2014. Published by Elsevier B.V.

  12. A question of ethics: Selling autologous stem cell therapies flaunts professional standards

    Directory of Open Access Journals (Sweden)

    Megan Munsie

    2014-11-01

    Full Text Available The idea that the body's own stem cells could act as a repair kit for many conditions, including cardiac repair, underpins regenerative medicine. While progress is being made, with hundreds of clinical trials underway to evaluate possible autologous cell-based therapies, some patients and physicians are not prepared to wait and are pursuing treatments without evidence that the proposed treatments are effective, or even safe. This article explores the inherent tension between patients, practitioners and the need to regulate the development and commercialization of new cellular therapies — even when the cells come from the patient.

  13. Neck Rhabdoid Tumors: Clinical Features and Consideration of Autologous Stem Cell Transplant.

    Science.gov (United States)

    Wolfe, Adam D; Capitini, Christian M; Salamat, Shahriar M; DeSantes, Kenneth; Bradley, Kristin A; Kennedy, Tabassum; Dehner, Louis P; Patel, Neha J

    2018-01-01

    Extrarenal malignant rhabdoid tumors (MRT) have a poor prognosis despite aggressive therapy. Adding high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) as consolidative therapy for MRT is controversial. We describe 2 patients, age 13 years and 19 months, with unresectable neck MRT. After chemotherapy and radiotherapy, both underwent HDC-ASCR and remain in remission over 4 years later. We reviewed all published cases of neck MRT, and found poorer outcomes and more variable age of presentation and time to progression than MRT at other sites. Neck MRT may represent a higher-risk subset of MRT, and addition of HDC-ASCR merits consideration.

  14. Natural Killer Cells Improve Hematopoietic Stem Cell Engraftment by Increasing Stem Cell Clonogenicity In Vitro and in a Humanized Mouse Model.

    Science.gov (United States)

    Escobedo-Cousin, Michelle; Jackson, Nicola; Laza-Briviesca, Raquel; Ariza-McNaughton, Linda; Luevano, Martha; Derniame, Sophie; Querol, Sergio; Blundell, Michael; Thrasher, Adrian; Soria, Bernat; Cooper, Nichola; Bonnet, Dominique; Madrigal, Alejandro; Saudemont, Aurore

    2015-01-01

    Cord blood (CB) is increasingly used as a source of hematopoietic stem cells (HSC) for transplantation. Low incidence and severity of graft-versus-host disease (GvHD) and a robust graft-versus-leukemia (GvL) effect are observed following CB transplantation (CBT). However, its main disadvantages are a limited number of HSC per unit, delayed immune reconstitution and a higher incidence of infection. Unmanipulated grafts contain accessory cells that may facilitate HSC engraftment. Therefore, the effects of accessory cells, particularly natural killer (NK) cells, on human CB HSC (CBSC) functions were assessed in vitro and in vivo. CBSC cultured with autologous CB NK cells showed higher levels of CXCR4 expression, a higher migration index and a higher number of colony forming units (CFU) after short-term and long-term cultures. We found that CBSC secreted CXCL9 following interaction with CB NK cells. In addition, recombinant CXCL9 increased CBSC clonogenicity, recapitulating the effect observed of CB NK cells on CBSC. Moreover, the co-infusion of CBSC with CB NK cells led to a higher level of CBSC engraftment in NSG mouse model. The results presented in this work offer the basis for an alternative approach to enhance HSC engraftment that could improve the outcome of CBT.

  15. GENE-CELL THERAPY OF HIV AND HEMATOLOGICAL MALIGNANCES BASED ON HEMATOPOIETIC STEM CELL TRANSPLANTATION AND SITE-SPECIFIC GENOME EDITING

    Directory of Open Access Journals (Sweden)

    M. О. Popova

    2017-01-01

    Full Text Available Based on the annual UNAIDS reports the number of HIVinfected patients is continually growing since 1983. Antiretroviral Therapy (ART allows to prolong life expectancy, but the problem of life quality and overall survival is still remaining. Nowadays, in the era of ART, one of the main cause of mortality in HIV-infected patients is malignancies. Lymphomas play one of the key roles in this group of diseases. The treatment of lymphomas includes combined regiments of chemotherapy with a curative potential. High dose chemotherapy with autologous hematopoietic stem cell transplant (auto-HSCT is the main path of the treatment for relapsed / refractory lymphomas. In the last few years with a development of the genome editing technology auto-HSCT is becoming one of the most promising methods of HIV treatment. The case of “Berlin patient” when allogeneic HSCT from donor with mutation CCR5-delta32 lead to cure from HIV and proof of concept the efficacy of the gene therapy for HIV based on HSCT. Hematopoietic stem cell transplantation with edited autologous HSC (CCR5 knockout by site-specific genome editing tools with engineering nucleases is a comprehensive treatment for this cohort of patients. On one hand, high dose chemotherapy with auto-HSCT cures the malignancy; on the other hand auto-HSCT works as a delivery method for the edited cells and creates an environment for the HIV eradication. This review is dedicated to HIV and oncology, methods of treatment of hematological malignancies and HIV-infection using genome editing technology based on HSCT.

  16. Bone marrow concentrate for autologous transplantation in minipigs. Characterization and osteogenic potential of mesenchymal stem cells.

    Science.gov (United States)

    Herten, M; Grassmann, J P; Sager, M; Benga, L; Fischer, J C; Jäger, M; Betsch, M; Wild, M; Hakimi, M; Jungbluth, P

    2013-01-01

    Autologous bone marrow plays an increasing role in the treatment of bone, cartilage and tendon healing disorders. Cell-based therapies display promising results in the support of local regeneration, especially therapies using intra-operative one-step treatments with autologous progenitor cells. In the present study, bone marrow-derived cells were concentrated in a point-of-care device and investigated for their mesenchymal stem cell (MSC) characteristics and their osteogenic potential. Bone marrow was harvested from the iliac crest of 16 minipigs. The mononucleated cells (MNC) were concentrated by gradient density centrifugation, cultivated, characterized by flow cytometry and stimulated into osteoblasts, adipocytes, and chondrocytes. Cell differentiation was investigated by histological and immunohistological staining of relevant lineage markers. The proliferation capacity was determined via colony forming units of fibroblast and of osteogenic alkaline-phosphatase-positive-cells. The MNC could be enriched 3.5-fold in nucleated cell concentrate in comparison to bone marrow. Flow cytometry analysis revealed a positive signal for the MSC markers. Cells could be differentiated into the three lines confirming the MSC character. The cellular osteogenic potential correlated significantly with the percentage of newly formed bone in vivo in a porcine metaphyseal long-bone defect model. This study demonstrates that bone marrow concentrate from minipigs display cells with MSC character and their osteogenic differentiation potential can be used for osseous defect repair in autologous transplantations.

  17. The Importance of Positive Immunomagnetic Cell Separation Prior to Autologous Hematopoetic Stem Cell Transplantation for Advanced Stage Lymphomas

    Directory of Open Access Journals (Sweden)

    Benedek István

    2016-12-01

    Full Text Available We present the method of immunomagnetic stem cell separation with the ISOLEX 300i device (Isolex® 300i Magnetic Cell Selection System, Nextell Therapeutics Inc. Irvine California 21618 USA and the results obtained using this method in patients admitted to the Hematology and Bone Marrow Transplantation Clinic of Tîrgu Mureş, Romania. Cell selection has a great importance in separating stem cells from tumor cells, therefore contributing to the success of autologous stem cell transplantation.

  18. The impact of preapheresis white blood cell count on autologous peripheral blood stem cell collection efficiency and HSC infusion side effect rate.

    Science.gov (United States)

    Sakashita, Araci M; Kondo, Andrea T; Yokoyama, Ana Paula H; Lira, Sanny M C; Bub, Carolina B; Souza, Aline M; Cipolletta, Andrea N F; Alvarez, Kelen C; Hamerschlak, Nelson; Kutner, Jose M; Chiattone, Carlos S

    2018-01-19

    Autologous peripheral blood hematopoietic stem cell (PBSC) collection efficiency (CE) is reportedly affected by the patient's blood properties; however, studies to identify factors correlated with CE have shown inconsistent results. Additionally, variables such as stem cell graft granulocyte content and patient age, sex, and underlying disease, may be associated with hematopietic stem cell (HSC) infusion-related adverse reactions. In this study, we evaluated the correlation of preleukapheresis PB granulocyte count and PBSC harvest variables with CD34 + collection yield and efficiency, and thawed HSC infusion side effect occurrence. We evaluated data from 361 patients who had undergone autologous PBSC transplant. Large volume leukapheresis was the method for PBSC collection. Complete Blood Count and CD34 + cell enumeration were performed in the preapheresis PB and the apheresis product sample. The PBSC grafts were submitted to non-controlled rate freezing after addition of 5% DMSO plus 6% hidroxyethylstarch as a cryoprotectant solution. The cryopreserved graft was thawed in a 37°C water bath and then infused without further manipulation. The CD34 + yield was associated with preapheresis PB CD34 + count and immature granulocyte count. The PBSC CE was negatively correlated with preapheresis white blood cell (WBC), immature granulocyte and granulocyte count. The leukapheresis product total nucleated cell (TNC) and granulocyte content was correlated with the thawed graft infusion side effect occurrence. This study has shown that preapheresis PB WBC and granulocyte counts were associated with leukapheresis CE. Additionally, the leukapheresis product TNC and granulocyte content was correlated with thawed graft infusion side effect occurrence. © 2018 Wiley Periodicals, Inc.

  19. Combined influence of biophysical and biochemical cues on maintenance and proliferation of hematopoietic stem cells.

    Science.gov (United States)

    Gvaramia, David; Müller, Eike; Müller, Katrin; Atallah, Passant; Tsurkan, Mikhail; Freudenberg, Uwe; Bornhäuser, Martin; Werner, Carsten

    2017-09-01

    Homeostasis of hematopoietic stem and progenitor cells (HSPC) is controlled by a combination of biochemical and biophysical environmental cues in the bone marrow (BM) niche, where a tight balance of quiescence and proliferation of HSPC is maintained. Specifically, alongside soluble factors and extracellular matrix (ECM) proteins, spatial confinement and ECM stiffness have been recognized to be critical for regulation of HSPC fate. Here we employ a modular, glycosaminoglycan (GAG)-based biohybrid hydrogel system to balance proliferation of human HSPC and maintenance of quiescent hematopoietic stem cells (HSC) through simultaneous regulation of exogenous biochemical and biophysical cues. Our results demonstrate that HSPC respond to increased spatial confinement with lowered proliferation and cell cycling, which results in higher frequency of quiescent LTC-IC (long-term culture initiating cells), while GAG-rich 3D environments further support maintenance of the cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Cerebral salt-wasting syndrome after hematopoietic stem cell transplantation in adolescents: 3 case reports

    Directory of Open Access Journals (Sweden)

    Yeon Jin Jeon

    2015-12-01

    Full Text Available Cerebral salt-wasting syndrome (CSWS is a rare disease characterized by a extracellular volume depletion and hyponatremia induced by marked natriuresis. It is mainly reported in patients who experience a central nervous system insult, such as cerebral hemorrhage or encephalitis. The syndrome of inappropriate antidiuretic hormone secretion is a main cause of severe hyponatremia after hematopoietic stem cell transplantation, whereas CSWS is rarely reported. We report 3 patients with childhood acute leukemia who developed CSWS with central nervous system complication after hematopoietic stem cell transplantation. The diagnosis of CSW was made on the basis of severe hyponatremia accompanied by increased urine output with clinical signs of dehydration. All patients showed elevated natriuretic peptide and normal antidiuretic hormone. Aggressive water and sodium replacement treatment was instituted in all 3 patients and 2 of them were effectively recovered, the other one was required to add fludrocortisone administration.

  3. Autologous stem-cell transplantation in Hodgkin’s lymphoma: analysis of a therapeutic option

    Directory of Open Access Journals (Sweden)

    Adriano de Moraes Arantes

    2011-06-01

    Full Text Available Objective: To report the clinical progress of patients with Hodgkin’slymphoma treated with autologous transplantation after failure orrelapse of first-line treatment with chemotherapy and/or radiationtherapy. Methods: The results of a retrospective analysis of 31patients submitted to autologous transplantation as second-linetreatment, between April 2000 and December 2008, were analyzed.Fourteen men and seventeen women, with a median age of 27 years,were submitted to autologous transplantation for relapsed (n = 21or refractory (n = 10 Hodgkin’s lymphoma. Results: Mortalityrelated to treatment in the first 100 days after transplant was 3.2%.With a mean follow-up period of 18 months (range: 1 to 88 months,the probability of global survival and progression-free survival in18 months was 84 and 80%, respectively. The probability of globalsurvival and progression-free survival at 18 months for patients withchemosensitive relapses (n = 21 was 95 and 90%, respectively,versus 60 and 45% for patients with relapses resistant to chemotherapy(n = 10 (p = 0.001 for global survival; p = 0.003 for progressionfreesurvival. In the multivariate analysis, absence of disease or pretransplant disease < 5 cm were favorable factors for global survival (p= 0.02; RR: 0.072; 95%CI: 0.01-0.85 and progression-free survival (p= 0.01; RR: 0.040; 95%CI: 0.007-0.78. Conclusion: Autologous transplantation of stem-cells is a therapeutic option for Hodgkin’s lymphoma patients after the first relapse. Promising results were observed in patients with a low tumor burden at transplant.

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

    Directory of Open Access Journals (Sweden)

    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

  5. Notch and Wnt signaling in the emergence of hematopoietic stem cells

    DEFF Research Database (Denmark)

    Bigas, Anna; Guiu, Jordi; Gama-Norton, Leonor

    2013-01-01

    Hematopoietic stem cells (HSC), which reside in the marrow of adult mammals and sustain hematopoiesis for the lifetime of the organism, are specified and generated during embryonic development. We are just beginning to understand how HSC develop from more primitive cells and the complexity of the...... of the signaling pathways involved. In this work, we review the role of two crucial pathways, Notch and Wnt, in the specification and development of HSC and their nascent microenvironment, the arterial vessels....

  6. Topical Cidofovir for Recalcitrant Verrucae in Individuals with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation.

    Science.gov (United States)

    Henrickson, Sarah E; Treat, James R

    2017-01-01

    Verrucae vulgaris in patients with severe combined immunodeficiency (SCID) after hematopoietic stem cell transplantation (HCST) can be challenging to manage. We describe two brothers with X-linked SCID who had severe, persistent verrucae that did not respond to traditional topical therapies, including liquid nitrogen, imiquimod, salicylic acid, sinecatechins, 40% urea, and 5-fluorourcil. Both brothers had full response to topical 3% cidofovir, which should be considered in recalcitrant warts in individuals with SCID after HSCT. © 2016 Wiley Periodicals, Inc.

  7. Difficulties in the revaccination program of hematopoietic stem cell transplantation recipients

    OpenAIRE

    da Silva, Paula Moreira; da Silva, Élen Monteiro; Simioni, Anderson João; de Souza, Mair Pedro; Colturato, Vergílio Antonio Rensi; Machado, Clarisse Martins

    2017-01-01

    ABSTRACT Hematopoietic stem cell transplant (HSCT) recipients should be routinely revaccinated after transplantation. We evaluated the difficulties met in the revaccination program and how a prospective and tailored follow-up could help to overcome these obstacles. HSCT recipients (n=122) were prospectively followed up and categorized into Group 1 (n=72), recipients who had already started the revaccination program, and Group 2 (n=50), recipients starting their vaccines. Whenever a difficulty...

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

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    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.

  9. [Biological characteristics of mesenchymal stem cell and hematopoietic stem cell in the co-culture system].

    Science.gov (United States)

    Wei, Wei; Xu, Chao; Ye, Zhi-Yong; Huang, Xiao-Jun; Yuan, Jia-En; Ma, Tian-Bao; Lin, Han-Biao; Chen, Xiu-Qiong

    2016-10-25

    The aim of the present study was to obtain the qualified hematopoietic stem/progenitor cells (HSC/HPC) and human umbilical cord-mesenchymal stem cells (MSC) in vitro in the co-culture system. Cord blood mononuclear cells were separated from umbilical cord blood by Ficoll lymphocyte separation medium, and then CD34 + HSC was collected by MACS immunomagnetic beads. The selected CD34 + HSC/HPC and MSC were transferred into culture flask. IMDM culture medium with 15% AB-type cord plasma supplemented with interleukin-3 (IL-3), IL-6, thrombopoietin (TPO), stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand (Flt-3L) factors were used as the co-culture system for the amplification of HSC/HPC and MSC. The cellular growth status and proliferation on day 6 and 10 after co-culture were observed by using inverted microscope. The percentage of positive expression of CD34 in HSC/HPC, as well as the percentages of positive expressions of CD105, CD90, CD73, CD45, CD34 and HLA-DR in the 4 th generation MSC, was tested by flow cytometry. Semisolid colony culture was used to test the HSC/HPC colony forming ability. The osteogenic, chondrogenesis and adipogenic ability of the 4 th generation MSC were assessed. The karyotype analysis of MSC was conducted by colchicines. The results demonstrated that the HSC/HPC of co-culture group showed higher ability of amplification, CFU-GM and higher CD34 + percentage compared with the control group. The co-cultured MSC maintained the ability to differentiate into bone cells, fat cells and chondrocytes. And the karyotype stability of MSC remained normal. These results reveal that the appropriate co-culture system for MSC and HSC is developed, and via this co-culture system we could gain both two kinds of these cells. The MSCs under the co-culture system maintain the biological characteristics. The CFU-GM ability, cell counting and the flow cytometry results of HSC/HPC under the co-culture system are conform to the criterion, showing that

  10. Pulmonary candidiasis after hematopoietic stem cell transplantation: thin-section CT findings.

    Science.gov (United States)

    Franquet, Tomás; Müller, Nestor L; Lee, Kyung S; Oikonomou, Anastasia; Flint, Julia D

    2005-07-01

    To retrospectively evaluate thin-section computed tomographic (CT) findings in hematopoietic stem cell transplant (ie, bone marrow transplant) patients with histopathologically proved pulmonary candidiasis. Ethical approval was obtained from the institutional review board of each of the three institutions; informed consent was not required. The study included 17 hematopoietic stem cell transplant recipients with proved pulmonary candidiasis. Histopathologic specimens were acquired at transbronchial biopsy (n = 8), open lung biopsy (n = 6), and autopsy (n = 3). The patients included seven men and 10 women (age range, 20-62 years; mean age, 37 years). The thin-section CT scans were retrospectively reviewed by two thoracic radiologists for the presence, appearance, and distribution of parenchymal abnormalities. Multiple nodules were present in 15 (88%) patients, including centrilobular nodules and tree-in-bud pattern in seven (41%) patients. Nodules were bilateral in 12 patients and unilateral in three. An associated halo of ground-glass opacity was identified in five (33%) patients. Nodules were the only CT finding in five patients (29%). Areas of air-space consolidation were identified in 11 (65%) patients. Areas of ground-glass opacity were seen in six (35%) of 17 patients and were always associated with other abnormalities. Other less common CT findings included pleural effusion (n = 3), thickening of the bronchial walls (n = 2), and cavitation (n = 1). The most common thin-section CT findings of pulmonary candidiasis in hematopoietic stem cell transplant patients are multiple bilateral nodular opacities often associated with areas of consolidation. Copyright RSNA, 2005

  11. 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 (Grb10 m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10 +/+ mice. After total body irradiation (TBI), Grb10 m/+ 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.

  12. Nutraceutical augmentation of circulating endothelial progenitor cells and hematopoietic stem cells in human subjects

    Directory of Open Access Journals (Sweden)

    Minev Boris

    2010-04-01

    Full Text Available Abstract The medical significance of circulating endothelial or hematopoietic progenitors is becoming increasing recognized. While therapeutic augmentation of circulating progenitor cells using G-CSF has resulted in promising preclinical and early clinical data for several degenerative conditions, this approach is limited by cost and inability to perform chronic administration. Stem-Kine is a food supplement that was previously reported to augment circulating EPC in a pilot study. Here we report a trial in 18 healthy volunteers administered Stem-Kine twice daily for a 2 week period. Significant increases in circulating CD133 and CD34 cells were observed at days 1, 2, 7, and 14 subsequent to initiation of administration, which correlated with increased hematopoietic progenitors as detected by the HALO assay. Augmentation of EPC numbers in circulation was detected by KDR-1/CD34 staining and colony forming assays. These data suggest Stem-Kine supplementation may be useful as a stimulator of reparative processes associated with mobilization of hematopoietic and endothelial progenitors.

  13. Long-term hematopoietic stem cell damage after external irradiation with X rays

    International Nuclear Information System (INIS)

    Grande, M.T.; Varas, F.; Bueren, J.A.

    1997-01-01

    We have investigated the functionality of the lympho-hematopoietic stem cells long-term (9 months) after the irradiation (X rays) of mice at different stages of development, by means of a competitive bone marrow repopulation assay. Our data revealed that a dose of 1 Gy was only capable of inducing significant long-term failures in the functionality of the primitive repopulating cells in mice irradiated at the young-adult stage (12 week-old), but not in mice irradiated at the late stages of foetus development (17 day-old fetuses) nor at the early development of the embryo (4 day-old embryos). The differential generation of long-term stem cell defects as a function of the age was confirmed in mice irradiated with 3 Gy. While no significant effects in the long-term repopulating cells were observed in 4 day-old embryos, significant repopulation deficiencies were observed in this population when mice were irradiated at the 17 day of foetus development, and more markedly at the adult stage of growth. These data offer new evidence about the influence of the developmental stage of the animal on the generation of residual hematopoietic dysfunctions by external irradiation, with particular relevance to the very primitive lympho-hematopoietic stem cells. (author)

  14. 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.......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....... Constitutive genetic deletion of Jarid1b did not impact steady-state hematopoiesis. In contrast, acute deletion of Jarid1b from bone marrow increased peripheral blood T cells and, following secondary transplantation, resulted in loss of bone marrow reconstitution. Our results reveal that deletion of Jarid1b...

  15. Todralazine protects zebra fish from lethal doses of ionizing radiation: role of hematopoietic stem cell expansion

    International Nuclear Information System (INIS)

    Dimri, Manali; Joshi, Jaidev; Indracanti, Prem Kumar

    2013-01-01

    Radiation induced cell killing and hematopoietic stem cell depletion leads to compromised immune functions and opportunistic infections which significantly affect the recovery and survival upon irradiation. Any agent which can expand residual hematopoietic stem cells in irradiated organism can render protection from the effects of lethal doses of ionizing radiation. Johns Hopkins Clinical compound library (JHCCL) was screened for protection against lethal doses of ionizing radiation using developing zebra fish as a model organism. Modulation of radiation induced reactive oxygen species by the small molecules were done by DCFDA staining and for visual identification and quantification of apoptosis acridine orange assay, flow cytometry were employed respectively. Hematopoietic stem cell expansion potential was assessed by quantifying runx1 expression, a marker for definitive stem cells, were done by RT-PCR and by the kinetics of recovery from chemically induced anaemia. Todralazine hydrochloride from JHCCL exhibited promising results with potential anti radiation effects. A dose of 5μM was found to be the most effective and has rendered significant organ and whole body protection (100% survival advantage over a period of 6 days) against 20 Gy. However todralazine did not modulated radiation induced free radicals (monitored within 2 h of irradiation) and apoptosis in zebra fish embryos analysed at 8 and 24h post irradiation. Flow cytometric quantification of pre G1 population suggested the same. Chemoinformatics approaches were further carried out to elucidate possible targets which are contributing to its radioprotection potential. Structural similarity search suggested several targets and possible hematopoietic stem cell expanding potential. Treatment of zebra fish embryos with todralazine has lead to significant proliferation of hematopoietic stem cell as indicated by increase in expression of runx1. HSC expanding potential of todralazine was further supported by

  16. Cost-effectiveness of hematopoietic stem cell mobilization strategies including plerixafor in multiple myeloma and lymphoma patients.

    Science.gov (United States)

    Tichopád, Aleš; Vítová, Veronika; Kořístek, Zdeněk; Lysák, Daniel

    2013-12-01

    Peripheral blood stem cells (PBSCs) are preferred source of hematopoietic stem cells for autologous transplantation. Mobilization of PBSCs using chemotherapy and/or granulocyte colony-stimulating factor (G-CSF) however fails in around 20%. Combining G-CSF with plerixafor increases the mobilizations success. We compared cost-effectiveness of following schemes: the use of plerixafor "on demand" (POD) during the first mobilization in all patients with inadequate response, the remobilization with plerixafor following failure of the first standard mobilization (SSP), and the standard (re)mobilization scheme without plerixafor (SSNP). Decision tree models populated with data from a first-of-a-kind patient registry in six Czech centers (n = 93) were built to compare clinical benefits and direct costs from the payer's perspective. The success rates and costs for POD, SSP and SSNP mobilizations were; 94.9%, $7,197; 94.7%, $8,049; 84.7%, $5,991, respectively. The direct cost per successfully treated patient was $7,586, $8,501, and $7,077, respectively. The cost of re-mobilization of a poor mobilizer was $5,808 with G-CSF only and $16,755 if plerixafor was added. The total cost of plerixafor "on-demand" in the sub-cohort of poor mobilizers was $17,120. Generally, plerixafor improves the mobilization success by 10% and allows an additional patient to be successfully mobilized for incremental $11,803. Plerixafor is better and cheaper if used "on demand" than within a subsequent remobilization. Copyright © 2013 Wiley Periodicals, Inc.

  17. Cost analysis and quality of life assessment comparing patients undergoing autologous peripheral blood stem cell transplantation or autologous bone marrow transplantation for refractory or relapsed non-Hodgkin's lymphoma or Hodgkin's disease : a prospective randomised trial

    NARCIS (Netherlands)

    van Agthoven, M; Vellenga, E; Fibbe, WE; Kingma, T; Uyl-de Groot, CA

    The cost-effectiveness of autologous peripheral blood stem cell transplantation (PBSCT) compared with autologous bone marrow transplantation (ABMT) for refractory or relapsed non-Hodgkin's lymphoma (NHL) or Morbus Hodgkin (MH) was assessed. Costs were determined from the induction chemotherapy

  18. 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

  19. Human autologous mesenchymal stem cells with extracorporeal shock wave therapy for nonunion of long bones.

    Science.gov (United States)

    Zhai, Lei; Ma, Xin-Long; Jiang, Chuan; Zhang, Bo; Liu, Shui-Tao; Xing, Geng-Yan

    2016-09-01

    Currently, the available treatments for long bone nonunion (LBN) are removing of focus of infection, bone marrow transplantation as well as Ilizarov methods etc. Due to a high percentage of failures, the treatments are complex and debated. To develop an effective method for the treatment of LBN, we explored the use of human autologous bone mesenchymal stems cells (hBMSCs) along with extracorporeal shock wave therapy (ESWT). Sixty three patients of LBN were subjected to ESWT treatment and were divided into hBMSCs transplantation group (Group A, 32 cases) and simple ESWT treatment group (Group B, 31 cases). The patients were evaluated for 12 months after treatment. In Group A, 14 patients were healed and 13 showed an improvement, with fracture healing rate 84.4%. In Group B, eight patients were healed and 13 showed an improvement, with fracture healing rate 67.7%. The healing rates of the two groups exhibited a significant difference ( P 0.05). However, the callus formation in Group A was significantly higher than that in the Group B after treatment for 6, 9, and 12 months ( P Autologous bone mesenchymal stems cell transplantation with ESWT can effectively promote the healing of long bone nonunions.

  20. Autologous Stem Cell Injection for Spinal Cord Injury - A Clinical Study from India.

    Directory of Open Access Journals (Sweden)

    Ravikumar R

    2007-01-01

    Full Text Available We studied 100 patients with Spinal Cord injury (SCI after Autologous Stem cell Injection in the Spinal fluid with a Follow up of 6 months post Stem cell injection. There were 69 males and 31 females; age ranging from 8 years to 55 years.? Time after Spinal Injury ranged from 11 years - 3 months (Average: 4.5 years. The Level of Injury ranged from Upper Thoracic (T1-T7 - 34 pts, Lower thoracic (T7-T12 -45 pts, Lumbar -12, Cervical-9 pts. All patients had an MRI Scan, urodynamic study and SSEP (somatosensory Evoked Potential tests before and 3 months after Stem cell Injection.80% of patients had Grade 0 power in the Lower limbs and rest had grade 1-2 power before stem cell injections. 70% of cases had complete lack of Bladder control and 95% had reduced detrusor function.We Extracted CD34 and CD 133 marked Stem cells from 100 ml of Bone marrow Aspirate using Ficoll Gradient method with Cell counting done using flowcytometry.15 ml of the Stem cell concentrate was injected into the Lumbar spinal fluid in aseptic conditions. The CD 34/CD45 counts ranged from 120-400 million cells in the total volume.6 months after Injection, 8 patients had more than 2 grades of Motor power improvement, 3 are able to walk with support. 1 patient with T12/L1 injury was able to walk without support. 12 had sensory tactile and Pain perception improvement and 8 had objective improvement in bladder control and Bladder Muscle contractility. A total of 18 patients had reported or observed improvement in Neurological status. 85% of patients who had motor Improvement had Lesions below T8. MRI, SSEP and Urodynamic Study data are gathered at regular intervals. Conclusion: This study shows that Quantitative and qualitative Improvement in the Neurological status of paralyzed patients after Spinal cord injury is possible after autologous bone marrow Stem cell Injections in select patients. There was no report of Allodynia indicating the safety of the procedure. Further studies to