scholarly journals Safety and feasibility of hematopoietic progenitor stem cell collection by mobilization with plerixafor followed by apheresis vs bone marrow harvest in patients with sickle cell disease in the multi‐center HGB ‐206 trial

2020 ◽  
Vol 95 (9) ◽  
Author(s):  
John F. Tisdale ◽  
Francis J. Pierciey ◽  
Melissa Bonner ◽  
Alexis A. Thompson ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Progenitor ◽  
Stem Cell Collection

scholarly journals Hematopoietic Stem Cell Function in a Murine Model of Sickle Cell Disease

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Elisabeth H. Javazon ◽  
Mohamed Radhi ◽  
Bagirath Gangadharan ◽  
Jennifer Perry ◽  
David R. Archer
Keyword(s):  
Cell Cycle ◽  
Lipid Peroxidation ◽  
Bone Marrow ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Cell Disease ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem

Previous studies have shown that the sickle environment is highly enriched for reactive oxygen species (ROS). We examined the oxidative effects of sickle cell disease on hematopoietic stem cell function in a sickle mouse model.In vitrocolony-forming assays showed a significant decrease in progenitor colony formation derived from sickle compared to control bone marrow (BM). Sickle BM possessed a significant decrease in the KSL (c-kit+, Sca-1+, Lineage−) progenitor population, and cell cycle analysis showed that there were fewer KSL cells in the G0phase of the cell cycle compared to controls. We found a significant increase in both lipid peroxidation and ROS in sickle-derived KSL cells.In vivoanalysis demonstrated that normal bone marrow cells engraft with increased frequency into sickle mice compared to control mice. Hematopoietic progenitor cells derived from sickle mice, however, demonstrated significant impairment in engraftment potential. We observed partial restoration of engraftment by n-acetyl cysteine (NAC) treatment of KSL cells prior to transplantation. Increased intracellular ROS and lipid peroxidation combined with improvement in engraftment following NAC treatment suggests that an altered redox environment in sickle mice affects hematopoietic progenitor and stem cell function.

Effects of Sickle Cell Disease on Hematopoietic Stem Cell Function and the Bone Marrow Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1227-1227
Author(s):  
Elisabeth H. Javazon ◽  
Leslie S. Kean ◽  
Jennifer Perry ◽  
Jessica Butler ◽  
David R. Archer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Function ◽  
Donor Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Cell Engraftment

Abstract Gene therapy and stem cell transplantation are attractive potential therapies for sickle cell disease (SCD). Previous studies have shown that the sickle environment is highly enriched for reactive oxygen species (ROS), but have not addressed whether or not the increased ROS may alter the bone marrow (BM) microenvironment or affect stem cell function. Using the Berkeley sickle mouse model, we examined the effects of sickle cell disease on hematopoietic stem cell function and the bone marrow microenvironment. We transplanted C57BL/6 (control) BM into C57BL/6 and homozygous sickle mice. Recipients received 2 × 106 BM cells and a conditioning regimen consisting of busulfan, anti-asialo GM1, and co-stimulation blockade (anti-CD40L and CTLA4-Ig). Following transplantation, sickle mice demonstrated increased donor cell engraftment in the peripheral blood compared to normal mice (58.3% vs. 33.1%, respectively). Similarly, BMT in a fully allogeneic system also resulted in enhanced engraftment in sickle recipients. Next we analyzed whether or not engraftment defects exist within the BM stem cell population of sickle mice. In vitro colony forming assays showed a significant decrease in progenitor colony formation in sickle compared to control BM. By flow cytometry, we determined that there was a significant decrease in the KSL (c-Kit+, Sca-1+, Lineage−) progenitor population within the BM of sickle mice. Cell cycle analysis of the KSL population demonstrated that significantly fewer sickle KSL cells were in G0 phase compared to control, suggesting that there are fewer quiescent stem cells in the BM of sickle mice. To assess the potential role of ROS and glutathione depletion in sickle mice, we tested the engraftment efficiency of KSL cells from untreated and n-acetyl-cysteine (NAC) treated control, hemizygous sickle (hemi), and sickle mice in a competitive repopulation experiment. Peripheral chimerism showed an engraftment defect from both hemizygous and homozygous sickle mice such that control KSL cells engrafted > hemi > sickle at a ratio of 1 : 0.4 : 0.25. Treatment with NAC for four months prior to transplantation partially restored KSL engraftment (control : hemi : sickle; 1 : 0.97 : 0.56 ). We have demonstrated that congenic and allogeneic BMT into sickle mice result in increased donor cell engraftment in the sickle recipients. Both the decreased number of KSL cells and the decreased percentage of quiescent KSL cells in the sickle mice indicate that more stem cells in the transgenic sickle mouse model are mobilized from the BM environment. The engraftment defect of sickle KSL cells that was partially ameliorated by NAC treatment suggests that an altered redox environment in sickle mice may contribute to the engraftment deficiencies that we observed.

Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Childhood: A Single Center Experience with 45 Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3103-3103 ◽  
Author(s):  
Laurence Dedeken ◽  
Phu-Quoc Le ◽  
Nadira Azzi ◽  
Cecile Brachet ◽  
Catherine Heijmans ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cord Blood ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Stem

Abstract Abstract 3103 Despite improvement in medical management, sickle cell disease (SCD) is still associated with high risk of morbidity, chronic disability and early death. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative approach. Since November 1988, 45 patients (median age: 8.3 years; range: 1.7–15.3 years) with severe SCD underwent related HSCT in our unit. Thirty-five received bone marrow transplant, 3 cord blood, 6 bone marrow and cord blood and 1 peripheral blood stem cells. Two donors result from preimplantation genetic diagnosis with HLA selection. All were HLA-identical sibling except one who had one class II mismatch. All had one or more severe manifestations: 24 patients presented more than 2 vaso-occlusive crises per year, 11 recurrent acute chest syndrome, 19 cerebral vasculopathy and 4 erythroid alloimmunisation. Conditioning regimen consisted of the standard combination of busulfan, cyclophosphamide and from November 1991 antithymocyte globulins (ATG) were added: ATG Fresenius first and from July 2000 ATG Merieux. Since 1995 all patients were treated with hydroxyurea (HU) prior to transplantation for a median duration of 2.7 years (range: 0.8–10.7 years). Acute graft versus host disease (GVHD) was observed in 11 patients (3 grade III and 2 grade IV). Ten patients were treated for CMV reactivation and 4 for EBV reactivation. Only one patient had presented a probable invasive fungal disease. After median follow-up of 6.5 years, 10 patients had presented chronic GVHD, none was extensive. Only one required therapy beyond 2 years from transplant. Engraftment was successful in 42/45. One rejection occurred 15 months after transplantation. Since HU introduction before transplant (1995), no graft failure occurred. Important mixed chimerism is present in 2 patients (AA donor) who remain free of any sickle cell disease symptoms. Two deaths occurred: 1 unexplained death 6 years after HSCT in a child free of any treatment and 1 cerebral hemorrhage 18 days after transplant in a child with severe cerebral vasculopathy. Growth was normal after transplant. As expected, gonadal function was impaired in the majority of girls. However 3 girls had spontaneous normal puberty and one had two spontaneous pregnancies with normal outcome. Our results are very encouraging showing excellent outcomes. Both the overall survival (OS: 95.6%) and the event-free survival (EFS: 86.7%) are comparable to the other published studies, ranging from 93 to 97%, and 82 to 86 % respectively. Since 1995, all the 33 patients engrafted successfully. Previous treatment with HU may have contributed to successful engraftment. After 5.3 years of follow-up, their OS and EFS are both at 96.9%. The difference in outcome before and after 1995 is strongly significant for EFS (58.3% vs 96.9%, p=0.003). Severe cerebral vasculopathy with its risk of CNS hemorrhage remains a true challenge. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Safe and efficient peripheral blood stem cell collection in patients with sickle cell disease using plerixafor

Haematologica ◽  
2020 ◽  
Vol 105 (10) ◽  
pp. e497 ◽  
Author(s):  
Naoya Uchida ◽  
Alexis Leonard ◽  
David Stroncek ◽  
Sandhya R. Panch ◽  
Kamille West ◽  
...  
Keyword(s):  
Stem Cell ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cell ◽  
Blood Stem Cell ◽  
Cell Disease ◽  
Stem Cell Collection

scholarly journals Bone Marrow as a Hematopoietic Stem Cell Source for Gene Therapy in Sickle Cell Disease: Evidence from Rhesus and SCD Patients

2017 ◽  
Vol 28 (3) ◽  
pp. 136-144 ◽  
Author(s):  
Naoya Uchida ◽  
Atsushi Fujita ◽  
Matthew M. Hsieh ◽  
Aylin C. Bonifacino ◽  
Allen E. Krouse ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Cell Disease ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Cell Source

Murine bone marrow mesenchymal stromal cells have reduced hematopoietic maintenance ability in sickle cell disease

Blood ◽  
2021 ◽  
Author(s):  
Alice Tang ◽  
Ana Nicolle Strat ◽  
Mahmudur Rahman ◽  
Helen Zhang ◽  
Weili Bao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Tissue Injury ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle Cell Disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contributes to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease but their functionality in SCD remains unclear. We identified for the first time murine SCD MSCs to have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis. Murine SCD MSCs had lower HSC maintenance ability in vitro and in vivo as manifested by increased HSC mobilization and decreased HSC engraftment following transplant. Activation of TLR4 through p65 in MSCs further contributed to MSC dysfunction. Transfusions led to improved MSC and HSC oxidative state in SCD mice. Improving the regulation between MSCs and HSCs has vital implications for enhancing clinical HSC transplantation and gene therapy outcomes and for identification of new molecular targets for alleviating SCD complications.

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