scholarly journals Long-Term Effect of Mesenchymal Stromal Cell Derived Extracellular Vesicles on the Restoration of Engraftment of Stem Cells in Radiation Exposed Mice

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5102-5102
Author(s):  
Sicheng Wen ◽  
Laura R Goldberg ◽  
Mark S Dooner ◽  
Mandy Pereira ◽  
Michael Del Tatto ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Extracellular Vesicles ◽  
Term Effect ◽  
Post Transplantation ◽  
Post Transplant ◽  
Cell Engraftment ◽  
Long Term Effect

Abstract Extracellular vesicles (EVs) including exosomes and microvesicles, have been found to deliver both mRNA and transcriptional modulators to target cells and affect their phenotype. Vesicles derived from mesenchymal stem cells (MSC) have been shown to affect the phenotype and induce healing of many different cell types. Our recent published work has shown that pretreated irradiated murine bone marrow stem cells with human or murine MSC-EV in vitro, could significantly improve the engraftment capacity of radiation-damaged stem cells up to 9 months post-transplantation. Interestingly, the restoration of engraftment was not significantly observed within the first month of post-transplant, the predominant reversal effect occurred on later period of post-transplant from 3 months up to 9 months. This is indicating a long-term effect of MSC-EVs on reversal of radiation damage of stem cell engraftment capacity. To confirm this hypothesis, in our current study, the effect of human MSC-EVs on reversal of engraftment capacity of bone marrow stem cells post-radiation was investigated by an in vivo study. C57BL/6 mice were exposed to 500 cGy total body irradiation. MSC-EVs or vehicle were then injected intravenously 24, 48 and 72 hours after irradiation. The whole bone marrow were harvested at 6, 12, 26 and 53 weeks post EV-injection and then transplanted into 950 cGy exposed B6.SJL mice and engraftment evaluated at 1 and 3 months post-transplantation. In those transplanted mice at 6 weeks post-EV injection, there was slight increase in the restoration of engraftment rate (the percent of irradiated mice with EV/Vehicle treatment engraftment rate compared to healthy non-irradiated mice engraftment rate) in EV treated mice (17.58±2.32% compared to untreated mice (13.80±1.41%) after 1 month post-transplantation. However, for those mice transplanted at 12, 26, and 53 weeks post-EV injection, there were the significant higher restorations of engraftment rate in EV treated mice (40.48±6.03%, 33.93±3.76%, and 56.62±3.635) compared to untreated mice (12.39±1.30%, 15.14±2.21%, 36.21±3.63%) after 1 month transplantation respectively. The similar restorations of engraftment were also seen in 3 months post-transplantation. Our study also showed that there was a significant inhibition of stem cell engraftment at 53 weeks post 500cGy whole body radiation mice which was 36.21±3.63% of engraftment rate from healthy mice. Thus our data suggest that there is a long-term effect of MSC-EVs on the restoration of engraftment of stem cells in radiation-exposed mice. Disclosures No relevant conflicts of interest to declare.

Growth factor treatment prior to low-dose total body irradiation increases donor cell engraftment after bone marrow transplantation in mice

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 312-317 ◽  
Author(s):  
Estelle J. K. Noach ◽  
Albertina Ausema ◽  
Jan H. Dillingh ◽  
Bert Dontje ◽  
Ellen Weersing ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factors ◽  
Low Dose ◽  
Donor Cell ◽  
Hematopoietic Growth Factors ◽  
Cell Engraftment ◽  
Total Body

Abstract Low-toxicity conditioning regimens prior to bone marrow transplantation (BMT) are widely explored. We developed a new protocol using hematopoietic growth factors prior to low-dose total body irradiation (TBI) in recipients of autologous transplants to establish high levels of long-term donor cell engraftment. We hypothesized that treatment of recipient mice with growth factors would selectively deplete stem cells, resulting in successful long-term donor cell engraftment after transplantation. Recipient mice were treated for 1 or 7 days with growth factors (stem cell factor [SCF] plus interleukin 11 [IL-11], SCF plus Flt-3 ligand [FL], or granulocyte colony-stimulating factor [G-CSF]) prior to low-dose TBI (4 Gy). Donor cell chimerism was measured after transplantation of congenic bone marrow cells. High levels of donor cell engraftment were observed in recipients pretreated for 7 days with SCF plus IL-11 or SCF plus FL. Although 1-day pretreatments with these cytokines initially resulted in reduced donor cell engraftment, a continuous increase in time was observed, finally resulting in highly significantly increased levels of donor cell contribution. In contrast, G-CSF treatment showed no beneficial effects on long-term engraftment. In vitro stem cell assays demonstrated the effect of cytokine treatment on stem cell numbers. Donor cell engraftment and number of remaining recipient stem cells after TBI were strongly inversely correlated, except for groups treated for 1 day with SCF plus IL-11 or SCF plus FL. We conclude that long-term donor cell engraftment can be strongly augmented by treatment of recipient mice prior to low-dose TBI with hematopoietic growth factors that act on primitive cells.

scholarly journals Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment

Blood ◽  
2018 ◽  
Vol 132 (7) ◽  
pp. 735-749 ◽  
Author(s):  
Simranpreet Kaur ◽  
Liza J. Raggatt ◽  
Susan M. Millard ◽  
Andy C. Wu ◽  
Lena Batoon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Key Points ◽  
Bone Marrow Engraftment

Key Points Recipient macrophages persist in hematopoietic tissues and self-repopulate via in situ proliferation after syngeneic transplantation. Targeted depletion of recipient CD169+ macrophages after transplant impaired long-term bone marrow engraftment of hematopoietic stem cells.

Autologous Stem Cell Transplantation (ABMT) for Recurrent Hodgkin’s Disease from 1990–2005: Factors Contributing to Post-Transplant Relapse.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2083-2083
Author(s):  
Brian Bolwell ◽  
Brad Pohlman ◽  
Matt Kalaycio ◽  
Steve Andresen ◽  
Elizabeth Kuczkowski ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Prior Chemotherapy ◽  
Post Transplant ◽  
Peripheral Stem Cells

Abstract Long-term results of conventional therapy of Hodgkin’s disease (HD) has demonstrated the importance of long-term and ongoing follow-up given the potential for later complications after curative therapy. While many transplant series report follow-up of several years after ABMT, few report a 15-year experience from a single institution. This report examines the outcomes of 220 patients receiving high-dose chemotherapy and autologous stem cell transplant (ABMT) at The Cleveland Clinic Foundation from January 1990 through June 2005. Median age was 33 years (range, 14–70 years); median time from diagnosis to transplant was 19 months; 47% received prior radiation therapy; 82% had nodular sclerosis histologic subtype; number of courses of prior chemotherapy were: 1 (16%), 2 (66%), 3 (14%), 4 or more (4%). All patients received salvage therapy prior to transplant: 29% were in a complete remission (CR), 55% in a partial remission (PR), and 16% refractory. All patients received a chemotherapy-only preparative regimen, most commonly Bu/Cy/VP (73%), followed by CBV (17%). 78% received peripheral stem cells alone; 22% received either autologous bone marrow or a combination of bone marrow plus peripheral stem cells. At the present time 60% of patients are alive. Of the 88 patients who died, the most common cause of death is relapse (69% of deaths). Secondary malignancy occurred in 11 patients (5%); 9 of these cases were secondary AML/MDS and 5 of these patients with secondary malignancies have died. 44% of the entire cohort has relapsed, at a median of 9 months post-transplant (range, 1.4–76 months). 10-year overall survival is 47%. A multivariable analysis showed that the two significant variables that correlated with post-BMT relapse were the number of prior chemotherapies (p = 0.011), and patients treated in remission vs. those not in remission (p = 0.002). Of patients receiving 2 or more prior courses of chemotherapy, 60% have relapsed 8 years post-transplant, compared to 40% of those receiving one course of prior chemotherapy. The risk of relapse by the number of prior chemotherapy courses is shown graphically below: Figure Figure In conclusion, this very large series of ABMT for recurrent HD with long-term follow-up demonstrates the importance of timely autografting in relapsed HD patients. The optimal time to proceed with ABMT is after failing one, and only one, course of chemotherapy. Delaying transplant for unrealistic long-term salvage with other courses of traditional chemotherapy will negatively affect the outcome of subsequent ABMT.

Loss of P-Selectin Promotes the Function of Aged Hematopoietic and Leukemic Stem Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1577-1577
Author(s):  
Yaoyu Chen ◽  
Sullivan Con ◽  
Yiguo Hu ◽  
Linghong Kong ◽  
Cong Peng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Bone Marrow Cells ◽  
Leukemic Stem Cells ◽  
Wild Type ◽  
Post Transplant ◽  
Marrow Cells

Abstract Abstract 1577 Hematopoiesis is a tightly regulated biological process that relies upon complicated interactions between the blood cells and their microenvironment. Adhesion molecules like P-selectin are essential to hematopoiesis, and their dysregulation has been implicated in leukemogenesis. We have previously shown a role for P-selectin in chronic myeloid leukemia and demonstrated that in its absence the disease process accelerates. Recently, there has also been speculation that P-selectin may play a role in the aging hematopoietic stem cells (HSCs), as its expression in upregulated as a mouse ages. In this study, we show that the loss of P-selectin function dysregulates the balance of stem cells and progenitors and that these differences become more pronounced with age. We compared the percentages of HSCs, long-term (LT)-HSCs, short-term (ST)-HSCs, multipotent progenitors (MPPs), CMPs, GMPs and MEPs in bone marrow by flow cytometry between wild type (WT) and Selp-/- mice. An age-dependent LT-HSC expansion was observed in WT mice. However, this expansion was prevented by the loss of Selp as observed in Selp-/-mice. Further, we demonstrate that with age LT-HSCs in particular express more elevated levels of P-selectin. LT-HSCs and ST-HSC/MPPs were isolated from the bone marrow of young (2 months old) and old (15 months old) WT mice and examined P-selectin expression by FACS. A significant increase in P-selectin expression was observed in LT-HSCs of old mice, and this increase was not observed in the ST-HSC+MPP subpopulations. We also show that the loss of P-selectin gene has profound effects of stem cell function, altering the capacity of these cells to home. Despite impaired homing capacity, stem cells lacking P-selectin possess a competitive advantage over their wild type counterparts. Using a stem cell competition assay, HSCs derived from Selp-/- mice (CD45.2+) and WT control mice (CD45.2+GFP+) were mixed in 1:1 ratio and transplanted into irradiated WT recipients (CD45.1). The initial findings were potentially indicative of the ability of cells derived from GFP mice to more efficiently home and engraft. Despite this initial advantage, cells derived from Selp-/- eventually exhibited a competitive and statistically significant advantage over the cells derived from GFP mice. At 30 days post-transplant, 49.9±1.4% of the CD45.2 subpopulation was GFP+. At 86 days post-transplant, 25.7±3.3 % of the CD45.2 cells derived from the peripheral blood were GFP+. Similarly, 23.0±3.7% of the CD45.2 cells derived from the bone marrow of these mice were GFP+. Indeed, we demonstrate that recipients of P-selectin deficient bone marrow cells more efficiently repopulate the bone marrow than controls and that this advantage extends and expands in the long-term. Finally, we demonstrate that recipients of leukemic cells lacking P-selectin develop a more accelerated form of leukemia accompanied by significant increases in stem and progenitor cells. Bone marrow cells from donor WT and Selp-/- mice were infected with retrovirus expressing BCR-ABL-GFP, and irradiated WT recipients were transplanted with 2×105 of these transduced donor cells. At 14 days post-transplant, recipient mice from each of the groups were sacrificed, and bone marrow cells were harvested and analyzed by flow cytometry. Recipients of leukemic Selp-/- cells possessed 3.5-fold more LSCs than recipients of wild-type cells. There were 3.1-fold more LT-LSCs and 3.8-fold more ST-LSCs and MPPs in recipients of Selp-/- cells than WT cells. In addition, recipients of leukemic Selp-/- cells possessed significantly more CMP (16.9-fold) and MEP (4.5-fold) cells. Because P-selectin expression increases with age on LT-HSCs, we sought to determine the role that age plays in CML development and progression. Bone marrow cells derived from 15-month-old donor Selp-/- and WT mice were transduced with BCR-ABL, respectively, followed by transplantation of the transduced cells into recipient mice. All recipients of BCR-ABL transduced Selp-/- cells died by 23 days after induction of CML and had a median survival of 19 days, whereas recipients of the transduced WT cells survived significantly longer. This pro-leukemic role for cells lacking P-selectin expression is leukemic stem cell-specific rather than stromal cell-specific and supports an essential role for P-selectin on leukemic stem cells. Disclosures: No relevant conflicts of interest to declare.

Recipient total bone marrow irradiation has no long-term effect on clonal behavior of transplanted murine hematopoietic stem cells

2014 ◽  
Vol 42 (8) ◽  
pp. S64
Author(s):  
Evgenia Verovskaya ◽  
Ronald van Os ◽  
Taco Koster ◽  
Erik Zwart ◽  
Martha Ritsema ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Term Effect ◽  
Hematopoietic Stem ◽  
Long Term Effect ◽  
Total Bone Marrow

Absence αof 4 Integrin in Hemopoietic Stem Cells Limits Their Self-Renewal Potential in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 118-118
Author(s):  
Thalia Papayannopoulou ◽  
Gregory V. Priestley ◽  
Linda M. Scott
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Self Renewal ◽  
Post Transplant ◽  
Adult Mice ◽  
Cell Niche

Abstract We have previously shown that bone marrow (BM) cells from adult mice with conditional ablation of α4 integrin transplanted into lethally-irradiated recipients have a partial impairment in their homing and especially their short-term engraftment (MCB, 23:9349, 2003). However, the ability of α4−/− stem cells (HSC) to maintain post-transplant long-term hematopoiesis and to self renew was not tested. Therefore, we performed competitive repopulation experiments: α4+/+ cells mixed in equal proportions with α4−/− cells (verified by FACS) were given to each of 10 lethally irradiated recipients (0.5x10 6/mouse). At 30, 100, 200, and 298 days post-transplant, engraftment was evaluated in blood (PB) and BM. By d. 200, 7 of the 9 surviving mice had 81.6±3% α4+/+ cells in their PB and 97.5±0.1% in their BM. In the remaining 2 mice the proportion of α4+/+ PB cells was 35.6±12%, however by d. 298 increased (93.4±2.5% in BM). To overcome a putative partial homing defect for long-term repopulating cells, similar to the one documented using a surrogate CFU-C assay, we repeated the competitive repopulation experiment using not only 1:1, but an increased ratio of α4−/− cells to 3:1 (or 6:1 by CFU-C ratio) given in splenectomized recipients. By 12 wks α4+/+ cells among Gr1+ were 77±3.7% in PB in 10 mice with 1:1 initial transplant and 79±3.8% in 10 given 3:1 cells. These results showed that 4+/+ cells greatly outcompete the α4−/−cells and contributions by α4−/− cells are lost early and late post-transplant. Further insight was provided by transplantation of α4−/− HSC without competitor cells. 12 mice transplanted with α4−/− BM cells were sacrificed at 2 wks (6 mice), at 10 wks (3 mice) and 1 year (3 mice) later. Despite normal PB counts, evaluation of bone marrow and spleen at all times post-transplant showed subnormal values for progenitor cells vs. concurrently transplanted controls. 10 wks post-transplant 1 of the 3 mice sacrificed showed ~50% α4+/+ cells in circulation, while the other 2 had mostly α4−/− cells. From the latter (pooled BM), 2° transplants were carried out and sacrificed 14 wks later. At that time the 5 recipients had 27.5%±4.7 α4+/+ cells in their circulation. At 1 year the 3 primary transplant surviving mice had mostly α4−/− hematapoiesis and served as donors (pooled BM) for 2° transplants (n=9), evaluated 26 wks later. 5 of 9 2° recipients showed mostly α4+/+ cells, whereas 4 recipients had a mean of 6.8±1.9% α4+/+ cells in their blood. Each of these 4 recipients served as a 3° donor for 20 transplants (5/donor) which again were evaluated 25 wks later. There was a 30% survival at that time, and all 6 surviving mice were reconstituted with α4+/+ cells (multi-lineage; contributed by host and not by non-ablated donor stem cells). These data suggested that although long-term repopulation can be established with α4−/− cells in 1°recipients, hematopoiesis is quantitatively abnormal and cannot be sustained beyond a 2° transplant. Taken together, all our transplantation experiments provide compelling evidence that α4−/− HSC have a competitive disadvantage compared to +/+ cells in transplantation, and a deficit in maintaining normal hematopoiesis and stem cell self-renewal. We speculate that α4−/− HSC either are not settled to extramedullary niches supporting sustained hematopoiesis, or do not respond to signals emanating from the stem cell niche. Either way, the data underscore the requirement of α4 integrin in the interaction of HSC with the stem cell niche in order to realize their full self-renewal potential.

scholarly journals Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development

Blood ◽  
2015 ◽  
Vol 125 (17) ◽  
pp. 2678-2688 ◽  
Author(s):  
Marisa Bowers ◽  
Bin Zhang ◽  
Yinwei Ho ◽  
Puneet Agarwal ◽  
Ching-Cheng Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Leukemia Development

Key Points Bone marrow OB ablation leads to reduced quiescence, long-term engraftment, and self-renewal capacity of hematopoietic stem cells. Significantly accelerated leukemia development and reduced survival are seen in transgenic BCR-ABL mice following OB ablation.

NOD-Rag1nullPrf1null Mice Support Long-Term Engraftment of Human Hematopoietic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1184-1184
Author(s):  
Hitoshi Minamiguchi ◽  
Anne G. Livingston ◽  
John R. Wingard ◽  
Leonard D. Shultz ◽  
Makio Ogawa
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Nk Cell ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Human Hscs

Abstract NOD-scid mice have been widely used as recipients in the xenograft assay for human hematopoietic stem cells (HSCs). One major problem with the strain is the low level of engraftment except when large numbers of cells are injected. This is probably caused by the presence of residual natural killer (NK) cell cytotoxic activity. NOD-scid/beta 2 microglobulin (B2m)null mice have been reported to have reduced NK cell cytotoxic activity and support higher levels of human cell engraftment. However, use of this strain of mice is limited by their difficulty in breeding and short life span caused by early development of lymphomas, which is accelerated by irradiation. Another immune-incompetent mouse model, NOD-recombination activating gene (Rag1)null mice allow longer observation of human cell engraftment than NOD-scid mice and are easier to breed. Genetic crossing of perforin (Prf) structure gene-targeted mutation onto NOD-Rag1null strain results in absence of NK cell cytotoxic function. In these mice, NK cells are not capable of killing target cells because of the absence of Prf, the major mediator of cytotoxic activity. We have tested the use of NOD-Rag1nullPrf1null mice as recipients of long-term xenograft assay for human HSCs by adopting Yoder’s method of conditioning newborn mice with minor modifications. Pregnant NOD-Rag1nullPrf1null dams were treated with 22.5mg/kg busulfan in 20% dimethylsulfoxide in Hank’s BSS on day 17.5 and 18.5 pc via subcutaneous injection. On the day of delivery, mononuclear cells (MNCs) were isolated from human cord blood (n=3) by density gradient centrifugation and T cell-depleted MNCs were separated by using mouse anti-human CD3, CD4, and CD8 antibodies and sheep anti-mouse IgG immunomagnetic beads to prevent preferential T cell engraftment. The busulfan-exposed pups were transplanted with 4–5 million T cell-depleted MNCs via the facial vein. At 6 months post-transplantation, human cells were detected in the bone marrow of 4 out of 10 transplanted mice. The levels of human CD45+ cells in the bone marrow of engrafted mice were 79.9, 69.8, 60.5, and 7.4%, and those in the peripheral blood were 6.3, 5.8, 4.1, and 1.3%. Multilineage engraftment was confirmed by phenotypic analysis. Next, we tested the hypothesis that human cord blood HSCs have dye efflux activity by injecting T cell-depleted Rhodamine 123 (Rho)− or + cells into conditioned newborn NOD-Rag1nullPrf1null mice. Six-month engraftment was found only with the Rho− cells. Thus, conditioned newborn NOD-Rag1nullPrf1null mice provide an excellent model for assaying long-term engrafting human HSCs.

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.

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