scholarly journals Decision Analysis of Peripheral Blood versus Bone Marrow Hematopoietic Stem Cells for Allogeneic Hematopoietic Cell Transplantation

2009 ◽  
Vol 15 (11) ◽  
pp. 1415-1421 ◽  
Author(s):  
Joseph Pidala ◽  
Claudio Anasetti ◽  
Mohamed A. Kharfan-Dabaja ◽  
Corey Cutler ◽  
Andy Sheldon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Decision Analysis ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Hematopoietic Stem

scholarly journals Depletion of murine fetal hematopoietic stem cells with c-Kit receptor and CD47 blockade improves neonatal engraftment

2018 ◽  
Vol 2 (24) ◽  
pp. 3602-3607 ◽  
Author(s):  
Russell G. Witt ◽  
Bowen Wang ◽  
Quoc-Hung Nguyen ◽  
Carlo Eikani ◽  
Aras N. Mattis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Hematopoietic Stem ◽  
Kit Receptor ◽  
Key Points ◽  
Immunocompetent Mice

Key Points Fetal injection of antibodies against the c-Kit receptor and CD47 effectively depletes host HSCs in immunocompetent mice. In utero depletion of host HSCs increases long-term engraftment after neonatal hematopoietic cell transplantation.

In Utero Depletion Of Fetal Host Hematopoietic Stem Cells Improves Engraftment Following Neonatal Transplantation In Mice

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3240-3240
Author(s):  
Chris Derderian ◽  
Charmin King ◽  
Priya Togarrati ◽  
Agnieszka Czechowicz ◽  
Ninnia Lescano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Hematopoietic Cell Transplantation ◽  
Mononuclear Cells ◽  
Fetal Liver ◽  
In Utero ◽  
Hematopoietic Stem ◽  
In Utero Transplantation

Abstract Introduction In utero hematopoietic cell transplantation (IUHCTx) is a promising strategy to treat congenital disorders as the fetal host can potentially be tolerized to transplanted cells early in gestation. However, levels of engraftment have been low and fetal host conditioning strategies to increase space in hematopoietic niches have not been widely explored. We hypothesized that depletion of fetal host hematopoietic stem cells (HSC) using an antibody against the c-kit receptor (ACK2), a strategy which selectively depletes HSC by disrupting stem cell factor (SCF) signaling, would improve engraftment after HSC transplantation. Methods Fetal C57B6.CD45.2 (B6) mice were injected with increasing doses of ACK2 (2.5-50 µg/fetus) or isotype control antibody on E14.5 and surviving pups were transplanted with congenic B6.CD45.1 fetal liver mononuclear cells (2.5×106 cells/pup) on day of life 1 (P1, 7 days after in utero injection), allowing post-transplantation host monitoring. Host HSC depletion and residual serum ACK2 concentration were examined on P1. Peripheral blood chimerism, defined as donor/(donor+host) CD45 cells, as well as the lineage distribution of chimeric cells, were determined beginning 4 weeks after transplantation. Results Survival to birth among fetuses injected with 2.5, 5, or 10 µg of ACK2 was similar to controls (control: 74%; 2.5 µg: 80%; 5 µg: 71%; 10 µg: 60%, p=0.2 by chi-square test, n≥45/group) but was significantly lower at higher concentrations (20 µg: 37%; 50 µg: 31%, p<0.001 vs. control, n≥70/group). Transient anemia and leukopenia were observed on P1 with doses ≥ 5 µg which resolved by P7 (n=17). Four of 19 pups previously treated with ACK2 (2.5-10 µg) and observed long-term had patchy coat discoloration, possibly a manifestation of disruption of C-kit+ melanocyte migration. In utero ACK2 treatment resulted in significant and dose-dependent depletion of host HSCs (defined as Lin-Sca-1+C-kit+, KLS) in the bone marrow of treated animals by P1 (Figure 1A). There was no depletion of KLS cells in the liver. Residual ACK2 antibody was undetectable in the serum by P1, validating our strategy of in utero depletion and neonatal transplantation. In animals receiving neonatal transplantation, ACK2 depletion resulted in a significant increase in levels of engraftment 4 weeks after transplantation compared to controls (control: 3.3±0.3%; 2.5 µg: 13±1.4%; 5 µg: 10±2.4%; 10 µg: 11±2.0%, p<0.05 for each dose vs control by ANOVA). Accordingly, we detected an increased number total bone marrow KLS cells 7 days after transplantation in ACK2 treated animals compared to controls (412±45.9 vs. 933±112 cells, p=0.01, n≥3/group). Moreover, levels of chimerism increased over time in treated animals (Figure 1B; 12 weeks: 2.5 µg: 190%; 5 µg: 170%; 10 µg: 160%) while they remained unchanged in controls. Overall, levels of chimerism achieved with ACK2 treatment were significantly higher than that observed in animals that received in utero transplantation without ACK2 depletion. Lineage analysis of peripheral blood for granulocytes, B cells, and T cells indicated an equal increase in all lineages, suggesting ACK2 depletes true HSCs and not committed progenitors. Interestingly, ACK2 depletion at doses 2.5-10 µg did not result in engraftment of allogeneic BALB/c cells (n=11), indicating that allogeneic neonatal transplantation, unlike in utero transplantation, is limited by a host immune response which is unaffected by ACK2. Conclusion We have demonstrated that fetal HSC depletion using ACK2 can lead to clinically relevant levels of donor cell engraftment with minimal toxicity. In previous studies with this antibody, host HSC depletion required either immunodeficient animals or concurrent irradiation, whereas we achieved depletion in wild-type fetal hosts, suggesting differences in fetal vs. adult HSC sensitivity to SCF signaling. Future studies should explore this strategy to improve engraftment in large animals models of IUHCTx. Disclosures: Weissman: Amgen, Systemix, Stem cells Inc, Cellerant: Consultancy, Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Phenotype, Function, and Regulation of Migrating Hematopoietic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2680-2680
Author(s):  
Amy J. Wagers ◽  
Susan S. Prohaska ◽  
Emmanuelle Passegue ◽  
Jessica Price ◽  
Irving L. Weissman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Molecular Mechanisms ◽  
Hematopoietic Cell Transplantation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Cycle Regulators ◽  
Hematopoietic Stem

Abstract Hematopoiesis in adult animals is maintained by a small population of clonogenic, multipotent hematopoietic stem cells (HSC), which maintain throughout life the capacity to self-renew and to differentiate to give rise to progeny cells that ultimately generate all lineages of mature blood cells. In adult mice and humans, the majority of HSC are found in the bone marrow (BM); however, HSC are also constitutively present at low levels in the circulation. The frequency of HSC in the blood can be significantly increased through the use of “mobilizing” agents, including cytotoxic drugs and/or cytokines, which often act both to drive HSC proliferation and to induce HSC migration from the BM into the bloodstream. Yet despite the increasingly common clinical exploitation of HSC in bone marrow and mobilized peripheral blood progenitor cell transplantation, both the evolutionary rationale and the molecular mechanisms that underlie the remarkable migratory capacity of HSC remain largely unknown. Therefore, to begin to elucidate the mechanisms and regulators of these events, we have used parabiotic and transplantation models to characterize normal blood-borne HSC. Our data clearly demonstrate that HSC are constitutively present in the blood of untreated mice and maintain a cell surface phenotype in the blood highly similar to their BM counterparts. Blood-borne HSC in normal mice can engraft both irradiated and non-irradiated BM niches, and subsequently are phenotypically and functionally indistinguishable from endogenous, host-type cells. These data suggest that BM homing of transplanted HSC in irradiated recipients and HSC mobilization in cytokine-treated animals likely makes use of pre-existing pathways that support the constitutive recirculation of these cells in normal animals. Finally, to extend these data and begin to uncover factors likely to play a role in stimulating HSC migration in both normal and mobilized mice, we have employed cDNA microarray technology to compare global gene expression profiles of normal and pre-migratory BM HSC, and have thus identified multiple candidate genes, including cell cycle regulators, signaling molecules, and transcription factors, that may be involved in HSC expansion or in HSC retention in and/or egress from the BM. Taken together, these findings provide significant insight into the dynamic nature and function of HSC, and may ultimately suggest novel and improved strategies for clinical hematopoietic cell transplantation.

Hematopoietic Cell Transplantation

2017 ◽  
Author(s):  
Fred Appelbaum
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
The United States ◽  
Hematopoietic Cell ◽  
Clinical Staging ◽  
Infection Prophylaxis ◽  
Hematopoietic Stem ◽  
Allogeneic Hct

Hematopoietic cell transplantation (HCT) can replace abnormal nonmalignant hematopoietic stem cells with cells from a healthy donor, making transplantation a potential cure for a variety of nonmalignant and malignant diseases. This review discusses the indications for HCT, source of stem cells, preparative regimen, engraftment, complications, late effects and long-term survivorship, and treatment of post-transplantation relapse. Figures show the estimated total numbers of allogeneic and autologous HCTs performed in the United States, the major histocompatibility loci on chromosome 6, an approximation of the relative intensities of various preparative regimens, the typical patterns of myeloid recovery after HCT, the description  and timing of major syndromes complicating allogeneic HCT, and erythema and desquamation associated with cutaneous acute graft versus host  disease (GVHD). Tables list estimated 3-year survival rates following HCT, probability of finding a donor for HCT, clinical staging and grading of acute GVHD, National Institutes of Health global severity score of chronic GVHD, typical approach to infection prophylaxis in allogeneic transplant recipients, and summary of Centers for Disease Control and Prevention HCT vaccine guidelines. Key words: Hematopoietic cell transplantation; HCT; Allogeneic HCT; Hematopoietic stem cell transplantation; HSCT; Diseases of the lymphohematopoietic system; Autologous HCT; Hematopoietic stem cells

scholarly journals In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice

Blood ◽  
2014 ◽  
Vol 124 (6) ◽  
pp. 973-980 ◽  
Author(s):  
S. Christopher Derderian ◽  
P. Priya Togarrati ◽  
Charmin King ◽  
Patriss W. Moradi ◽  
Damien Reynaud ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
In Utero ◽  
Hematopoietic Cell ◽  
Hematopoietic Stem ◽  
Kit Receptor ◽  
Key Points

Key Points In utero injection of an antibody against the c-Kit receptor can effectively deplete host HSCs in mice. In utero depletion of host HSCs leads to significantly increased engraftment after neonatal congenic hematopoietic cell transplantation.

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