期刊
BLOOD
卷 103, 期 6, 页码 2071-2078出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2003-06-2099
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资金
- NCI NIH HHS [R01 CA86412] Funding Source: Medline
- NHLBI NIH HHS [R01 HL074333, R01 HL61796] Funding Source: Medline
- NIAID NIH HHS [R01 AI25011] Funding Source: Medline
The mechanisms regulating the homing/ mobilization of hematopoietic stem/progenitor cells (HSPCs) are not fully understood. In our previous studies we showed that the complement C3 activation peptide, C3a, sensitizes responses of HSPCs to stromal-derived factor 1 (SDF-1). in this study, mobilization was induced with granulocyte colony-stimulating factor (G-CSF) in both C3-deficient (C3(-/-)) and C3a receptor-deficient (C3aR(-/-)) mice as well as in wild-type (wt) mice in the presence or absence of a C3aR antagonist, SB 290157. The data indicated (1) significantly increased G-CSF-induced mobilization in C3(-/-) and C3aR(-/-) mice compared with wt mice, (2) significantly accelerated and enhanced G-CSF-induced mobilization in wt, but not in C3(-/-) or C3aR-/-, mice treated with SB 290157, and (3) deposition of C3lb/iC3b fragments onto the viable bone marrow (BM) cells of G-CSF-treated animals. Furthermore, mobilization studies performed in chimeric mice revealed that wt mice reconstituted with C3aR(-/-) BM cells, but not C3aR(-/-) mice reconstituted with wt BM cells, are more sensitive to G-CSF-induced mobilization, suggesting that CUR deficiency on graft-derived cells is responsible for this increased mobilization. Hence we suggest that C3 is activated in mobilized BM into C3a and C3b, and that the C3a-C3aR axis plays an important and novel role in retention of HSPCs (by counteracting mobilization) by increasing their responsiveness to SDF-11, the concentration of which is reduced in. BM during mobilization. The C3a-C3aR axis may prevent an uncontrolled, release of HSPCs into peripheral blood. These data further suggest that the C3aR antagonist SB 290157 could be developed as a drug to mobilize HSPCs for transplantation. (C) 2004 by The American Society of Hematology.
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