JOURNAL ARTICLE

Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow

Janina Ratajczak, Ryan Reca, Magda Kucia, Marcin Majka, Daniel J Allendorf, Jarek T Baran, Anna Janowska-Wieczorek, Rick A Wetsel, Gordon D Ross, Mariusz Z Ratajczak
Blood 2004 March 15, 103 (6): 2071-8
14604969
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 C3b/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 C3aR 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-1, 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.

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