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Mice deficient in complement C3 (C3-/-) are hematologically normal under steady-state conditions, and yet displayed a significant delay in hematopoietic recovery from either irradiation or transplantation of wild-type (WT) hematopoietic stem/progenitor cells (HSPC). Transplantation of histocompatible WT Sca-1+ cells into C3-/- mice resulted in a (i) decrease in day 12 CFU-S, (ii) 5-7-day delay in platelet and leukocyte recovery, and (iii) reduced number of BM CFU-GM progenitors at day 16 after transplantation. Nevertheless, HSPC from C3-/- mice engrafted normally into irradiated WT mice, suggesting that there was a defect in the hematopoietic environment of C3-/- mice. Since C3-/- mice cannot activate/cleave C3, the C3 fragments C3a, C3ades-Arg, and iC3b were examined for a role in HSPC engraftment. Liquid-phase C3a and C3ades-Arg increased CXCR4 incorporation into membrane lipid rafts (thus potentiating HSPC responses to SDF-1 gradients), whereas iC3b was deposited onto irradiated BM cells and functioned to tether CR3(CD11b/CD18)+HSPC to damaged stroma. The activity of C3ades-Arg suggested that C3aR+HSPC also expressed the C5L2 (receptor for C3a and C3ades-Arg) and this was confirmed. In conclusion, a novel mechanism for HSC engraftment was identified, which involves complement activation and specific C3 fragments that promote conditioning for transplantation and enhance HSPC engraftment.Leukemia (2004) 18, 1482-1490. doi:10.1038/sj.leu.2403446 Published online 29 July 2004 [ABSTRACT FROM AUTHOR]