Figure 6. SDF-1 and C3 cleavage fragments create “super-gradient” for HSPC.

Conditioning for transplantation by radio-chemotherapy upregulates in BM i) expression of SDF-1 (12) and ii) activates complement cascade (18, 22, 23, 28, 29). While SDF-1 directly chemoattracts HSPCs by interacting with CXCR4 receptor, our work revealed that the homing function of the SDF-1-CXCR4 axis is modulated by C3 cleavage fragments (C3a _{and des}ArgC3a) — both in C3aR-dependent and C3aR-independent manner. In a first mechanism, C3a (but not _desArgC3a) activates C3aR and increases adhesiveness of HSPCs as well as secretion of MMP-9 by these cells. In a second one (C3aR independent) both C3a and _desArgC3a enhance/prime responsiveness of HSPCs to SDF-1 gradient by increasing incorporation of CXCR4 into membrane lipid rafts. CXCR4 incorporated in lipid rafts is better connected with signal transduction proteins what explains why CXCR4⁺ HSPCs respond more robust to SDF-1. However, the identification of receptor/receptors? involved in this C3a and _desArgC3s mediated “priming” effect requires further studies.