Abstract
Recently we demonstrated that complement (C) is activated in bone marrow (BM) during conditioning for transplantation and hematopoietic stem/progenitor cells (HSPC) express on their surface the C3a receptor (C3aR) and in the presence of the third C component - C3 cleavage fragments (C3a and desArgC3a) respond more robustly to a chemotactic gradient of stromal-derived factor (SDF)-1 (Reca et al., Blood2003, 101, 3784). The molecular explanation for this phenomenon is a C3a mediated increase in the incorporation of CXCR4 into membrane lipid rafts what enables CXCR4 to interact better with small GTPases from the Rho/Rac family (Wysoczynski et al. Blood2005, 105, 40–48). To elucidate this phenomenon better and to learn more on the role of the C3a-C3aR axis in homing/engraftment of HSPC we studied i) engraftment of murine HSPC derived from C3aR-deficient mice into wild type littermates and ii) human HSPC on which C3aR was blocked by C3aR antagonist SB290157 into NOD/SCID mice. We noticed that wt mice transplanted with C3aR−/ − HSPC engrafted significantly worse compared to normal littermates. Accordingly, transplantation of the same numbers of Sca-1+ cells from C3aR−/ − mice into wt littermates as compared to transplantation of wt cells resulted in i) delay by ~5–7 days in recovery of platelets and leukocytes, ii) decrease in day 12 CFU-S, and iii) decrease in the number of CFU-GM progenitors detectable in the BM cavities at day 16 after transplantation. Similarly in parallel experiments, human CD34+ cells exposed to nontoxic doses of C3aR antagonist SB29007 engrafted worse in NOD/SCID mice (p<0.0001). Next, we studied the different steps of homing of HSPC and noticed that sensitization of cells to an SDF-1 chemotactic gradient was compensated in C3aR−/ − mice probably by the activation of another putative receptor for C3a, however, the C3aR was indispensable for optimal adhesion of HSPC to endothelium and SDF-1-dependent MMP-9 secretion. In conclusion, activation of the C cascade in BM during conditioning for transplantation exposes a natural neoantigen which is recognized by immunoglobulins activating C by the classical pathway. As a consequence, C3 cleavage product, C3a, activates the C3aR on transplanted HSPC increasing the SDF-1 mediated homing of these cells.
The role of the LTB 4 -BLT1 axis in chemotactic gradient sensing and directed leukocyte migration
