DEFECTIVE ENGRAFTMENT OF C3aR-/- HEMATOPOIETIC STEM PROGENITOR CELLS REVEALS A NOVEL ROLE OF THE C3a-C3aR AXIS IN BONE MARROW HOMING

We reported that complement (C) becomes activated and cleaved in bone marrow (BM) during preconditioning for hematopoietic transplantation and the third C component (C3) cleavage fragments C3a and desArgC3a increase responsiveness of hematopoietic stem/progenitor cells (HSPCs) to stromal derived factor-1 (SDF-1). We also demonstrated that this homing promoting effect is not C3a receptor (C3aR) dependent. Herein, we report our new observation that transplantation of C3aR-/- HSPCs into lethally irradiated recipients results in: 1) ∼5-7 day delay in recovery of platelets and leukocytes; 2) decrease in formation of day 12 colony-forming units-spleen (CFU-S); and 3) decrease in the number of donor-derived CFU-granulocyte-macrophage (GM) progenitors detectable in the BM cavities at day 16 after transplantation. In agreement with the murine data, blockage of C3aR on human umbilical cord blood CD34+ cells by C3aR antagonist SB290157 impairs their engraftment in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. However, HSPCs from C3aR-/- mice stimulated by C3a still better responded to SDF-1 gradient, after exposure to C3a, they secrete less matrix metalloprotease-9 (MMP-9) and show impaired adhesion to stroma cells. We conclude that C3a, in addition to enhancing responsiveness of HSPCs to SDF-1 gradient in a C3aR independent manner, may also directly modulate HSPC homing by augmenting C3aR-mediated secretion of MMP-9 and cell adhesion.