Defective engraftment of C3aR−/− hematopoietic stem progenitor cells shows a novel role of the C3a–C3aR axis in bone marrow homing

Abstract

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.