Defective engraftment of C3aR-/- hematopoietic stem progenitor cells shows a novel role of the C3a-C3aR axis in bone marrow homing.
We reported that complement (C) becomes activated and cleaved in bone marrow during preconditioning for hematopoietic transplantation and the third C component (C3) cleavage fragments, C3a and (desArg)C3a, increase responsiveness of hematopoietic stem/progenitor cells (HSPCs) to stromal-derived factor-1 (SDF-1). We also showed 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) approximately 5-7 day delay in recovery of platelets and leukocytes; (2) decrease in formation of day 12 colony-forming units-spleen; and (3) decrease in the number of donor-derived CFU-granulocyte-macrophage progenitors detectable in the bone marrow 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 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 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 matrix metalloprotease-9 and cell adhesion.
Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
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D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D003114:Colony-Forming Units Assay; D015926:Complement C3a / Q000502:physiology*; D005312:Fetal Blood / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000473:pathology / Q000601:surgery; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011828:Radiation Chimera; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous
D011951:Receptors, Complement; C085567:complement C3a receptor; D015926:Complement C3a; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse