Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells.
Mice deficient in complement C3 (C3(-/-)) are hematologically normal under steady-state conditions, and yet displayed a significant delay in hematopoietic recovery from either irradiation or transplantation of wild-type (WT) hematopoietic stem/progenitor cells (HSPC). Transplantation of histocompatible WT Sca-1(+) cells into C3(-/-) mice resulted in a (i) decrease in day 12 CFU-S, (ii) 5-7-day delay in platelet and leukocyte recovery, and (iii) reduced number of BM CFU-GM progenitors at day 16 after transplantation. Nevertheless, HSPC from C3(-/-) mice engrafted normally into irradiated WT mice, suggesting that there was a defect in the hematopoietic environment of C3(-/-) mice. Since C3(-/-) mice cannot activate/cleave C3, the C3 fragments C3a, C3a(des-Arg), and iC3b were examined for a role in HSPC engraftment. Liquid-phase C3a and C3a(des-Arg) increased CXCR4 incorporation into membrane lipid rafts (thus potentiating HSPC responses to SDF-1 gradients), whereas iC3b was deposited onto irradiated BM cells and functioned to tether CR3(CD11b/CD18)(+)HSPC to damaged stroma. The activity of C3a(des-Arg) suggested that C3aR(+)HSPC also expressed the C5L2 (receptor for C3a and C3a(des-Arg)) and this was confirmed. In conclusion, a novel mechanism for HSC engraftment was identified, which involves complement activation and specific C3 fragments that promote conditioning for transplantation and enhance HSPC engraftment.
Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. mzrata01@louisville.edu
M Z
MZ
Ratajczak
R
R
Reca
M
M
Wysoczynski
M
M
Kucia
J T
JT
Baran
D J
DJ
Allendorf
J
J
Ratajczak
G D
GD
Ross
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D003167:Complement Activation; D003176:Complement C3 / Q000235:genetics / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000378:metabolism; D011951:Receptors, Complement / Q000235:genetics / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology; D014916:Whole-Body Irradiation
D000950:Antigens, Ly; D003176:Complement C3; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D011951:Receptors, Complement; C085567:complement C3a receptor; D016179:Granulocyte Colony-Stimulating Factor