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.
Ratajczak
M Z
MZ
Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. mzrata01@louisville.edu
Reca
R
R
Wysoczynski
M
M
Kucia
M
M
Baran
J T
JT
Allendorf
D J
DJ
Ratajczak
J
J
Ross
G D
GD
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