Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow.
The mechanisms regulating the homing/mobilization of hematopoietic stem/progenitor cells (HSPCs) are not fully understood. In our previous studies we showed that the complement C3 activation peptide, C3a, sensitizes responses of HSPCs to stromal-derived factor 1 (SDF-1). In this study, mobilization was induced with granulocyte colony-stimulating factor (G-CSF) in both C3-deficient (C3-/-) and C3a receptor-deficient (C3aR-/-) mice as well as in wild-type (wt) mice in the presence or absence of a C3aR antagonist, SB 290157. The data indicated (1) significantly increased G-CSF-induced mobilization in C3-/- and C3aR-/- mice compared with wt mice, (2) significantly accelerated and enhanced G-CSF-induced mobilization in wt, but not in C3-/- or C3aR-/-, mice treated with SB 290157, and (3) deposition of C3b/iC3b fragments onto the viable bone marrow (BM) cells of G-CSF-treated animals. Furthermore, mobilization studies performed in chimeric mice revealed that wt mice reconstituted with C3aR-/- BM cells, but not C3aR-/- mice reconstituted with wt BM cells, are more sensitive to G-CSF-induced mobilization, suggesting that C3aR deficiency on graft-derived cells is responsible for this increased mobilization. Hence we suggest that C3 is activated in mobilized BM into C3a and C3b, and that the C3a-C3aR axis plays an important and novel role in retention of HSPCs (by counteracting mobilization) by increasing their responsiveness to SDF-1, the concentration of which is reduced in BM during mobilization. The C3a-C3aR axis may prevent an uncontrolled release of HSPCs into peripheral blood. These data further suggest that the C3aR antagonist SB 290157 could be developed as a drug to mobilize HSPCs for transplantation.
Ratajczak
Janina
J
Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, 529 South Jackson St, KY 40202, USA. mzrata01@louisville.edu
Reca
Ryan
R
Kucia
Magda
M
Majka
Marcin
M
Allendorf
Daniel J
DJ
Baran
Jarek T
JT
Janowska-Wieczorek
Anna
A
Wetsel
Rick A
RA
Ross
Gordon D
GD
Ratajczak
Mariusz Z
MZ
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000235:genetics*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011828:Radiation Chimera; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000235:genetics*
D001559:Benzhydryl Compounds; D003176:Complement C3; D008565:Membrane Proteins; D011951:Receptors, Complement; C431907:SB 290157; C085567:complement C3a receptor; D016179:Granulocyte Colony-Stimulating Factor; D001120:Arginine