Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs.
In the bone marrow, hematopoietic stem cells (HSCs) reside in specific niches near osteoblast-lineage cells at the endosteum. To investigate the regulation of these endosteal niches, we studied the mobilization of HSCs into the bloodstream in response to granulocyte colony-stimulating factor (G-CSF). We report that G-CSF mobilization rapidly depletes endosteal osteoblasts, leading to suppressed endosteal bone formation and decreased expression of factors required for HSC retention and self-renewal. Importantly, G-CSF administration also depleted a population of trophic endosteal macrophages (osteomacs) that support osteoblast function. Osteomac loss, osteoblast suppression, and HSC mobilization occurred concomitantly, suggesting that osteomac loss could disrupt endosteal niches. Indeed, in vivo depletion of macrophages, in either macrophage Fas-induced apoptosis (Mafia) transgenic mice or by administration of clodronate-loaded liposomes to wild-type mice, recapitulated the: (1) loss of endosteal osteoblasts and (2) marked reduction of HSC-trophic cytokines at the endosteum, with (3) HSC mobilization into the blood, as observed during G-CSF administration. Together, these results establish that bone marrow macrophages are pivotal to maintain the endosteal HSC niche and that the loss of such macrophages leads to the egress of HSCs into the blood.
Winkler
Ingrid G
IG
Haematopoietic Stem Cell Laboratory, Mater Medical Research Institute, South Brisbane, Australia.
Sims
Natalie A
NA
Pettit
Allison R
AR
Barbier
Valérie
V
Nowlan
Bianca
B
Helwani
Falak
F
Poulton
Ingrid J
IJ
van Rooijen
Nico
N
Alexander
Kylie A
KA
Raggatt
Liza J
LJ
Lévesque
Jean-Pierre
JP
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement / Q000502:physiology; D002469:Cell Separation; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D007150:Immunohistochemistry; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055153:Stem Cell Niche / Q000378:metabolism*
D016179:Granulocyte Colony-Stimulating Factor