Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs

IG Winkler, NA Sims, AR Pettit, V Barbier… - Blood, The Journal …, 2010 - ashpublications.org
IG Winkler, NA Sims, AR Pettit, V Barbier, B Nowlan, F Helwani, IJ Poulton, N van Rooijen
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
Abstract
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.
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