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

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 colonystimulating 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

Hematopoietic stem cell mobilizing agents G-CSF, cyclophosphamide or AMD3100 have distinct mechanisms of action on bone marrow HSC niches and bone formation

“…10 In the past 5 years, it has emerged that G-CSF mobilizes in part by (1) blocking proliferation and osteogenic differentiation of mesenchymal stem cells (MSC), 11 (2) inducing osteoblast apoptosis 12 and (3) blocking bone formation. 13,14 This results in a dramatic reduction in the expression of chemokines and cytokines necessary to maintain and retain HSC in their endosteal and perivascular niches such as CXCL12, kit ligand (KL) and angiopoietin-1. 11,13,14 Once these endosteal niches are shutdown, HSC mobilization is initiated and possibly further amplified by protease-dependant mechanisms 13 involving neutrophil proteases, 15 CD26, 16 activation of the complement cascade 17 --19 and the thrombolytic pathway.…”

“…11,13,14 Once these endosteal niches are shutdown, HSC mobilization is initiated and possibly further amplified by protease-dependant mechanisms 13 involving neutrophil proteases, 15 CD26, 16 activation of the complement cascade 17 --19 and the thrombolytic pathway. 20 It has recently been reported that specific populations of BM macrophages are necessary to maintain the function of HSC niches in the BM and for the mobilizing effect of G-CSF 13,21,22 in particular osteoblast-supportive endosteal phagocytic macrophages called osteomacs 13,23 and CD11b þ F4/80 þ Ly-6G þ phagocytic macrophages expressing CD169, which are in close association with MSC. 13,21 Whether these two macrophage populations are distinct according to niche location or functionally overlap remains unknown.…”

“…20 It has recently been reported that specific populations of BM macrophages are necessary to maintain the function of HSC niches in the BM and for the mobilizing effect of G-CSF 13,21,22 in particular osteoblast-supportive endosteal phagocytic macrophages called osteomacs 13,23 and CD11b þ F4/80 þ Ly-6G þ phagocytic macrophages expressing CD169, which are in close association with MSC. 13,21 Whether these two macrophage populations are distinct according to niche location or functionally overlap remains unknown. G-CSF depletes both these endosteal and BM macrophages in vivo 13,21,22 and macrophage depletion transiently inhibits niche function with loss of endosteal osteoblasts, arrest in bone formation and HSC mobilization 13,21,22 A single injection of CYP is also sufficient to elicit robust HSC mobilization.…”

“…13,21 Whether these two macrophage populations are distinct according to niche location or functionally overlap remains unknown. G-CSF depletes both these endosteal and BM macrophages in vivo 13,21,22 and macrophage depletion transiently inhibits niche function with loss of endosteal osteoblasts, arrest in bone formation and HSC mobilization 13,21,22 A single injection of CYP is also sufficient to elicit robust HSC mobilization. In BALB/c mice, CYP increases the release of neutrophil proteases in the BM, with cleavage of VCAM-1 (ref.…”

“…The effect of G-CSF on osteoblasts, HSC niches and BM macrophages has recently been reported, 12,13,21,22 however, it is not known whether CYP and AMD3100 have similar effects. As AMD3100 is progressively replacing CYP as adjuvant to G-CSF to mobilize HSC in lymphoma and multiple myeloma patients who previously failed to mobilize in response to G-CSF alone, 2 we compared the effect of these three mobilizing agents on BM macrophages, bone formation, osteoblasts and HSC niche function.…”