Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche

TLDR

Hematopoietic stem cells reside in bone marrow niches regulated by the sympathetic nervous system. The study investigates whether mononuclear phagocytes modulate the HSC niche. The authors identified three bone marrow mononuclear phagocyte subsets—Gr‑1hi monocytes, Gr‑1lo monocytes, and macrophages—using markers Gr‑1, CD115, F4/80, and CD169. Conditional depletion of bone marrow mononuclear phagocytes, especially CD169⁺ macrophages, reduces CXCL12 and HSC‑retention genes, promotes HSC egress, and enhances mobilization by CXCR4 antagonists or G‑CSF, revealing macrophage‑mediated retention versus SNS‑driven egress and suggesting macrophage targeting could improve stem‑cell mobilization.

Abstract

Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1hi monocytes (MOs), Gr-1lo MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin+ niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169+ MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin+ niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.