Csf1 from marrow adipogenic precursors is required for osteoclast formation and hematopoiesis in bone

Abstract

Colony stimulating factor 1 (Csf1) is an essential growth factor for osteoclast progenitors and an important regulator for bone resorption. It remains elusive which mesenchymal cells synthesize Csf1 to stimulate osteoclastogenesis. We recently identified a novel mesenchymal cell population, marrow adipogenic lineage precursors (MALPs), in bone. Compared to other mesenchymal subpopulations, MALPs expressed Csf1 at a much higher level and this expression was further increased during aging. To investigate its role, we constructed MALP-deficient Csf1 CKO mice using AdipoqCre. These mice had increased femoral trabecular bone mass, but their cortical bone appeared normal. In comparison, depletion of Csf1 in the entire mesenchymal lineage using Prrx1Cre led to a more striking high bone mass phenotype, suggesting that additional mesenchymal subpopulations secrete Csf1. TRAP staining revealed diminished osteoclasts in the femoral secondary spongiosa region of Csf1 CKOAdipoq mice, but not at the chondral-osseous junction nor at the endosteal surface of cortical bone. Moreover, Csf1 CKOAdipoq mice were resistant to LPS-induced calvarial osteolysis. Bone marrow cellularity, hematopoietic progenitors, and macrophages were also reduced in these mice. Taken together, our studies demonstrate that MALPs synthesize Csf1 to control bone remodeling and hematopoiesis.

Mapping the Cellular Biogeography of Human Bone Marrow Niches Using Single-Cell Transcriptomics and Proteomic Imaging

“…Within the non-hematopoietic cells, we identified three major lineages – vascular smooth muscle ( ACTA2 , RGS5, TAGLN ), endothelial cells ( CDH5 , PECAM1, VWF ), and mesenchymal cells ( CXCL12, PDGFRA) including osteolineage cells and mesenchymal stromal cells (MSCs) (Figure 1B-D, Supplemental Table S2, Supplemental Figure S1E). Contrary to previous results from human bone marrow aspirate samples 19 which found that MSCs were relatively homogenous and expressed an adipocytic transcriptional profile 23 , we observed that mesenchymal stromal cells from digested bone marrow were highly heterogenous with numerous clusters identified (Figure 1B, Supplemental Figure 1F).…”

GDF15 mediates inflammation-associated bone loss through a brain-bone axis

“…RANKL production by MALPs was shown to be essential for bone homeostasis, which was confirmed by independent research groups 40,41 . Moreover, it was previously assumed that osteoblasts and mature bone marrow adipocytes were the main producers of M-CSF in the bone, however recent evidence shows that MALPs are likely the main source of M-CSF 40,42 . Finally, to the best of our knowledge, we are the first to document the existence of MALPs in human and to show that they express the bAR.…”

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

“…The BM adipocyte differentiation axis is gaining attention as a fundamental component of bone and blood physiology, with several recent studies focusing on the BM stroma population as a key player in the maintenance of the balance between bone and BM space 8,55 . Ablation of the BM adipocyte precursor population leads to massive accumulation of bone in the medullary cavity 4,7,14,52,54 which in turn reduces the volume available for hematopoietic tissue.…”

“…The bone, long considered a merely structural organ, is now seen as a highly dynamic tissue in which various processes, including hematopoiesis, bone remodeling, immunity and metabolism are tightly regulated 1,2 . These processes rely on specialized microenvironments, termed niches, that play a critical role in cell fate regulation 3 , with the bone marrow adipose tissue (BMAT) being an emerging niche component [4][5][6][7][8] . The bone marrow (BM) niche regulates hematopoietic stem and progenitor cell (HSPC) quiescence, self-renewal and commitment towards differentiated cells thanks to a combination of soluble factors and cell-cell interactions 1,3,9,10 .…”

“…Subsequent studies showing a positive effect of the BM adipocyte lineage on hematopoietic recovery called these results into question 5,14,15 . Recent work has uncovered a more nuanced role of non-lipidated BM adipogenic precursors in the control of bone homeostasis 6,7 and favoring hematopoietic recovery upon irradiation 8,16 . As for other adipose depots, the BMAT is plastic and can be remodeled upon injury and dietary or pharmacological stimulation 13,[17][18][19][20][21] .…”