SSCs/MSPCs were also reported to express the receptor kinase PDGFRβ, which, in response to activation by platelet-derived growth factor B (PDGF-B), promotes bone formation and regeneration ( Böhm et al., 2019 Xie et al., 2014). Expression of the markers Gremlin 1 and CD105 labels a population of reticular SSCs, which can give rise to chondrocytes, osteoblasts, and BM perivascular stromal cells ( Worthley et al., 2015). LepR + BMSCs include cells that express markers of stem cells and neurons, namely Thy (CD90) and Nestin ( Isern et al., 2014 Méndez-Ferrer et al., 2010 Worthley et al., 2015). LepR + cells can also give rise to osteoblast lineage cells and have been implicated in bone formation ( Ding et al., 2012 Zhou et al., 2014). Another important BMSC subpopulation is CXCL12-abundant reticular (CAR) cells, which are similar or identical to leptin receptor-positive (LepR +) cells, are tightly associated with the sinusoidal BM vasculature, and function as critical regulators of hematopoiesis ( Ding et al., 2012 Sugiyama et al., 2006). SSCs exist within the growth plate or periosteum in early long-bone development but have been also been found in adult periosteum and bone marrow (BM) ( Chan et al., 2015, 2018 Debnath et al., 2018 Mizuhashi et al., 2018 Ono et al., 2019 Ortinau et al., 2019). Some key features are not shared by all BMSCs and, instead, are probably confined to comparably rare mesenchymal stem and progenitor cells (MSPCs) or skeletal stem cells (SSCs), which are characterized by self-renewal capacity and multipotency, i.e., the ability to give rise to multiple differentiated cell types in a clonal fashion ( Bianco et al., 2008 Nombela-Arrieta et al., 2011 Ono et al., 2019 Sacchetti et al., 2007 Uccelli et al., 2008). BMSCs are a heterogenous mixture of different cell subpopulations, which are often associated with progenitor properties, colony-forming capacity ex vivo, and the potential to generate bone, cartilage, fat, fibroblasts, and vascular support cells (i.e., pericytes and vascular smooth muscle cells) ( Bianco et al., 2008 Nombela-Arrieta et al., 2011 Ortinau et al., 2019 Zhou et al., 2014). Some of these interactions persist after the completion of developmental bone formation and remain relevant in the context of lifelong hematopoiesis, homeostasis of the skeletal system, fracture healing, or osteoporotic bone loss ( Gerber and Ferrara, 2000 Maes and Clemens, 2014 Sacchetti et al., 2007 Sivaraj and Adams, 2016 Zelzer and Olsen, 2005). The sum of our findings improves our understanding of BMSC development, lineage relationships, and differentiation.ĭevelopmental growth of the skeletal system involves extensive communication between different stromal cell types, including mesenchymal stem/progenitor cells, committed osteoblast lineage cells, mature osteocytes, chondrocytes, vascular cells, and bone-degrading osteoclasts ( Bianco et al., 2008, 2014 Cook and Genever, 2013 Olsen et al., 2000). Finally, we show that BMSC fate is controlled by platelet-derived growth factor receptor β (PDGFRβ) signaling and the transcription factor Jun-B. Fate-tracking experiments and single-cell RNA sequencing indicate that bone-forming osteoblast lineage cells and dpMSCs, including leptin receptor-positive (LepR +) reticular cells in bone marrow, emerge from mpMSCs in the postnatal metaphysis. Here, we show with mouse genetics, ex vivo cell differentiation assays, and transcriptional profiling that BMSCs from metaphysis (mpMSCs) and diaphysis (dpMSCs) are fundamentally distinct. The lineage relationship between BMSC subsets and their regulation by intrinsic and extrinsic factors are not well understood. Mesenchymal stromal cells from bone (BMSCs) represent a heterogenous mixture of different subpopulations with distinct molecular and functional properties. Bone stroma contributes to the regulation of osteogenesis and hematopoiesis but also to fracture healing and disease processes.
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