Regional specialization and fate specification of bone stromal cells in skeletal development

Summary

Bone stroma contributes to the regulation of osteogenesis and hematopoiesis but also to fracture healing and disease processes. Mesenchymal stromal cells from bone (BMSCs) represent a heterogenous mixture of different subpopulations with distinct molecular and functional properties. The lineage relationship between BMSC subsets and their regulation by intrinsic and extrinsic factors are not well understood. 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. 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. Finally, we show that BMSC fate is controlled by platelet-derived growth factor receptor β (PDGFRβ) signaling and the transcription factor Jun-B. The sum of our findings improves our understanding of BMSC development, lineage relationships, and differentiation.

Graphical abstract

Highlights

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  Mesenchymal stromal cells from metaphysis and diaphysis have distinct properties

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  Metaphyseal mpMSCs include cells with multi-lineage differentiation potential

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  mpMSCs give rise to osteoprogenitors and reticular cells in marrow during development

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  Microenvironmental cues and cell-autonomous transcription factors control BMSC fate

Abstract

Sivaraj et al. characterize the heterogeneity of bone mesenchymal stromal cells (BMSCs) during skeletal development. A subpopulation of metaphyseal MSCs (mpMSCs) has self-renewing and multi-lineage differentiation potential to generate bone cells and LepR ⁺ marrow stromal cells. BMSCs fate determination is controlled extrinsically by PDGF-B and intrinsically by Jun-B.