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

• DOI: 10.1016/j.celrep.2021.109352
• Publication Date: 2021-07-13T15:05:51Z
• Authors: Kishor K. Sivaraj; Hyun-Woo Jeong; Backialakshmi Dha...; Dagmar Zeuschner; Susanne Adams; Michael Potente; Ralf H. Adams
• Keywords: 0301 basic medicine; osteoblast lineage cells; Transcription, Genetic; QH301-705.5; adipocytes; Article; Bone and Bones; Receptor, Platelet-Derived Growth Factor beta; Mice; 03 medical and health sciences; diaphysis; Animals; Cell Lineage; Biology (General); metaphysis; 0303 health sciences; Bone Development; Endothelial Cells; Cell Differentiation; Mesenchymal Stem Cells; bone mesenchymal stromal cells; mouse genetics; Mice, Inbred C57BL; Animals, Newborn; Cardiovascular and Metabolic Diseases; Organ Specificity; Single-Cell Analysis; Stromal Cells; Signal Transduction

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.