Hypertrophic Chondrocytes Serve as a Reservoir for Unique Marrow Associated Skeletal Stem and Progenitor Cells, Osteoblasts, and Adipocytes During Skeletal Development

Skeletal stem and progenitor cells (SSPCs) reside within niches localized to the intramedullary bone marrow and periosteal tissues surrounding bones, with most being capable of becoming osteoblasts, chondrocytes, and adipocytes during bone development and/or regeneration. SSPCs within the periosteum can give rise to intramedullary SSPCs, osteoblasts, osteocytes, and adipocytes during bone development; however, whether they are the sole source of these cells remains to be determined. Growth plate chondrocytes contribute to the osteoblast lineage and trabecular bone formation; however, the cellular process used to achieve this is unknown. We utilized hypertrophic chondrocyte genetic reporter mouse models combined with single cell RNA-sequencing, immunofluorescent staining, and bulk RNA-sequencing approaches to determine that hypertrophic chondrocytes undergo a process of dedifferentiation to generate unique bone marrow associated SSPC populations that likely serve as a primary source of osteogenic cells during skeletal development, while also contributing to the adipogenic lineage with age.