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

By Jason T. Long, Abigail Leinroth, Yihan Liao, Yinshi Ren, Anthony J. Mirando, Tuyet Nguyen, Wendi Guo, Deepika Sharma, Colleen Wu, Kathryn Cheah, Courtney M. Karner, Matthew J. Hilton

Posted 18 May 2021
bioRxiv DOI: 10.1101/2021.05.18.444731

Hypertrophic chondrocytes give rise to osteoblasts during skeletal development, however the process by which these non-mitotic cells make this transition is not well understood. Prior studies have also suggested that skeletal stem and progenitor cells (SSPCs) localized to the surrounding periosteum serve as the primary source of marrow associated SSPCs, osteoblasts, osteocytes, and adipocytes during skeletal development. To further understand the cell transition process by which hypertrophic chondrocytes contribute to osteoblasts or other marrow associated cells, we utilized hypertrophic chondrocyte genetic reporter mouse models combined with single cell RNA-sequencing, immunofluorescence staining, and bulk RNA-sequencing approaches. Our data demonstrate that hypertrophic chondrocytes undergo a process of dedifferentiation to generate unique marrow associated SSPCs, previously characterized as a CXCL12-abundant reticular (CAR) cells, that not only establish a molecular niche for hematopoiesis, but also serve as a primary source of osteoblasts during skeletal development and contribute to the adipogenic lineage with age.

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