Hypertrophic chondrocytes serve as a reservoir for marrow-associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development

• Published in: eLife Vol. 11
• Main Authors: Long, Jason T, Leinroth, Abigail, Liao, Yihan, Ren, Yinshi, Mirando, Anthony J, Nguyen, Tuyet, Guo, Wendi, Sharma, Deepika, Rouse, Douglas, Wu, Colleen, Cheah, Kathryn Song Eng, Karner, Courtney M, Hilton, Matthew J
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 18.02.2022; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adipocytes; Animal models; Animals; Bone Marrow; Cartilage; Cell cycle; Cell Differentiation; Chondrocytes; Collagen; CXCL12 protein; Developmental Biology; Genetic engineering; Growth factors; hypertrophic chondrocytes; Immunofluorescence; Journalists; Mice; Osteoblasts; Osteocytes; Osteogenesis; Osteoprogenitor cells; Periosteum; Phenotypes; Progenitor cells; RNA - metabolism; Sarcopenia; skeletal stem; Stem Cells - metabolism; Transplantation; United Kingdom; hypertrophic chondrocytes; mouse; developmental biology; progenitor cells; osteoblasts; skeletal stem; adipocytes; bone marrow
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/ELIFE.76932

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) localize to the surrounding periosteum and serve as a major 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 inducible and constitutive hypertrophic chondrocyte lineage tracing and reporter mouse models ( and ) in combination with a transgenic line, single-cell RNA-sequencing, bulk RNA-sequencing, immunofluorescence staining, and cell transplantation assays. Our data demonstrate that hypertrophic chondrocytes undergo a process of dedifferentiation to generate marrow-associated SSPCs that serve as a primary source of osteoblasts during skeletal development. These hypertrophic chondrocyte-derived SSPCs commit to a CXCL12-abundant reticular (CAR) cell phenotype during skeletal development and demonstrate unique abilities to recruit vasculature and promote bone marrow establishment, while also contributing to the adipogenic lineage.