Hypertrophic chondrocytes serve as a reservoir for marrow associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development
- Duke University School of Medicine, United States
- University of Hong Kong, Hong Kong
Abstract
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 (Col10a1CreERT2; Rosa26fs-tdTomato and Col10a1Cre; Rosa26fs-tdTomato) in combination with a PDGFRaH2B-GFP 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.
Data availability
All raw data has been made available as source data files within the manuscript. All sequencing datasets are available via the Gene Expression Omnibus (GEO) under the accession numbers: GSE179174, GSE190616, and GSE179148.
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Collagen10a1-Cre;Rosa26-tdTomato Bone marrow colony forming unitsNCBI Gene Expression Omnibus, GSE179174.
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Collagen10-Cre;Rosa26-tdTomato e16.5 single cell RNA-sequencingNCBI Gene Expression Omnibus, GSE190616.
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Collagen10-Cre;Rosa26-tdTomato bone marrow single cell RNA-sequencingNCBI Gene Expression Omnibus, GSE179148.
Article and author information
Author details
Kathryn Song Eng Cheah
Funding
NIH/NIAMS (R01AR071722)
- Matthew J Hilton
NIH/NIAMS (R01AR063071)
- Matthew J Hilton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to and approved by the Duke University Institutional Animal Care and Use Committees (IACUC) (A068-20-03).
Reviewing Editor
- Mei Wan, Johns Hopkins University School of Medicine, United States
Version history
- Preprint posted: May 18, 2021 (view preprint)
- Received: January 10, 2022
- Accepted: February 13, 2022
- Accepted Manuscript published: February 18, 2022 (version 1)
- Version of Record published: March 3, 2022 (version 2)
Copyright
© 2022, Long et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Hypertrophic chondrocytes serve as a reservoir for marrow associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development
eLife 11:e76932.
https://doi.org/10.7554/eLife.76932
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