Recapitulation of endochondral ossification by hPSC-derived SOX9+ sclerotomal progenitors

Jingfei Xiong, Runxin Ma, Kun Xie, Ce Shan, Hanyi Chen, Yuqing Wang, Yuansong Liao, Yanhui Deng, Guogen Ye, Yifu Wang, Qing Zhu, Yunqiu Zhang, Haoyang Cai, Weihua Guo, Yike Yin () and Zhonghan Li ()
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Jingfei Xiong: Sichuan University
Runxin Ma: Sichuan University
Kun Xie: Sichuan University
Ce Shan: Sichuan University
Hanyi Chen: Sichuan University
Yuqing Wang: Sichuan University
Yuansong Liao: Sichuan University
Yanhui Deng: Sichuan University
Guogen Ye: Sichuan University
Yifu Wang: Sichuan University
Qing Zhu: Sichuan University
Yunqiu Zhang: Sichuan University
Haoyang Cai: Sichuan University
Weihua Guo: Kunming Medical University
Yike Yin: Sichuan University
Zhonghan Li: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Endochondral ossification generates most of the load-bearing bones, recapitulating it in human cells remains a challenge. Here, we report generation of SOX9+ sclerotomal progenitors (scl-progenitors), a mesenchymal precursor at the pre-condensation stage, from human pluripotent stem cells and development of osteochondral induction methods for these cells. Upon lineage-specific induction, SOX9+ scl-progenitors have not only generated articular cartilage but have also undergone spontaneous condensation, cartilaginous anlagen formation, chondrocyte hypertrophy, vascular invasion, and finally bone formation with stroma, thereby recapitulating key stages during endochondral ossification. Moreover, self-organized growth plate-like structures have also been induced using SOX9+ scl-progenitor-derived fusion constructs with chondro- and osteo-spheroids, exhibiting molecular and cellular similarities to the primary growth plates. Furthermore, we have identified ITGA9 as a specific surface marker for reporter-independent isolation of SOX9+ scl-progenitors and established a culture system to support their expansion. Our work highlights SOX9+ scl-progenitors as a promising tool for modeling human skeletal development and bone/cartilage bioengineering.

Date: 2025
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DOI: 10.1038/s41467-025-58122-9

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