2. Academic Validation
  3. A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration

A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration

  • Bone Res. 2022 Apr 27;10(1):38. doi: 10.1038/s41413-022-00209-w.
Yishan Chen  # 1 2 3,  Yeke Yu  # 1 4,  Ya Wen  # 1 2 3,  Juan Chen 5,  Junxin Lin 1 3,  Zixuan Sheng 1 2 3,  Wenyan Zhou 1 2 3,  Heng Sun 1 2 3,  Chengrui An 1 2 3,  Jiansong Chen 6,  Weiliang Wu 6,  Chong Teng 7,  Wei Wei 7,  Hongwei Ouyang 8 9 10 11
Affiliations

Affiliations

  • 1 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2 Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 3 Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 4 Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
  • 5 Department of General Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 6 Department of Orthopedic Surgery, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
  • 7 Department of Orthopedic Surgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China.
  • 8 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 9 Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 10 Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310058, China. [email protected].
  • 11 China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, 310058, China. [email protected].
  • # Contributed equally.
PMID: 35477573 DOI: 10.1038/s41413-022-00209-w
Abstract

Articular cartilage damage is a universal health problem. Despite recent progress, chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration. Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions, but the characteristics and intermediate molecular mechanisms remain unclear. In this study, we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation. We performed various assays, such as single-cell RNA sequencing (scRNA-seq), live-cell metabolic assays, and assays for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages. Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation, whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling. Using the chemical inhibitor BTB06584, we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss. Notably, this two-stage transition was also validated in human chondrocytes. An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers. Overall, this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.

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