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

作　　者：Yishan Chen Yeke Yu Ya Wen Juan Chen Junxin Lin Zixuan Sheng Wenyan Zhou Heng Sun Chengrui An Jiansong Chen Weiliang Wu Chong Teng Wei Wei Hongwei Ouyang 

机构地区：[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]China Orthopedic Regenerative Medicine Group(CORMed),Hangzhou 310058,China

出　　处：《Bone Research》2022年第3期578-593,共16页骨研究（英文版）

基　　金：supported by the National Key R&D Program of China(2017YFA0104900);National Natural Science Foundation of China(T2121004,31830029,82002319)。

摘　　要：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.

关 键 词：CHONDROCYTE CARTILAGE metabolism 

分 类 号：R684[医药卫生—骨科学]