@article{Chen2022, 
author = {Yishan Chen and Yeke Yu and Ya Wen and Juan Chen and Junxin Lin and Zixuan Sheng and Wenyan Zhou and Heng Sun and Chengrui An and Jiansong Chen and Weiliang Wu and Chong Teng and Wei Wei and Hongwei Ouyang},
title = {A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration},
year = {2022},
journal = {Bone Research},
volume = {10},
pages = {38},
url = {https://www.sciopen.com/article/10.1038/s41413-022-00209-w},
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.}
}