A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration
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 condi...
Main Authors: | , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
Springer Nature
2022
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Online Access: | View Fulltext in Publisher |
LEADER | 02615nam a2200289Ia 4500 | ||
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001 | 10.1038-s41413-022-00209-w | ||
008 | 220510s2022 CNT 000 0 und d | ||
020 | |a 20954700 (ISSN) | ||
245 | 1 | 0 | |a A high-resolution route map reveals distinct stages of chondrocyte dedifferentiation for cartilage regeneration |
260 | 0 | |b Springer Nature |c 2022 | |
856 | |z View Fulltext in Publisher |u https://doi.org/10.1038/s41413-022-00209-w | ||
520 | 3 | |a 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. © 2022, The Author(s). | |
700 | 1 | |a An, C. |e author | |
700 | 1 | |a Chen, J. |e author | |
700 | 1 | |a Chen, J. |e author | |
700 | 1 | |a Chen, Y. |e author | |
700 | 1 | |a Lin, J. |e author | |
700 | 1 | |a Ouyang, H. |e author | |
700 | 1 | |a Sheng, Z. |e author | |
700 | 1 | |a Sun, H. |e author | |
700 | 1 | |a Teng, C. |e author | |
700 | 1 | |a Wei, W. |e author | |
700 | 1 | |a Wen, Y. |e author | |
700 | 1 | |a Wu, W. |e author | |
700 | 1 | |a Yu, Y. |e author | |
700 | 1 | |a Zhou, W. |e author | |
773 | |t Bone Research |