High-Resolution Dissection of Chemical Reprogramming from Mouse Embryonic Fibroblasts into Fibrocartilaginous Cells
High-Resolution Dissection of Chemical Reprogramming from Mouse Embryonic Fibroblasts into Fibrocartilaginous Cells
复制标题
小鼠胚胎成纤维细胞化学重编程为纤维软骨细胞的高分辨率解剖
DOI：
10.1016/j.stemcr.2020.01.013
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发表时间：
2020-03-10
影响因子：
5.9
通讯作者：
Ouyang, Hongwei
中科院分区：
文献类型：
--
作者：
Chen, Yishan;Wu, Bingbing;Ouyang, Hongwei
关节软骨损伤和退变引起的疼痛和生活质量的丧失已经成为日益老龄化的人群面临的一个严重问题。鉴于成人软骨细胞自我更新能力差，需要替代的功能性细胞来源。通过小分子直接重编程可能提供了一种无癌基因和成本效益的方法来生成软骨细胞，但尚未进行研究。在这里，我们使用含有化学鸡尾酒VCRTC(丙戊酸、CHIR98014、Repsox、TTNPB和塞来昔布)的3D系统将小鼠胚胎成纤维细胞直接重编程为PRG4+软骨细胞。利用单细胞转录组，我们揭示了在早期再编程中成纤维细胞特征的抑制和软骨形成途径的激活，以及类似于软骨发育的中间细胞过程。将化学诱导的软骨细胞移植到关节缺损处，促进了骨缺损的愈合，挽救了63.4%的机械功能丧失。我们的方法直接将成纤维细胞转化为功能性软骨细胞，也为未来软骨再生的潜在药物策略提供了见解。
Articular cartilage injury and degeneration causing pain and loss of quality-of-life has become a serious problem for increasingly aged populations. Given the poor self-renewal of adult human chondrocytes, alternative functional cell sources are needed. Direct reprogramming by small molecules potentially offers an oncogene-free and cost-effective approach to generate chondrocytes, but has yet to be investigated. Here, we directly reprogrammed mouse embryonic fibroblasts into PRG4+ chondrocytes using a 3D system with a chemical cocktail, VCRTc (valproic acid, CHIR98014, Repsox, TTNPB, and celecoxib). Using single-cell transcriptomics, we revealed the inhibition of fibroblast features and activation of chondrogenesis pathways in early reprograming, and the intermediate cellular process resembling cartilage development. The in vivo implantation of chemical-induced chondrocytes at defective articular surfaces promoted defect healing and rescued 63.4% of mechanical function loss. Our approach directly converts fibroblasts into functional cartilaginous cells, and also provides insights into potential pharmacological strategies for future cartilage regeneration.