{"title":"退行性髓核细胞在特定因子的作用下发生类似去分化的重编程,变成类似脊索的细胞。","authors":"Yuang Zhang, Chengzhen Liang, Haibin Xu, Yi Li, Kaishun Xia, Liyin Wang, Xianpeng Huang, Jiangjie Chen, Jiawei Shu, Feng Cheng, Kesi Shi, Jingkai Wang, Yiqing Tao, Shaoke Wang, Yongxiang Zhang, Hao Li, Shoumin Feng, Fangcai Li, Xiaopeng Zhou, Qixin Chen","doi":"10.1016/j.ymthe.2024.06.018","DOIUrl":null,"url":null,"abstract":"<p><p>The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. Currently, a cellular reprogramming approach enabling directly generating corresponding progenitor populations from degenerative somatic cells remains elusive. The present study focused on intervertebral disc degeneration (IVDD) and identified a three-factor combination (OCT4, FOXA2, TBXT [OFT]) that could induce the dedifferentiation-like reprogramming of degenerative nucleus pulposus cells (dNPCs) toward induced notochordal-like cells (iNCs). Single-cell transcriptomics dissected the transitions of cell identity during reprogramming. Further, OCT4 was found to directly interact with bromodomain PHD-finger transcription factor to remodel the chromatin during the early phases, which was crucial for initiating this dedifferentiation-like reprogramming. In rat models, intradiscal injection of adeno-associated virus carrying OFT generated iNCs from in situ dNPCs and reversed IVDD. These results collectively present a proof-of-concept for dedifferentiation-like reprogramming of degenerated somatic cells into corresponding progenitors through the development of a factor-based strategy, providing a promising approach for regeneration in degenerative disc diseases.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1000,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dedifferentiation-like reprogramming of degenerative nucleus pulposus cells into notochordal-like cells by defined factors.\",\"authors\":\"Yuang Zhang, Chengzhen Liang, Haibin Xu, Yi Li, Kaishun Xia, Liyin Wang, Xianpeng Huang, Jiangjie Chen, Jiawei Shu, Feng Cheng, Kesi Shi, Jingkai Wang, Yiqing Tao, Shaoke Wang, Yongxiang Zhang, Hao Li, Shoumin Feng, Fangcai Li, Xiaopeng Zhou, Qixin Chen\",\"doi\":\"10.1016/j.ymthe.2024.06.018\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. 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引用次数: 0
摘要
功能性体细胞的广泛退化和内源性干细胞/祖细胞群的耗竭给退行性疾病的组织再生带来了重大挑战。目前,从退化体细胞直接生成相应祖细胞群的细胞重编程方法仍未出现。本研究以椎间盘变性(IVDD)为研究对象,发现了一种三因子组合(OCT4、FOXA2、TBXT(OFT))可以诱导变性髓核细胞(dNPCs)向诱导性脊索软骨样细胞(iNCs)进行类似于去分化的重编程。单细胞转录组学剖析了重编程过程中细胞身份的转变。此外,研究还发现OCT4与溴域PHD-手指转录因子(BPTF)直接相互作用,在早期阶段重塑染色质,这对启动这种类似于去分化的重编程至关重要。在大鼠模型中,椎间盘内注射携带 OFT 的腺相关病毒可从原位 dNPCs 生成 iNCs 并逆转 IVDD。这些结果共同证明了一种概念,即通过开发一种基于因子的策略,将退化的体细胞进行类似于去分化的重编程,使其成为相应的祖细胞,为椎间盘退行性疾病的再生提供了一种前景广阔的方法。
Dedifferentiation-like reprogramming of degenerative nucleus pulposus cells into notochordal-like cells by defined factors.
The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. Currently, a cellular reprogramming approach enabling directly generating corresponding progenitor populations from degenerative somatic cells remains elusive. The present study focused on intervertebral disc degeneration (IVDD) and identified a three-factor combination (OCT4, FOXA2, TBXT [OFT]) that could induce the dedifferentiation-like reprogramming of degenerative nucleus pulposus cells (dNPCs) toward induced notochordal-like cells (iNCs). Single-cell transcriptomics dissected the transitions of cell identity during reprogramming. Further, OCT4 was found to directly interact with bromodomain PHD-finger transcription factor to remodel the chromatin during the early phases, which was crucial for initiating this dedifferentiation-like reprogramming. In rat models, intradiscal injection of adeno-associated virus carrying OFT generated iNCs from in situ dNPCs and reversed IVDD. These results collectively present a proof-of-concept for dedifferentiation-like reprogramming of degenerated somatic cells into corresponding progenitors through the development of a factor-based strategy, providing a promising approach for regeneration in degenerative disc diseases.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.