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 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.

中文翻译：

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通过特定因素将退变髓核细胞去分化重编程为脊索样细胞


功能性体细胞的广泛退化和内源干细胞/祖细胞群的耗竭对退行性疾病中的组织再生提出了重大挑战。目前，能够从退化体细胞直接产生相应祖细胞群的细胞重编程方法仍然难以捉摸。本研究重点关注椎间盘退变 (IVDD)，并确定了一种三因子组合（OCT4、FOXA2、TBXT [OFT]），可以诱导退变髓核细胞 (dNPC) 向诱导性脊索样细胞进行去分化样重编程（iNC）。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，发现 OCT4 直接与溴结构域 PHD-finger 转录因子相互作用，在早期重塑染色质，这对于启动这种去分化样重编程至关重要。在大鼠模型中，椎间盘内注射携带 OFT 的腺相关病毒可从 dNPC 中产生 iNC，并逆转 IVDD。这些结果共同提出了通过开发基于因子的策略将退化体细胞去分化样重编程为相应祖细胞的概念验证，为退行性椎间盘疾病的再生提供了一种有前途的方法。