State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, P. R. China.
Department of Orthopedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
Prog Neurobiol. 2022 Jul;214:102284. doi: 10.1016/j.pneurobio.2022.102284. Epub 2022 May 6.
Neurons in the central nervous system (CNS) are terminally differentiated cells that gradually lose their ability to support regeneration during maturation due to changes in transcriptomic and chromatin landscape. Similar transcriptomic changes also occur during development when stem cells differentiate into different types of somatic cells. Importantly, differentiated cells can be reprogrammed back to induced pluripotent stems cells (iPSCs) via global epigenetic remodeling by combined overexpression of pluripotent reprogramming factors, including Oct4, Sox2, Klf4, c-Myc, Nanog, and/or Lin28. Moreover, recent findings showed that many proneural transcription factors were able to convert non-neural somatic cells into neurons bypassing the pluripotent stage via direct reprogramming. Interestingly, many of these factors have recently been identified as key regulators of CNS neural regeneration. Recent studies indicated that these factors could rejuvenate mature CNS neurons back to a younger state through cellular state reprogramming, thus favoring regeneration. Here we will review some recent findings regarding the roles of genetic cellular state reprogramming in regulation of neural regeneration and explore the potential underlying molecular mechanisms. Moreover, by using newly emerging techniques, such as multiomics sequencing with big data analysis and Crispr-based gene editing, we will discuss future research directions focusing on better revealing cellular state reprogramming-induced remodeling of chromatin landscape and potential translational application.
中枢神经系统（CNS）中的神经元是终末分化细胞，由于转录组和染色质景观的变化，在成熟过程中逐渐丧失支持再生的能力。类似的转录组变化也发生在干细胞分化为不同类型体细胞的发育过程中。重要的是，通过组合过表达多能重编程因子，包括 Oct4、Sox2、Klf4、c-Myc、Nanog 和/或 Lin28，分化细胞可以通过全局表观遗传重塑重新编程为诱导多能干细胞（iPSCs）。此外，最近的发现表明，许多神经前体细胞转录因子能够通过直接重编程绕过多能阶段将非神经体细胞转化为神经元。有趣的是，这些因子中的许多最近被确定为 CNS 神经再生的关键调节因子。最近的研究表明，这些因子可以通过细胞状态重编程使成熟的 CNS 神经元恢复到更年轻的状态，从而有利于再生。在这里，我们将回顾一些关于遗传细胞状态重编程在调节神经再生中的作用的最新发现，并探讨潜在的分子机制。此外，通过使用新兴技术，如大数据分析的多组学测序和基于 Crispr 的基因编辑，我们将讨论未来的研究方向，重点是更好地揭示细胞状态重编程诱导的染色质景观重塑和潜在的转化应用。
