Yang Jie, Jiang Wei
Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China.
Front Cell Dev Biol. 2020 Jul 21;8:653. doi: 10.3389/fcell.2020.00653. eCollection 2020.
Human embryonic stem cells (hESCs) possess the potential of long-term self-renewal and three primary germ layers differentiation, and thus hESCs are expected to have broad applications in cell therapy, drug screening and basic research on human early embryonic development. Many efforts have been put to dissect the regulation of pluripotency and direct differentiation of hESCs. TGFβ/Activin/Nodal signal pathway critically regulates pluripotency maintenance and cell differentiation through the main signal transducer SMAD2/3 in hESCs, but the action manners of SMAD2/3 in hESCs are sophisticated and not documented yet. Here we review and discuss the roles of SMAD2/3 in hESC pluripotency maintenance and differentiation initiation separately. We summarize that SMAD2/3 regulates pluripotency and differentiation mainly through four aspects, (1) controlling divergent transcriptional networks of pluripotency and differentiation; (2) interacting with chromatin modifiers to make the chromatin accessible or recruiting METTL3-METTL14-WTAP complex and depositing m6A to the mRNA of pluripotency genes; (3) acting as a transcription factor to activate endoderm-specific genes to thus initiate definitive endoderm differentiation, which happens as cyclin D/CDK4/6 downstream target in later G1 phase as well; (4) interacting with endoderm specific lncRNAs to promote differentiation.
人类胚胎干细胞（hESCs）具有长期自我更新和分化为三个主要胚层的潜力，因此有望在细胞治疗、药物筛选以及人类早期胚胎发育的基础研究中得到广泛应用。人们已经做出了许多努力来剖析hESCs多能性的调控和直接分化机制。转化生长因子β/激活素/Nodal信号通路通过hESCs中的主要信号转导分子SMAD2/3来严格调控多能性维持和细胞分化，但SMAD2/3在hESCs中的作用方式复杂，尚未有文献记载。在此，我们分别综述并讨论SMAD2/3在hESC多能性维持和分化起始中的作用。我们总结出，SMAD2/3主要通过四个方面来调控多能性和分化：（1）控制多能性和分化的不同转录网络；（2）与染色质修饰因子相互作用，使染色质可及，或招募METTL3-METTL14-WTAP复合物并将m6A沉积到多能性基因的mRNA上；（3）作为转录因子激活内胚层特异性基因，从而启动定形内胚层分化，这也发生在G1期后期细胞周期蛋白D/细胞周期蛋白依赖性激酶4/6的下游靶点处；（4）与内胚层特异性长链非编码RNA相互作用以促进分化。
