分化潜能是干细胞重要生物学特征，按照分化潜能的大小可分为全能性干细胞、多能性干细胞和单能干细胞。目前，人们对干细胞分化潜能的获得、失去和维持机制并不完全清楚。近日，研究人员以诱导多能干细胞（induced pluripotent stem cell，iPSC）为研究模型，揭示了ADAR1在iPSC多能性获得和丧失中的作用。相关研究结果发表在Cell·Stem Cell期刊上。已有研究表明，腺苷到肌苷（adenosine to inosine，A-to-I）的RNA编辑由ADAR1催化完成，同时会显着改变细胞转录组，但该过程在体细胞重编程中的功能作用尚不清楚。在该研究中，研究人员发现ADAR1介导的A-to-I编辑的缺失会破坏iPSC重编程过程中间充质到上皮的转变（mesenchymal-to-epithelial transition，MET），并阻碍干细胞多能性的获得。利用化学和遗传方法，研究人员发现ADAR1依赖的RNA编辑缺失通过双链RNA（double-stranded RNA，dsRNAs）传感器MDA5诱导异常的先天免疫应答，释放内质网应激并阻碍上皮细胞性获得。此外，A-to-I编辑还会阻碍MDA5感知和dsRNAs编码膜蛋白的隔离，而dsRNAs编码膜蛋白通过激活依赖于PERK的未折叠蛋白反应通路来促进MET和内质网稳态。该研究确定了ADAR1及其A-to-I编辑活动在诱导多能干细胞多能性获得和细胞命运转换过程中的关键作用，并描绘了MET控制有效重编程的关键调控层。
推荐阅读原文：
ADAR1-Dependent RNA Editing Promotes MET and iPSC Reprogramming by Alleviating ER Stress.
RNA editing of adenosine to inosine (A to I) is catalyzed by ADAR1 and dramatically alters the cellular transcriptome, although its functional roles in somatic cell reprogramming are largely unexplored. Here, we show that loss of ADAR1-mediated A-to-I editing disrupts mesenchymal-to-epithelial transition (MET) during induced pluripotent stem cell (iPSC) reprogramming and impedes acquisition of induced pluripotency. Using chemical and genetic approaches, we show that absence of ADAR1-dependent RNA editing induces aberrant innate immune responses through the double-stranded RNA (dsRNA) sensor MDA5, unleashing endoplasmic reticulum (ER) stress and hindering epithelial fate acquisition. We found that A-to-I editing impedes MDA5 sensing and sequestration of dsRNAs encoding membrane proteins, which promote ER homeostasis by activating the PERK-dependent unfolded protein response pathway to consequently facilitate MET. This study therefore establishes a critical role for ADAR1 and its A-to-I editing activity during cell fate transitions and delineates a key regulatory layer underlying MET to control efficient reprogramming.
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