由于能使成体细胞“返老还童”为干细胞，诱导多功能干细胞(iPS细胞)是近年来干细胞领域的研究热点。中国科学院广州生物医药与健康研究院裴端卿研究员、陈捷凯副研究员等人经过多年努力，近日破解了iPS细胞诱导过程中一个极为重要的障碍，论文2日在线发表在《自然・遗传学》杂志上。

研究过程中，裴端卿及其团队发现iPS细胞诱导过程中大量出现一类细胞克隆，外观、生长速度等各方面酷似干细胞，却没有干细胞应有的基因表达和功能。

经过深入研究，科学家发现诱导培养iPS细胞所使用的血清是诱发这个“路障”的元凶：细胞中的一种蛋白――BMP蛋白对重编程过程起抑制作用。

研究人员进一步发现，这些酷似干细胞的“假货”在某些诱导条件下，如用维生素C处理，也会变成货真价实的诱导多功能干细胞。

哈佛大学再生医学中心教授康拉德说，这一发现是决定细胞命运的分子机制研究的重大突破，将使研究者更高效更高质量地制备诱导多功能干细胞，加快制备来自病人疾病的特异细胞系，加快阿尔茨海默氏症、帕金森氏症 等疾病的药物研发。

doi:10.1038/ng.2491

PMC:
PMID:

H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs

Jiekai Chen, He Liu, Jing Liu, Jing Qi， Bei Wei， Jiaqi Yang， Hanquan Liang， You Chen， Jing Chen， Yaran Wu， Lin Guo， Jieying Zhu， Xiangjie Zhao， Tianran Peng， Yixin Zhang， Shen Chen， Xuejia Li， Dongwei Li， Tao Wang， Duanqing Pei

The induction of pluripotent stem cells (iPSCs) by defined factors is poorly understood stepwise. Here, we show that histone H3 lysine 9 (H3K9) methylation is the primary epigenetic determinant for the intermediate pre-iPSC state, and its removal leads to fully reprogrammed iPSCs. We generated a panel of stable pre-iPSCs that exhibit pluripotent properties but do not activate the core pluripotency network, although they remain sensitive to vitamin C for conversion into iPSCs. Bone morphogenetic proteins (BMPs) were subsequently identified in serum as critical signaling molecules in arresting reprogramming at the pre-iPSC state. Mechanistically, we identified H3K9 methyltransferases as downstream targets of BMPs and showed that they function with their corresponding demethylases as the on/off switch for the pre-iPSC fate by regulating H3K9 methylation status at the core pluripotency loci. Our results not only establish pre-iPSCs as an epigenetically stable signpost along the reprogramming road map, but they also provide mechanistic insights into the epigenetic reprogramming of cell fate.