Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice
Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice
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DOI：
10.1126/science.abg5159
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发表时间：
2021-09-24
期刊：
影响因子：
56.9
通讯作者：
Braun, Thomas
中科院分区：
文献类型：
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作者：
Chen, Yanpu;Luttmann, Felipe F.;Braun, Thomas
在成年哺乳动物心脏中，心肌细胞（CM）的替换非常缓慢，阻止了受损心肌的再生。相比之下，胎儿心脏显示相当大的再生潜力，由于存在不太成熟的CM，仍然有增殖能力。在这项研究中，我们证明了Oct 4，Sox 2，Klf 4和c-Myc（OSKM）的心脏特异性表达诱导成年CM去分化，赋予成年心脏再生能力。OSKM的瞬时CM特异性表达延长了出生后小鼠心脏的再生窗口，并诱导成人CM中类似于胎儿CM的基因表达程序。CM中OSKM的延长表达导致细胞重编程和心脏肿瘤形成。心肌梗死前和心肌梗死期间的短期OSKM表达可改善心肌损伤并改善心脏功能，表明时间控制的去分化和重编程使哺乳动物CM能够重新进入细胞周期并促进心脏再生。
Cardiomyocyte (CM) replacement is very slow in adultmammalian hearts, preventing regeneration of damaged myocardium. By contrast, fetal hearts display considerable regenerative potential owing to the presence of less mature CMs that still have the ability to proliferate. In this study, we demonstrate that heart-specific expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) induces adult CMs to dedifferentiate, conferring regenerative capacity to adult hearts. Transient, CM-specific expression of OSKM extends the regenerative window for postnatal mouse hearts and induces a gene expression program in adult CMs that resembles that of fetal CMs. Extended expression of OSKM in CMs leads to cellular reprogramming and heart tumor formation. Short-term OSKM expression before and during myocardial infarction ameliorates myocardial damage and improves cardiac function, demonstrating that temporally controlled dedifferentiation and reprogramming enable cell cycle reentry of mammalian CMs and facilitate heart regeneration.