In vivo activation of a conserved microRNA program induces robust mammalian heart regeneration (RNA-Seq)

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here, we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c, and their protein targets smarca5 and fntb, as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response following myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof-of-concept for identifying and activating conserved molecular programs to regenerate the damaged heart.心力衰竭（Heart failure）是发达国家致死与致残的首要病因，部分原因在于哺乳动物不具备心脏组织再生的能力。目前学界尚不清楚，这一现象究竟源于其他生物所拥有的再生机制在进化过程中发生丢失，还是哺乳动物无法激活此类再生机制。本研究解析了成年斑马鱼（zebrafish）心脏再生的潜在分子机制，并证实该再生应答的核心调控通路在哺乳动物中具有保守性。我们鉴定出miR-99/100与Let-7a/c，以及它们的蛋白靶点smarca5和fntb，是斑马鱼中心肌细胞（cardiomyocyte）去分化与心脏再生的关键调控因子。尽管人类及成年小鼠的心肌细胞在心肌梗死（myocardial infarction）后无法触发内源性再生应答，但本研究证实，在小鼠体内对该分子调控系统进行干预，可诱导心肌细胞发生去分化，并改善损伤后心脏的功能状态。本研究数据为鉴定并激活保守性再生调控程序以修复受损心脏提供了概念验证（proof-of-concept）。