Aguirre Aitor, Montserrat Nuria, Zacchigna Serena, Nivet Emmanuel, Hishida Tomoaki, Krause Marie N, Kurian Leo, Ocampo Alejandro, Vazquez-Ferrer Eric, Rodriguez-Esteban Concepcion, Kumar Sachin, Moresco James J, Yates John R, Campistol Josep M, Sancho-Martinez Ignacio, Giacca Mauro, Izpisua Belmonte Juan Carlos
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Center of Regenerative Medicine of Barcelona (CMRB), 08003 Barcelona, Spain.
Cell Stem Cell. 2014 Nov 6;15(5):589-604. doi: 10.1016/j.stem.2014.10.003.
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 after 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.
心力衰竭是发达国家死亡率和发病率的主要原因之一，部分原因是哺乳动物缺乏心脏组织再生能力。目前尚不清楚这是由于其他生物中存在的再生机制在进化过程中丧失，还是由于无法激活这些机制。在此，我们解析了成年斑马鱼心脏再生的潜在机制，并表明这种反应的分子调节因子在哺乳动物中是保守的。我们确定了miR-99/100和Let-7a/c及其蛋白质靶点smarca5和fntb是斑马鱼心肌细胞去分化和心脏再生的关键调节因子。虽然人类和小鼠的成年心肌细胞在心肌梗死后无法引发内源性再生反应，但我们表明，在小鼠体内对这种分子机制进行操作会导致心肌细胞去分化，并在损伤后改善心脏功能。这些数据为识别和激活保守的分子程序以再生受损心脏提供了概念验证。
