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Epicardial FSTL1 reconstitution regenerates the adult mammalian heart

2015; Nature Portfolio; Volume: 525; Issue: 7570 Linguagem: Inglês

10.1038/nature15372

1476-4687

Ke Wei, Vahid Serpooshan, Cecilia Hurtado, Marta Diez-Cuñado, Mingming Zhao, Sonomi Maruyama, Wenhong Zhu, Giovanni Fajardo, Michela Noseda, Kazuto Nakamura, Xueying Tian, Qiaozhen Liu, Andrew Wang, Yuka Matsuura, Paul J. Bushway, Wenqing Cai, A. K. Savchenko, Morteza Mahmoudi, Michael Schneider, Maurice J.B. van den Hoff, Manish J. Butte, Phillip C. Yang, Kenneth Walsh, Bin Zhou, Daniel Bernstein, Mark Mercola, Pilar Ruiz‐Lozano,

Cardiac Fibrosis and Remodeling

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans. The secreted factor follistatin-like 1 (FSTL1) becomes undetectable in the epicardium of infarcted hearts; when reconstituted using a collagen patch sutured onto an infarcted heart, FSTL1 can induce cell cycle entry and division of pre-existing cardiomyocytes, thus boosting heart function and survival in mouse and pig models of myocardial infarction. Human heart tissue has a limited capacity to regenerate but recent studies have suggested that the epicardium might preserve function of the adult myocardium following injury to some extent, possibly by providing myogenic progenitors. This study identifies the secreted factor follistatin-like 1 (FSTL1) as a regenerative factor that is normally present in healthy epicardium, but lost following myocardial infarction, suggesting a mechanism whereby injury diminishes the regenerative potency of the mammalian heart. Reconstitution of FSTL1 by an engineered epicardial biomaterial improved cardiac function in animal models of myocardial infarction, with evidence of cardiomyocyte regeneration amenable to clinical translation.