The extracellular matrix protein Agrin promotes heart regeneration in mice
Elad Bassat, Yara Eid Mutlak, Alex Genzelinakh, Ilya Y. Shadrin, Kfir Baruch-Umansky, Oren Yifa, David Kain, Dana Rajchman, John Leach, Daria Riabov Bassat, Yael Udi, Rachel Sarig, Irit Sagi, James F. Martin, Nenad Bursac, Shenhav Cohen and Eldad Tzahor
The adult mammalian heart is non-regenerative due to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only for the first week of life. Here we show that changes in the composition of the extracellular matrix (ECM) during this week can affect cardiomyocyte growth and differentiation in mice. We identify Agrin, a component of neonatal ECM, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant Agrin promotes the division of mouse and human iPSC-derived cardiomyocytes via a mechanism that involves the disassembly of the dystrophin glycoprotein complex and Yap and ERK-mediated signaling. In vivo, a single administration of Agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests additional therapeutic mechanisms. Collectively, we uncover a new inducer of mammalian heart regeneration, highlighting fundamental roles of the ECM in cardiac repair.