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 ()
Additional contact information
Elad Bassat: Weizmann Institute of Science
Yara Eid Mutlak: Faculty of Biology
Alex Genzelinakh: Weizmann Institute of Science
Ilya Y. Shadrin: Duke University
Kfir Baruch Umansky: Weizmann Institute of Science
Oren Yifa: Weizmann Institute of Science
David Kain: Weizmann Institute of Science
Dana Rajchman: Weizmann Institute of Science
John Leach: Baylor College of Medicine and The Texas Heart Institute
Daria Riabov Bassat: Weizmann Institute of Science
Yael Udi: Weizmann Institute of Science
Rachel Sarig: Weizmann Institute of Science
Irit Sagi: Weizmann Institute of Science
James F. Martin: Baylor College of Medicine and The Texas Heart Institute
Nenad Bursac: Duke University
Shenhav Cohen: Faculty of Biology
Eldad Tzahor: Weizmann Institute of Science

Nature, 2017, vol. 547, issue 7662, 179-184

Abstract: Abstract The adult mammalian heart is non-regenerative owing to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only during the first week of life. Here we show that changes in the composition of the extracellular matrix during this week can affect cardiomyocyte growth and differentiation in mice. We identify agrin, a component of neonatal extracellular matrix, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant agrin promotes the division of cardiomyocytes that are derived from mouse and human induced pluripotent stem cells through a mechanism that involves the disassembly of the dystrophin–glycoprotein complex, and Yap- and ERK-mediated signalling. 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 that there are additional therapeutic mechanisms. Together, our results uncover a new inducer of mammalian heart regeneration and highlight fundamental roles of the extracellular matrix in cardiac repair.

Date: 2017
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DOI: 10.1038/nature22978

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