The extracellular matrix protein agrin promotes heart regeneration in mice

• Published in: Nature (London) 2017-07, Vol.547 (7662), p.179-184
• Main Authors: Bassat, Elad, Mutlak, Yara Eid, Genzelinakh, Alex, Shadrin, Ilya Y., Baruch Umansky, Kfir, Yifa, Oren, Kain, David, Rajchman, Dana, Leach, John, Riabov Bassat, Daria, Udi, Yael, Sarig, Rachel, Sagi, Irit, Martin, James F., Bursac, Nenad, Cohen, Shenhav, Tzahor, Eldad
• Format: Article
• Language: English
• Subjects: 13/100; 13/106; 13/107; 13/51; 14/19; 14/63; 38/77; 631/80; 692/699/75; Adaptor Proteins, Signal Transducing - metabolism; Agrin; Agrin - metabolism; Animals; Animals, Newborn; Cardiomyocytes; Care and treatment; Cell Cycle Proteins; Cell growth; Cell Proliferation; Dystroglycans - metabolism; Dystrophin; Extracellular matrix; Extracellular Matrix Proteins - metabolism; Female; Glycoproteins; Health aspects; Heart; Heart - physiology; Heart diseases; Humanities and Social Sciences; Mammals; Matrix protein; Medical research; Methods; Mice; multidisciplinary; Myocardial infarction; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocardium - cytology; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Neonates; Phosphoproteins - metabolism; Pluripotency; Proteins; Regeneration; Regenerative medicine; Rodents; Science; Signaling; Stem cell transplantation; Stem cells; Yes-associated protein
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature22978

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. The extracellular matrix protein agrin promotes cardiac regeneration in adult mice after myocardial infarction; it modulates cardiac differentiation and proliferation by interacting with the dystrophin–glycoprotein complex, Yap and ERK-mediated signalling. Born Agrin mouse hearts The neonatal mouse heart can regenerate during a limited time period after birth, but this property is rapidly lost. Eldad Tzahor and colleagues identify a component of the neonatal heart extracellular matrix, agrin, which is required for heart regeneration in neonatal mice. They further show that recombinant agrin can be used to improve the function of adult mouse hearts after myocardial infarction. The mechanism by which agrin can promote heart function and regeneration may be multi-faceted, but the authors also show that it can boost cardiomyocyte proliferation, which could contribute to the observed effects.