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Functional screening identifies miRNAs inducing cardiac regeneration
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Journal Article
Functional screening identifies miRNAs inducing cardiac regeneration
2012
Overview
In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes
ex vivo
and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.
The human heart regenerates poorly, causing insufficient healing after injury; here, microRNAs screened for the ability to induce cardiomyocyte proliferation are shown to stimulate cardiac regeneration and almost complete recovery of the heart after infarction.
MicroRNA boosts heart regeneration
The mammalian heart has a poor capacity to regenerate, with the ability of cardiomyocytes to proliferate disappearing soon after birth. In this study, Mauro Giacca and colleagues screened a synthetic microRNA (miRNA) library of human origin for the ability to induce cardiomyocyte proliferation, with aim of identifying potential human therapeutics. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in rodent cardiomyocytes. The two most potent, hsa-miR-590 and hsa-miR-199a, were tested further and shown to induce cardiac regeneration after myocardial infarction in mice.
In vivo
treatment with these miRNAs led to almost complete and stable recovery of cardiac function.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Biological and medical sciences
/ Heart
/ Heart - growth & development
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mice
/ MicroRNA
/ Myocardial Infarction - genetics
/ Myocardial Infarction - pathology
/ Myocardial Infarction - prevention & control
/ Myocardial Infarction - therapy
/ Myocarditis. Cardiomyopathies
/ Myocytes, Cardiac - cytology
/ Myocytes, Cardiac - metabolism
/ Rats
/ Rodents
/ Science
