Functional screening identifies miRNAs inducing cardiac regeneration

Abstract

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.

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…The dedifferentiation model for the cellular sources of cardiac repair/regeneration was supported by the fact that cardiac muscles mainly regenerate from pre-existing cardiomyocytes after injury in zebrafish [8,9] and mammals [10][11][12]. The stem cell/progenitor cell model for cardiac regeneration in mammals was also recognized by the existence of Sca1 + and c-Kit + cardiac stem cells in mice [13,14], while the transdifferentiation or lineage reprogramming model was proposed partly based on the ability of cardiac fibroblast transdifferentiation into myocytes upon induction by reprogramming factors or microRNA in mice [15][16][17] and reprogramming of embryonic atrial into ventricular myocytes after injury in zebrafish [18].…”

MicroRNA in cardiovascular biology and disease

“…MiR-199 and miR-590 have been shown to promote regeneration of the myocardium and to improve cardiac function. 25 Stem cell-based therapies represent an attractive approach for treating cardiovascular diseases. However, regenerative therapy based on delivering stem cells into the heart has not yet been successful in clinical trials.…”

Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection

“…Only recently this approach has been extended to miRNAs 20,21 , and is yet to be applied for the identification of miRNAs critical for infection by bacterial pathogens.…”