In Vivo Activation of a Conserved MicroRNA Program Induces Mammalian Heart Regeneration

Abstract

SUMMARY Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here, we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c, and their protein targets smarca5 and fntb, as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response following myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof-of-concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

Mending a Faltering Heart

“…The recalcitrance of adult cardiomyocytes to go through cytokinesis may have multiple causes, such as physical hindrance by sarcomeres, 26 lack of hormonal or neural signals controlling postnatal growth, 5,27 and changes in epigenetic pathways. 28 As the body of evidence supporting cardiomyocytes as the most important cellular source of heart regeneration grows, it has become critically important to unlock the mechanisms that control mitosis and cytokinesis of adult cardiomyocytes and identify strategies to enhance cardiomyocyte regeneration.…”

“…61 Our group recently identified miR-99/100 and Let-7a/c as critical regulators of zebrafish heart regeneration by systematic screening of genes differentially regulated during the process. 28 These miRs are highly expressed in the uninjured heart but undergo rapid downregulation during injury. We further identified ftnb (β-subunit of farnesyl transferase) and Smarca5 (SWI/SNF-related matrixassociated actin-dependent regulator of chromatin subfamily a, member 5) as downstream targets of miR-99/100 and as important regulators of cardiomyocyte dedifferentiation.…”

The Transcriptional Landscape of Regenerating Newborn Mouse Hearts

“…In vivo silencing of both Let-7a/c and miR-99/100 in adult mice after myocardial infarction promoted cardiomyocyte dedifferentiation and improved heart function. 11 Altogether, the systematic integrative transcriptional profiling approach by O'Meara et al identified a core set of factors with proven and potential functions in the regulation of cell-cycle re-entry and cardiomyocyte dedifferentiation in damaged hearts ( Figure 1).…”

Conserved MicroRNA Program as Key to Mammalian Cardiac Regeneration

“…In contrast, lower vertebrates such as Zebrafish can completely regenerate the organ after damage. A recent article from Aguirre et al 1 in Cell Stem Cell shows that this difference is because of a microRNA program that is active in Zebrafish but silent in mammals. Crucially, reactivation of this dormant microRNA program in the murine heart induces regeneration of the myocardium.…”