Human Cardiac Stem Cell Differentiation Is Regulated by a Mircrine Mechanism

Abstract

Background Cardiac stem cells (CSCs) delivered to the infarcted heart generate a large number of small fetal-neonatal cardiomyocytes which fail to acquire the differentiated phenotype. However, the interaction of CSCs with post-mitotic myocytes results in the formation of cells with adult characteristics. Methods and Results Based on in vitro and in vivo assays, we report that the commitment of human CSCs (hCSCs) to the myocyte lineage and the generation of mature working cardiomyocytes are influenced by microRNA-499 (miR-499) which is barely detectable in hCSCs, but is highly expressed in post-mitotic human cardiomyocytes. miR-499 traverses gap junction channels and translocates to structurally coupled hCSCs favoring their differentiation into functionally-competent cells. Expression of miR-499 in hCSCs represses the miR-499 target genes Sox6 and Rod1, enhancing cardiomyogenesis in vitro and after infarction in vivo. Although cardiac repair was detected in all cell-treated infarcted hearts, the aggregate volume of the regenerated myocyte mass and myocyte cell volume were greater in animals injected with hCSCs overexpressing miR-499. Treatment with hCSCs resulted in an improvement in ventricular function, consisting of a better preservation of developed pressure, and positive and negative dP/dt after infarction. An additional positive effect on cardiac performance occurred with miR-499, pointing to enhanced myocyte differentiation/hypertrophy as the mechanism by which miR-499 potentiated the restoration of myocardial mass and function in the infarcted heart. Conclusions The recognition that miR-499 promotes the differentiation of hCSCs into mechanically integrated cardiomyocytes has important clinical implications for the treatment of human heart failure.

MicroRNA in cardiovascular biology and disease

“…27 Similar results are achieved by transplanting c-kit+ cardiac progenitor cells overexpressing miR-499. 28 Cardiac fibrosis following myocardial infarction, resulting from excessive fibroblast activation, reduces regeneration, leads to pathological remodeling, impairs systolic function and increases susceptibility to arrhythmias. It has been shown that the expression of a suitable combination of transcription factor genes (Gata4, Mef2c, Tbx5) could convert resident cardiac non-myocyte fibroblasts into contractile cells by direct reprogramming.…”

Circulating miR-499 as a potential biomarker for acute myocardial infarction

“…For example, the overexpression of miRNA-499 increased the expression of MEF2, SRF and other cardiac transcription factors that activate the expression of cardiac genes encoding many contractile proteins (15), while MEF2 was found to bind to the intronic enhancer of miRNA-499 to activate its expression in ventricular myocytes (16,17). In addition, miRNA-499 was reported to induce structural and functional differentiation of cardiac stem cells (CSCs) into cardiomyocytes, therefor promoting the recovery of heart after injury (18).…”

Concise Review: Mechanotransduction via p190RhoGAP Regulates a Switch Between Cardiomyogenic and Endothelial Lineages in Adult Cardiac Progenitors

“…Extensive knowledge has been accumulated regarding mechanisms underlying stem cell proliferation [3], differentiation [4,5], and morphogenesis [6,7]. Many extracellular cues, in particular growth factors and mechanical cues, are known to strongly influence the above phenomena, when analyzed separately both in vitro, and in vivo [8].…”