Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways

Abstract

Early heart development takes place through a complex series of steps, including the induction of cardiac mesoderm, formation of the cardiovascular progenitor cells and the commitment of cardiovascular lineage cells, such as cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs). Recently, microRNAs, a family of endogenous, small non-coding RNAs, have been implicated as critical regulators at the posttranscriptional level in cardiogenesis as well as cardiovascular disease. Previous studies demonstrated that microRNA-1 (miR-1) could promote cardiac differentiation from mouse and human embryonic stem (ES) cells. However, the underlying mechanism largely remained unclear. We performed microRNA deep sequencing among human ES cells, ES cell derived-multipotent cardiovascular progenitors (MCPs), and MCP-specified CMs, ECs, and SMCs. A specific enrichment of miR-1 was found in CMs, not in SMCs or ECs, implying a key role of miR-1 in determining cardiovascular commitment from MCPs. When overexpressed in human pluripotent stem cells, miR-1 enhanced the expression of key cardiac transcriptional factors and sarcomeric genes. Importantly, we found miR-1 promoted CM differentiation and suppressed EC commitment from MCPs by modulating the activities of WNT and FGF signaling pathways. FZD7 and FRS2 were confirmed as miR-1 targets using luciferase reporter assay and western blot. Overall, this study reveals a switch role of miR-1 at early human cardiovascular commitment stage via suppressing both WNT and FGF signaling pathways.

MicroRNA MiR-199a-5p Regulates Smooth Muscle Cell Proliferation and Morphology by Targeting WNT2 Signaling Pathway

“…Interestingly, similar to miR-199a-5p, muscle-specific miR-1 suppresses WNT signaling and promotes differentiation of cardiomyocytes by modulating the activities of WNT and FGF signaling pathways (54). Our results suggest the existence of a positive feedback loop between SRF/myocardin and miR199a-5p that promotes the SM-specific gene expression.…”

microRNA regulation of Wnt signaling pathways in development and disease

“…miR-1 is a key muscle-specific miRNA expressed in cardiac and smooth muscle cells [251,252]. miR-1 promotes differentiation of cardiomyocytes by suppressing the activities of Wnt and FGF signaling pathways [253]. Specifically, miR-1 directly inhibits FZ7 to repress Wnt signaling [253].…”

“…miR-1 promotes differentiation of cardiomyocytes by suppressing the activities of Wnt and FGF signaling pathways [253]. Specifically, miR-1 directly inhibits FZ7 to repress Wnt signaling [253]. Because miRNAs are able to regulate all stages of cardiac development, certain miRNA expression signatures are used for clinical diagnosis of human heart disease [245].…”

Knockdown of Plakophilin 2 Downregulates miR-184 Through CpG Hypermethylation and Suppression of the E2F1 Pathway and Leads to Enhanced Adipogenesis In Vitro

“…18-20 . MiRNAs are largely “nudgers and tweakers of genome management” as their effects on transcript levels, by-and-large, are modest 21 .…”

“…MiRNAs are largely “nudgers and tweakers of genome management” as their effects on transcript levels, by-and-large, are modest 21 . Because of multiplicity of their targets, however, miRNAs influence various molecular networks and biological processes 20, 22-30 . MiRNAs are also targets of various signaling pathways, including Hippo and the canonical Wnt pathways, which are implicated in AC 20, 22-2930 .…”