Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways.
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 identified as critical regulators in cardiogenesis and 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 remained largely 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 induced 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 fate-switching role of miR-1 at early human cardiovascular commitment stage via suppressing both WNT and FGF signaling pathways.
Department of Developmental Biology, School of Medicine, University of Pittsburgh, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA.
Tung-Ying
TY
Lu
Bo
B
Lin
Yang
Y
Li
Arshi
A
Arora
Lu
L
Han
Cheng
C
Cui
Claudia
C
Coronnello
Yi
Y
Sheng
Panayiotis V
PV
Benos
Lei
L
Yang
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D034622:RNA Interference; D015203:Reproducibility of Results; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D051157:Frizzled Receptors; C544547:MIRN1 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors
Cardiomyocyte; Induced pluripotent stem cells; Multipotent cardiovascular progenitors; microRNA-1