title: MicroRNA-1 transfected embryonic stem cells enhance cardiac myocyte differentiation and inhibit apoptosis by modulating the PTEN/Akt pathway in the infarcted heart.
abstract: microRNAs (miRs) have emerged as critical modulators of various physiological processes including stem cell differentiation. Indeed, miR-1 has been reported to play an integral role in the regulation of cardiac muscle progenitor cell differentiation. However, whether overexpression of miR-1 in embryonic stem (ES) cells (miR-1-ES cells) will enhance cardiac myocyte differentiation following transplantation into the infarcted myocardium is unknown. In the present study, myocardial infarction (MI) was produced in C57BL/6 mice by left anterior descending artery ligation. miR-1-ES cells, ES cells, or culture medium (control) was transplanted into the border zone of the infarcted heart, and 2 wk post-MI, cardiac myocyte differentiation, adverse ventricular remodeling, and cardiac function were assessed. We provide evidence demonstrating enhanced cardiac myocyte commitment of transplanted miR-1-ES cells in the mouse infarcted heart as compared with ES cells. Assessment of apoptosis revealed that overexpression of miR-1 in transplanted ES cells protected host myocardium from MI-induced apoptosis through activation of p-AKT and inhibition of caspase-3, phosphatase and tensin homolog, and superoxide production. A significant reduction in interstitial and vascular fibrosis was quantified in miR-1-ES cell and ES cell transplanted groups compared with control MI. However, no statistical significance between miR-1-ES cell and ES cell groups was observed. Finally, mice receiving miR-1-ES cell transplantation post-MI had significantly improved heart function compared with respective controls (P < 0.05). Our data suggest miR-1 drives cardiac myocyte differentiation from transplanted ES cells and inhibits apoptosis post-MI, ultimately giving rise to enhanced cardiac repair, regeneration, and function.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
authors.forename: Carley
authors.initials: C
authors.lastname: Glass
authors.forename: Dinender K
authors.initials: DK
authors.lastname: Singla
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000637:transplantation*; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000637:transplantation*; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020127:Recovery of Function; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016276:Ventricular Function; D020257:Ventricular Remodeling
chemical_list: D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3