Insulin-like growth factor-1-mediated regulation of miR-193a expression promotes the migration and proliferation of c-kit-positive mouse cardiac stem cells

Abstract

BackgroundC-kit-positive cardiac stem cells (CSCs) have been shown to be a promising candidate treatment for myocardial infarction and heart failure. Insulin-like growth factor (IGF)-1 is an anabolic growth hormone that regulates cellular proliferation, differentiation, senescence, and death in various tissues. Although IGF-1 promotes the migration and proliferation of c-kit-positive mouse CSCs, the underlying mechanism remains unclear.MethodsCells were isolated from adult mouse hearts, and c-kit-positive CSCs were separated using magnetic beads. The cells were cultured with or without IGF-1, and c-kit expression was measured by Western blotting. IGF-1 induced CSC proliferation and migration, as measured through Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The miR-193a expression was measured by quantitative real-time PCR (qPCR) assays.ResultsIGF-1 enhanced c-kit expression in c-kit-positive CSCs. The activities of the phosphoinositol 3-kinase (PI3K)/AKT signaling pathway and DNA methyltransferases (DNMTs) were enhanced, and their respective inhibitors LY294002 and 5-azacytidine (5-AZA) blunted c-kit expression. Based on the results of quantitative real-time PCR (qPCR) assays, the expression of miR-193a, which is embedded in a CpG island, was down-regulated in the IGF-1-stimulated group and negatively correlated with c-kit expression, whereas c-kit-positive CSCs infected with lentivirus carrying micro-RNA193a displayed reduced c-kit expression, migration and proliferation.ConclusionsIGF-1 upregulated c-kit expression in c-kit-positive CSCs resulting in enhanced CSC proliferation and migration by activating the PI3K/AKT/DNMT signaling pathway to epigenetically silence miR-193a, which negatively modifies the c-kit expression level.Electronic supplementary materialThe online version of this article (10.1186/s13287-017-0762-4) contains supplementary material, which is available to authorized users.

Insulin-like growth factor-1 short-period therapy improves cardiomyopathy stimulating cardiac progenitor cells survival in obese mice

“…We also demonstrated increased c-kit expression ( Fig. 5D), corroborating previous data from Sun and coworkers [46], which demonstrated that IGF-1-mediated activation of the PI3K/AKT pathway enhanced in vitro CSC migration and proliferation by upregulating c-kit expression.…”

Detection of Novel Potential Regulators of Stem Cell Differentiation and Cardiogenesis through Combined Genome-Wide Profiling of Protein-Coding Transcripts and microRNAs

“…In the context of heart development, miRNAs with peaks at days 8, 12 and 16 seem especially relevant. MiR-126-3p, peaking at day eight, was identified as a potential biomarker for coronary artery disease [55], while miR193a-5p with a peak at day 12 was shown to repress proliferation and migration of cardiac stem cells (CSCs) through the downregulation of c-kit [56]. Peaks at day 16 were detected for members of the let-7 family that have been linked to the regulation of multiple processes, including heart development and cardiac differentiation, as well as cardiovascular diseases [52].…”

Cellular Senescence Affects Cardiac Regeneration and Repair in Ischemic Heart Disease

“…Saheera S et al found that oxidative stress and senescence of CSCs were alleviated after treatment with metoprolol, which increased the migration and proliferation of CSCs and was beneficial in delaying progressive cardiac remodeling [148]. Insulin-like growth factor-1 is a synthetic growth hormone that regulates cell proliferation, differentiation, senescence and death; Sun Y et al found that IGF-1 promotes the proliferation and migration of CSCs by activating the PI3K/AKT/DNMT signaling pathway [149].…”

“…Insulin-like growth factor-1 is a synthetic growth hormone that regulates cell proliferation, differentiation, senescence and death; Sun Y et al . found that IGF-1 promotes the proliferation and migration of CSCs by activating the PI3K/AKT/DNMT signaling pathway [ 149 ].…”