Islet-1 induces the differentiation of mesenchymal stem cells into cardiomyocyte-like cells through the regulation of Gcn5 and DNMT-1

Abstract

Previous studies from this group demonstrated that insulin gene enhancer binding protein ISL-1 (Islet-1) specifically induces the differentiation of mesenchymal stem cells (MSCs) into cardiomyocyte-like cells through histone acetylation. However, the underlying mechanisms remain unclear. In the present study, the role of the histone acetylation and DNA methylation on the regulatory mechanism of the Islet-1 was further investigated by methylation-specific polymerase chain reaction (PCR), chromatin immunoprecipitation quantitative PCR and western blot analysis. The results demonstrated that Islet-1 upregulated expression of general control of amino acid biosynthesis protein 5 (Gcn5) and enhanced the binding of Gcn5 to the promoters of GATA binding protein 4 (GATA4) and NK2 homeobox 5 (Nkx2.5). In addition, Islet-1 downregulated DNA methyltransferase (DNMT)-1 expression and reduced its binding to the GATA4 promoter. In contrast, the amount of DNMT-1 binding on Nkx2.5 did not match the expression trend. Therefore, it was concluded that Islet-1 may influence the histone acetylation and DNA methylation of GATA4 promoter region via Gcn5 and DNMT-1 during the MSC differentiation into cardiomyocyte-like cells, thus prompting the expression of GATA4. The Nkx2.5 was likely only affected by histone acetylation instead of DNA methylation. The present study demonstrated that Islet-1 induces the differentiation of mesenchymal stem cells into cardiomyocyte-like cells through a specific interaction between histone acetylation and DNA methylation on regulating GATA4.

ISL1 overexpression enhances the survival of transplanted human mesenchymal stem cells in a murine myocardial infarction model

“…ISL1 has been shown to play an essential role in heart embryogenesis, and ISL1-positive cells have been demonstrated to be cardiovascular progenitors [ 17 , 18 ]. Although a recent study demonstrated that overexpression of ISL1 in MSCs induced cardiomyocyte differentiation [ 19 ], a prior study conducted by our group obtained different results [ 10 ]. In our previous study, we found that ISL1 overexpression did not affect their ability to differentiate into cardiomyocytes or endotheliocytes.…”

Comparison of the Cardiomyogenic Potency of Human Amniotic Fluid and Bone Marrow Mesenchymal Stem Cells

“…Though under undifferentiated conditions both MSC types had a comparable expression of cardiac transcription factors GATA-4, Nkx2.5 and ISL-1 genes but after 5-Aza induction, AF-MSC exhibited a significantly higher expression of these transcription factors at gene as well as protein levels. These transcription factors are key regulators of the expression of cardiac structural genes in MSC as well as in other stem cells and promote their differentiation into cardiomyocytes (20,21). Among these, ISL-1 is of particular importance as it is the earliest transcription factor having a crucial role in cardiogenesis during embryonic development and cardiomyocyte differentiation following cardiac injury in adults (22) and we have observed 40% of AF-MSC to express ISL-1.…”

Insulin gene enhancer binding protein 1 induces adipose tissue‑derived stem cells to differentiate into pacemaker‑like cells

“…It is well known that ISL-1 is essential to the proper formation and development of the heart. ISL1-positive cells, isolated from embryonic stem cells (ESCs), induced pluripotent stem cells, bone mesenchymal stem cells and embryonic or postnatal heart tissues, have the potential to give rise to diverse cell types in the cardiovascular system, including cardiomyocytes, smooth muscle cells, endothelial cells and pacemaker cells (33-35). ISL-1-overexpressing cardiomyocytes exhibit higher beating frequencies in mouse ESC-derived regions and Xenopus hearts, which are associated with the upregulation of nodal‑specific genes and the downregulation of genes associated with the working myocardium (26).…”