Evaluation of the role of mico-RNAs in cardiomyocytes differentiation of mesenchymal stem cells

Cardiomyocytes proliferate and form the heart in the embryonic period, but proliferation stops soon after birth. Cardiac diseases stay the leading reason of death universal, both in developed and developing countries. Cardiac diseases can develop quickly, including acute myocardial infarction, or progress slowly, such as cardiac remodeling, which is determined by cardiac hypertrophy and myocardial fibrosis that can finally cause to heart failure. Stem cells are a good alternative for regenerative medicine because of their characteristics such as self-renewal and differentiation potential. They are classified into different types of stem cells including embryonic stem cells, induced pluripotent stem cells, multipotent stem cells, and ultimately uni-potent stem cells. Albeit embryonic stem cells are able to differentiate into cardiac cells and show powerful therapeutic potential for heart diseases, the ethical controversies surrounding the origin of embryonic stem cells hinder its broad usage in patients. Mesenchymal stem cells can be differentiated into a different of cell types including osteoblasts, chondrocytes, adipocytes, and stromal cells.  They can be extracted from different tissues including the liver, blood, bone marrow, synovium, umbilical cord blood, gut, lungs, adipose tissue, umbilical cord Wharton’s jelly, eye conjunctiva, dermis, dental pulp and amniotic fluid. Also, mesenchymal stem cells can be expressed CD105, CD73 and CD90, and lack expression of the haematopoietic markers CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Mesenchymal stem cells have various advantages of easy accessibility, strong capacity of proliferation, immune modulatory properties, and migration to damaged tissues. Due to the lack of graft loss, they are an appreciate option for cell therapy, especially ischemic heart disease. Nowadays, it is generally accepted that the observed therapeutic impact induced by mesenchymal stem cells is chiefly based on the secretion of paracrine factors rather than on the differentiation into cardiomyocytes.Many agents such as cytokines, growth factors, and small molecules have been shown to promote cardiac cell differentiation both in vivo and in vitro. Direct and indirect culture systems with myocardial cells and other cardiac cells in order to benefit from the factors secreted by these cells can increase the differentiation of mesenchymal stem cells into cardiomyocytes like cells. The cardiomyocytes differentiation is regulated by different transcription factors such as GATA4, and Nkx2.5. Also, different signaling pathways such as Transforming growth factor β1 (TGF-β), Fibroblast Growth Factor (FGF), WNT, and Notch play key roles in regulating proliferation, cardiomyocytes differentiation, and survival of mesenchymal stem cells. In this review, we focus on miRNAs and their roles on cardiomyocytes differentiation of mesenchymal stem cells. Following an introduction to the non-coding RNAs, micro-RNAs and mechanism of miro-RNA functions, we then discuss what is currently known about the expression of miRNAs in embryonic and mesenchymal stem cells. Finally, we discuss current knowledge of miRNAs regulatory role in mesenchymal stem cells differentiation into cardiomyocytes. microRNAs (miRNAs) are a class of non-coding small RNA (21–25 nucleotides) involved in regulation of cell behavior either through inhibition of mRNA translation or promoting mRNA degradation. Since its identification as a major component of a broadly conserved mechanism that regulates gene expression post-transcriptionally, the miRNA pathway has emerged as one of the most widely evaluated pathways of the past decade. miRNAs are both pleiotropic and redundant, and it has been suggested that at least 30% of human genes are regulated by the cooperation among miRNAs: one mRNA can be recognize by various miRNAs and one miRNA can recognize several mRNAs. miRNA profile studies have showed that miRNAs are selectively expressed in various tissues and at different developmental stages. miRNA signatures for mesenchymal stem cells of different origin have shown the expression of defined patterns of miRNAs involved in the maintenance of stem cell properties such as proliferation, self-renewal, and differentiation capacity. Many miRNAs are expressed in various tissues; they can be used as biomarkers in the diagnosis of certain diseases. Also, mi-RNAs have been studied more than other types of non-coding RNAs. The increasing evidence displays that miRNAs are involved in many pathological conditions, such as cancer, arrhythmias, cardiac infarction, virus infection, and Alzheimerchr('39')s disease, which has been suggested as a new target to cure these diseases. The regulatory function of the miRNA is mostly applied via, and controlled by, different transcription factors and other regulatory mechanisms of gene expression. These complex interactions between miRNAs and other regulators of gene expression at the epigenetic, transcriptional and post-transcriptional levels integrate miRNAs into the cellular network of regulation of gene expression that defines the stem cell fate and behavior. New studies have displayed that different of these key transcription factors directly regulate miRNA expression in embryonic stem cells. Known pluripotent related markers, such as miR-302a, b, c, and d, and miR-200c.Recently, different miRNAs were proposed to associate with cardiomyocyte differentiation of stem cells. Over-expression of some miRNAs such as mi-R1-2 in mouse bone marrow- mesenchymal stem cells could induce their differentiation into cardiomyocytes through Wnt/β-catenin signaling pathway. Also, the miR1 has been reported to be able to modulate cardiomyogenesis and preserve the expression of muscle genes via down regulating the Notch or STAT3 signaling pathways. Furthermore, except mir-1-2 over-expression of miR-499 in rat bone marrow- mesenchymal stem cells induces them toward cardiac differentiation via the activating the wnt/b-catenin signal pathway. Conversely, microRNA-133 blocks the cardiac differentiation of mouse and human mesenchymal stem cells. By modulating miR-1 and -499 expression levels, human cardiomyocyte progenitor cells function can be altered and differentiation directed, thereby enhancing cardiomyogenic differentiation. Overexpression of miR-499a-5p increased the expression of cardiomyogenic differentiation markers in human bone marrow mesenchymal stem cells. Down regulation of miR-199b-5p induced differentiation of bone marrow mesenchymal stem cells toward cardiomyocyte-like cells through the HSF1/HSP70 signaling pathway, and had no influence on bone marrow mesenchymal stem cells proliferation and migration. MicroRNAs affect cardiac cellular signaling and gene expression, and implicate miR-199b as a therapeutic target in heart failure. The cooperative association and reciprocal interactions between genetic and epigenetic regulatory factors and miRNAs regulate the self-renewal and differentiation of mesenchymal and embryonic stem cells.