MicroRNA regulatory network involved in impaired functionality in cardiomyocytes derived from human embryonic stem cells

摘要

Human embryonic stem cells (hESCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types e.g. cardiomyocytes. However, previous studies have shown that the expression of cardiac ion channels and genes involved in the Ca~(2+)-handling machinery is immature in the stem cell derived cardiomyocytes, and novel approaches are therefore needed to improve the differentiation protocols and produce more functional cardiomyocytes. MicroRNAs (miRNAs) are small molecules, which play key roles in regulation of cellular development and may therefore be powerful tools to improve the differentiation. This paper presents a method to derive a miRNA-mRNA regulatory network, which likely are important for the regulation of the functionality that currently is lacking in the hESC-derived cardiomyocytes. In total 14 ion channels and 9 calcium handling genes that have important roles in cardiac tissue and which have shown to be significantly lower expressed in hESC-derived cardiomyocytes compared to their in vivo counterpart, were investigated and scanned for putative miRNA target sites. For each of the predicted miRNAs, a combined prediction score (CPS) was calculated and a miRNA regulatory network was generated consisting of miRNAs with a high CPS and with multiple targets among the investigated genes. Results from this study propose that the miRNA network presented here is highly involved in the hampered functionality seen in hESC-derived cardiomyocytes, and that it therefore will constitute an important tool to select candidate miRNAs for future knockout- and overexpression studies.