Identification of miRNAs in control of aberrant gene transcription in human pluripotent stem cell-derived hepatocytes

摘要

Human pluripotent stem cells (hPSCs) have unique properties of proliferation and self-renewal, and can be differentiated into various functional cell types e.g. hepatocytes. However, despite large effort in development of efficient differentiation protocols, hPSC-derived hepatocytes still lack some important functionality that prevents their use in drug discovery and toxicity testing studies. Novel approaches are therefore needed to improve the differentiation protocols, and produce more functional hepatocytes, which better mimic their in vivo counterparts. MicroRNAs (miRNAs) are small molecules, which play key roles in regulation of cellular development and may therefore be powerful tools to direct the differentiation. This paper identifies comprehensive miRNA regulatory networks, which may control the impaired hepatic functionality observed in hPSC-derived hepatocytes. An efficient method to derive miRNA-mRNA regulatory network is presented. The identified miRNAs are likely involved in the regulation of the hampered functionality observed in the hPSC-derived hepatocytes. In total 20 hepatocyte-related genes with known miss-regulation in hPSC-derived hepatocytes were identified from literature [1-5]. These genes are responsible for various types of functionality in the hepatocytes. This list of genes was investigated and scanned for putative miRNA target sites. For each of the predicted miRNAs, a target prediction score was calculated and miRNA regulatory networks were generated consisting of miRNAs with a high prediction score or with multiple targets among the investigated genes. Results from this study propose miRNA networks, which likely are highly involved in the hampered functionality observed in hPSC-derived hepatocytes. The presented miRNA-mRNA networks will provide valuable information when selecting candidate miRNAs for future knockout- and overexpression studies.