Abstract
Despite the extensive hepatic differentiation potential of human umbilical cord lining-derived mesenchymal stem cells (hUC-MSC), little is known about the molecular mechanisms of hUC-MSC differentiation. At the post-transcriptional level, microRNAs are key players in the control of cell fate determination during differentiation. In this study, we aimed to identify microRNAs involved in the hepatic differentiation of hUC-MSCs. After successfully isolating hUC- MSCs, we induced hepatocyte formation in vitro with growth factors. After 26 days of induction, hUC-MSCs could express hepatocyte-specific genes, synthesize urea and glycogen and uptake low-density lipoprotein. Cellular total RNA from hUC-MSCs and hepatic differentiated hUC-MSCs was collected at 7 time points, including 2 days, 6 days, 10 days, 14 days, 22 days and 26 days, for microRNA microarray analysis. Dynamic microRNA profiles were identified that did not overlap or only partially overlapped with microRNAs reported to be involved in human liver development, hepatocyte regeneration or hepatic differentiation of liver-derived progenitor cells. A total of 61 microRNAs among 1205 human and 144 human viral microRNAs displayed consistent changes and were altered at least 2-fold between hUC-MSCs and hepatic differentiated hUC-MSCs. Among these microRNAs, 25 were over-expressed; this over-expression occurred either gradually or increased sharply and was maintained at a high level. A total of 36 microRNAs were under-expressed, with an expression pattern similar to that of the over-expressed microRNAs. The expression of the altered expressed microRNAs was also confirmed by quantitative reverse-transcription polymerase chain reaction. We also found that microRNAs involved in hepatic differentiation were not enriched in hepatocyte or hepatocellular carcinoma cells and can potentially target liver-enriched transcription factors and genes. The elucidation of the microRNA profile during the hepatic differentiation of hUC-MSCs provides the basis for clarifying the role of microRNAs in hUC-MSC hepatic differentiation and specific microRNA selection for the conversion of hUC-MSCs to hepatocytes.
Highlights
At the post-transcriptional level, microRNAs are emerging as key players in the control of proliferation and cell fate determination during differentiation
HUC-Mesenchymal stem cells (MSCs) can be Successfully Induced Into Hepatocytes in vitro
The hepatic differentiation efficiency of human umbilical cord lining-derived mesenchymal stem cells (hUC-MSC) was first evaluated by analyzing hepatocyte-specific gene expression at the mRNA and protein levels
Summary
At the post-transcriptional level, microRNAs are emerging as key players in the control of proliferation and cell fate determination during differentiation. The expression of the miR-302/367 cluster can rapidly and efficiently reprogram mouse and human somatic cells to an iPSC state without requiring exogenous transcription factors [5,6]. The neurogenic transcription factors ASCL1 and MYT1L can enhance the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone in the absence of miR-9/9*-124 is ineffective [7]. These studies indicate that one or several specific microRNAs can be used to convert adult cells derived from other sources into hepatocytes to efficiently obtain hepatocytes in vitro
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