生物通报道：来自第四军医大学樊代明院士研究组的研究人员发表了题为“Dynamic microRNA Profiles of Hepatic Differentiated Human Umbilical Cord Lining-Derived Mesenchymal Stem Cells”的文章，揭示出了人类脐带来源的间充质干细胞在分化成肝细胞的过程中，出现的microRNA，绘制了七个时间点的microRNA表达谱，这将有助于阐明microRNAs在hUC-MSCs肝分化中的分子机理。相关成果公布在PLoS ONE上。

microRNA是转录后修饰水平中一个关键的调控因子，能调控细胞增殖，以及确定分化过程中细胞的命运。研究表明，每种类型的细胞分化都受到一个特特殊microRNA的调控。例如，成人神经干细胞，或者称祖细胞的增殖，和神经细胞分化都受到microRNA簇：miR-106b-25的调控。还有miR-150能通过靶向转录因子c-myb，调控B细胞分化等等。

此外，小分子RNA也能能介导细胞转分化。特殊的microRNA可以用于细胞的初始化。比如miR-302/367簇能快速有效的令小鼠和人类的体细胞重新编程，回到多能干细胞的状态，而且无需外源性转录因子。这些研究表明，利用一个或多个特定的microRNA能将其它来源的成体细胞转换为肝细胞，有效获取体外干细胞。

骨髓间充质干细胞（MSCs）具有可塑性，能分化成脂肪组织，骨骼，软骨，肌腱和肌肉，因此MSCs在治疗应用方法具有巨大前景。成人骨髓间充质干细胞是临床应用最常见的来源。但是骨髓的供应是有限的，并且年龄越大，数量越少。

人类脐带来源的间充质干细胞（human umbilical cord-derived MSCs ，hUC-MSCs）具有良好了免疫原性，同样也能用于治疗大鼠肝纤维化，促进肝硬化大鼠的葡萄糖稳态。然而关于条件培养基中，调控hUC-MSCs分化成低免疫原性肝细胞样细胞的分子机制至今还并不清楚，尤其是其中小分子RNA的作用。

在这篇文章中，研究人员利用miRNA芯片和qRT-PCR技术，分析了HGF诱导的hUC-MSCs肝细胞分化过程中，七个时间点上的microRNA表达谱。其中发现了一个独特的表达谱与hUC-MSCs肝分化有关，这个表达谱在hUC-MSCs，肝细胞和肝癌细胞中都不多。

研究人员分析了hUC-MSCs肝分化过程中的这个表达谱，找到了参与这一过程的miRNAs，在1205个人类miRNAs和144个病毒miRNAs中，有61个表现出一致性，在hUC-MSCs和肝分化hUC-MSCs存在至少两倍的变化。其中有25个miRNAs过表达，过程缓慢或者增长的非常快，并保持在高水平上。还有36个表达水平降低，模式与增长的miRNAs相似。

研究人员还发现，肝分化过程中的miRNAs并没有在肝细胞，或者肝癌细胞中富集，这说明这些小分子也许靶向肝富集转录因子。这些研究有助于阐明microRNAs在hUC-MSCs肝分化中的分子机理，以及描述hUC-MSCs向肝细胞转换过程中的特殊miRNAs选择。

（生物通：万纹）

原文摘要：

Dynamic microRNA Profiles of Hepatic Differentiated Human Umbilical Cord Lining-Derived Mesenchymal Stem Cells.

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.
 

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