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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways
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Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways

机译:microRNA-1的过表达通过抑制WNT和FGF信号通路促进人类心血管祖细胞的心肌定型

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Early heart development takes place through a complex series of steps, including the induction of cardiac mesoderm, formation of the cardiovascular progenitor cells and the commitment of cardiovascular lineage cells, such as cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs). Recently, microRNAs, a family of endogenous, small non-coding RNAs, have been identified as critical regulators in cardiogenesis and cardiovascular disease. Previous studies demonstrated that microRNA-1 (miR-1) could promote cardiac differentiation from mouse and human embryonic stem (ES) cells. However, the underlying mechanism remained largely unclear. We performed microRNA deep sequencing among human ES cells, ES cell derived-multipotent cardiovascular progenitors (MCPs), and MCP-specified CMs, ECs, and SMCs. A specific enrichment of miR-1 was found in CMs, not in SMCs or ECs, implying a key role of miR-1 in determining cardiovascular commitment from MCPs. When overexpressed in human induced pluripotent stem cells, miR-1 enhanced the expression of key cardiac transcriptional factors and sarcomeric genes. Importantly, we found miR-1 promoted CM differentiation and suppressed EC commitment from MCPs by modulating the activities of WNT and FGF signaling pathways. FZD7 and FRS2 were confirmed as miR-1 targets using luciferase reporter assay and western blot. Overall, this study reveals a fate-switching role of miR-1 at early human cardiovascular commitment stage via suppressing both WNT and FGF signaling pathways.
机译:心脏的早期发育需要一系列复杂的步骤,包括诱导中胚层,形成心血管祖细胞以及确定心血管谱系细胞(例如心肌细胞(CMs),平滑肌细胞(SMCs)和内皮细胞( ECs)。最近,已经确定了microRNA(一种内源性,小的非编码RNA)家族,是心脏发生和心血管疾病的关键调节剂。先前的研究表明,microRNA-1(miR-1)可以促进小鼠和人类胚胎干(ES)细胞的心脏分化。但是,基本机制仍不清楚。我们在人类ES细胞,ES细胞衍生的多能心血管祖细胞(MCP)和MCP指定的CM,EC和SMC之间进行了microRNA深度测序。在CM中发现了miR-1的特定富集,而在SMC或EC中则没有,这表明miR-1在确定MCP的心血管活动中起着关键作用。当在人类诱导的多能干细胞中过表达时,miR-1会增强关键心脏转录因子和肌节基因的表达。重要的是,我们发现miR-1通过调节WNT和FGF信号通路的活性,促进了CM分化并抑制了MCP的EC承诺。 FZD7和FRS2被证实为miR-1靶标,通过荧光素酶报告基因检测和Western blot检测。总的来说,这项研究揭示了通过抑制WNT和FGF信号通路,miR-1在人类心血管早期发育阶段的命运转换作用。

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