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Integrative miRNA and Gene Expression Profiling Analysis of Human Quiescent Hepatic Stellate Cells.

机译:人类静态肝星状细胞的整合miRNA和基因表达谱分析。

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摘要

Unveiling the regulatory pathways maintaining hepatic stellate cells (HSC) in a quiescent (q) phenotype is essential to develop new therapeutic strategies to treat fibrogenic diseases. To uncover the miRNA-mRNA regulatory interactions in qHSCs, HSCs were FACS-sorted from healthy livers and activated HSCs (aHSCs) were generated in vitro. MiRNA Taqman array analysis showed HSCs expressed a low number of miRNAs (n = 259), from which 47 were down-regulated and 212 up-regulated upon activation. Computational integration of miRNA and gene expression profiles revealed that 66% of qHSC-associated miRNAs correlated with more than 6 altered target mRNAs (17,28 ± 10,7 targets/miRNA) whereas aHSC-associated miRNAs had an average of 1,49 targeted genes. Interestingly, interaction networks generated by miRNA-targeted genes in qHSCs were associated with key HSC activation processes. Next, selected miRNAs were validated in healthy and cirrhotic human livers and miR-192 was chosen for functional analysis. Down-regulation of miR-192 in HSCs was found to be an early event during fibrosis progression in mouse models of liver injury. Moreover, mimic assays for miR-192 in HSCs revealed its role in HSC activation, proliferation and migration. Together, these results uncover the importance of miRNAs in the maintenance of the qHSC phenotype and form the basis for understanding the regulatory networks in HSCs.
机译:揭示维持静态(q)表型的肝星状细胞(HSC)的调控途径对于开发治疗纤维变性疾病的新治疗策略至关重要。为了揭示qHSC中的miRNA-mRNA调控相互作用,从健康肝脏中对HSC进行了FACS分选,并在体外生成了活化的HSC(aHSC)。 MiRNA Taqman阵列分析显示,HSCs表达的miRNA数量少(n = 259),其中47个在激活后被下调,而212个在激活后被上调。对miRNA和基因表达谱的计算整合显示,与qHSC相关的miRNA中有66%与超过6个改变的靶标mRNA相关(17,28±±10,7个靶标/ miRNA),而与aHSC相关的miRNA平均具有1,49个靶标基因。有趣的是,由qHSCs中的miRNA靶向基因产生的相互作用网络与关键的HSC激活过程相关。接下来,在健康和肝硬化的人类肝脏中验证了选定的miRNA,并选择了miR-192进行功能分析。在肝损伤的小鼠模型中,发现HSC中miR-192的下调是纤维化进程中的早期事件。此外,在HSC中对miR-192进行的模拟分析显示了其在HSC激活,增殖和迁移中的作用。总之,这些结果揭示了miRNA在维持qHSC表型中的重要性,并为理解HSC中的调控网络奠定了基础。

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