CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation
CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation
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CHIR-99021 在内胚层分化过程中通过 β-catenin 信号传导和 miRNA 表达调节线粒体重塑
DOI：
10.1242/jcs.229948
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发表时间：
2019-08-01
影响因子：
4
通讯作者：
Zhang, Haiyan
中科院分区：
文献类型：
--
作者：
Ma, Yuejiao;Ma, Minghui;Zhang, Haiyan
线粒体重构是干细胞分化的核心特征。然而，对这些过程中的调控机制知之甚少。之前，我们发现糖原合成酶激酶-3 α和-3 β的药理学抑制剂CHIR-99021可以启动人脂肪干细胞分化为人终代内皮层祖细胞（hepc），在进一步的可溶性因子联合处理后，hepc被引导同步分化为肝细胞样细胞。在这项研究中，我们发现CHIR-99021促进线粒体生物发生、PGC-1 α（也称为PPARGC1A）、TFAM和NRF1（也称为NFE2L1）的表达、氧化磷酸化能力以及hepc中活性氧的产生。使用靶向DRP1（也称为DNM1L）的siRNA阻断线粒体动力学会损害最终的内胚层分化。下调β -catenin （CTNNB1）表达减弱了CHIR-99021诱导线粒体重构和线粒体生物发生转录因子表达的作用。此外，CHIR-99021降低了hepc中miR-19b-2-5p、miR-23a-3p、miR-23c、miR-130a-3p和miR-130a-5p的表达，这些细胞是线粒体生物发生的靶向转录因子。这些数据表明，CHIR-99021通过激活β -catenin信号通路在线粒体结构和功能重塑中发挥作用，并抑制内胚层最终分化过程中mirna的表达。本文以第一人称采访了该论文的第一作者。
Mitochondrial remodelling is a central feature of stem cell differentiation. However, little is known about the regulatory mechanisms during these processes. Previously, we found that a pharmacological inhibitor of glycogen synthase kinase-3 alpha and -3 beta, CHIR-99021, initiates human adipose stem cell differentiation into human definitive endodermal progenitor cells (hEPCs), which were directed to differentiate synchronously into hepatocyte-like cells after further treatment with combinations of soluble factors. In this study, we show that CHIR-99021 promotes mitochondrial biogenesis, the expression of PGC-1 alpha (also known as PPARGC1A), TFAM and NRF1 (also known as NFE2L1), oxidative phosphorylation capacities, and the production of reactive oxygen species in hEPCs. Blocking mitochondrial dynamics using siRNA targeting DRP1 (also known as DNM1L) impaired definitive endodermal differentiation. Downregulation of beta-catenin (CTNNB1) expression weakened the effect of CHIR-99021 on the induction of mitochondrial remodelling and the expression of transcription factors for mitochondrial biogenesis. Moreover, CHIR-99021 decreased the expression of miR-19b-2-5p, miR-23a-3p, miR-23c, miR-130a-3p and miR-130a-5p in hEPCs, which target transcription factors for mitochondrial biogenesis. These data demonstrate that CHIR-99021 plays a role in mitochondrial structure and function remodelling via activation of the beta-catenin signalling pathway and inhibits the expression of miRNAs during definitive endodermal differentiation.This article has an associated First Person interview with the first author of the paper.