Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT.
Downregulation of E-cadherin in pluripotent stem cells triggers partial EMT.
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DOI：
10.1038/s41598-021-81735-1
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发表时间：
2021-01-21
影响因子：
4.6
通讯作者：
Luzzani C
中科院分区：
文献类型：
--
作者：
Aban CE;Lombardi A;Neiman G;Biani MC;La Greca A;Waisman A;Moro LN;Sevlever G;Miriuka S;Luzzani C
上皮向间充质转化(EMT)是胚胎发育和肿瘤转移过程中的一个重要的细胞过程，也参与了胚胎干细胞分化等多种生理和病理过程。在分化的早期阶段，人类胚胎干细胞通过EMT，在那里发生更深层次的形态、分子和生化变化。虽然EMT过程最初被认为是两个状态之间的决定，但现在被认为是一个流体转变，细胞存在于中间状态的谱上。在这项工作中，利用人胚胎干细胞中的CRISPR干扰系统，我们描述了E-钙粘蛋白下调的影响的分子特征，E-钙粘蛋白是EMT的主要启动事件之一，作为一个独特的起始信号。我们的结果表明，E-钙粘蛋白的减少和非局部化导致了不完全的EMT，在这种情况下，细胞保持其未分化状态，同时表达了间质样表型的一些特征。也就是说，我们发现E-钙粘素下调诱导SNAI1和SNAI2上调，促进MALAT1和LINC-RoR下调，调节紧密连接阻滞素1和缝隙连接连接蛋白43的表达，增加人胚胎干细胞的迁移能力，并使β-连环蛋白去定位。总之，我们相信我们的结果提供了一个有用的工具来模拟不稳定中间态的分子事件，并进一步识别在部分EMT过程中发生的多层分子变化。
Epithelial to mesenchymal transition (EMT) is a critical cellular process that has been well characterized during embryonic development and cancer metastasis and it also is implicated in several physiological and pathological events including embryonic stem cell differentiation. During early stages of differentiation, human embryonic stem cells pass through EMT where deeper morphological, molecular and biochemical changes occur. Though initially considered as a decision between two states, EMT process is now regarded as a fluid transition where cells exist on a spectrum of intermediate states. In this work, using a CRISPR interference system in human embryonic stem cells, we describe a molecular characterization of the effects of downregulation of E-cadherin, one of the main initiation events of EMT, as a unique start signal. Our results suggest that the decrease and delocalization of E-cadherin causes an incomplete EMT where cells retain their undifferentiated state while expressing several characteristics of a mesenchymal-like phenotype. Namely, we found that E-cadherin downregulation induces SNAI1 and SNAI2 upregulation, promotes MALAT1 and LINC-ROR downregulation, modulates the expression of tight junction occludin 1 and gap junction connexin 43, increases human embryonic stem cells migratory capacity and delocalize β-catenin. Altogether, we believe our results provide a useful tool to model the molecular events of an unstable intermediate state and further identify multiple layers of molecular changes that occur during partial EMT.
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