Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation.
Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation.
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DOI：
10.1016/j.stemcr.2016.07.006
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发表时间：
2016-08-09
影响因子：
5.9
通讯作者：
Kimber SJ
中科院分区：
文献类型：
--
作者：
Vitillo L;Baxter M;Iskender B;Whiting P;Kimber SJ
人胚胎干细胞（hESC）可以维持在细胞外基质基质上的完全限定的小生境中，它们通过整合素受体附着在细胞外基质上。然而，潜在的整合素信号传导机制，以及它们对hESC行为的贡献，在很大程度上是未知的。在这里，我们表明，粘着斑激酶（FAK）转导整合素激活，并支持人胚胎干细胞的生存，基板粘附，和维持未分化状态。在抑制FAK激酶活性后，我们发现hESC经历细胞凋亡依赖性凋亡或分化。我们还报告了FAK下游靶点AKT和MDM 2的失活，以及p53的上调，这些都是hESC调控网络中的关键参与者。整联蛋白活性或FAK的丧失也诱导细胞聚集，揭示了hESC的细胞-细胞相互作用中的作用。本研究提供了对hESC中激活的整合素信号级联的深入了解，并揭示了FAK在维持hESC存活和未分化状态中的关键作用。FAK激酶转导hESC中的整合素活化FAK保护hESC免受AKT/MDM 2/p53级联上游的失巢凋亡FAK是维持hESC的低收缩性和附着所必需的FAK的长期抑制诱导非偏向性hESC分化在这项研究中，Kimber及其同事揭示了细胞外基质依赖性信号传导在控制人胚胎干细胞行为中的关键作用。这些信号主要由粘着斑激酶信号传导介导，粘着斑激酶信号传导与内在多能干细胞调节因子（如AKT和p53）连接，防止分离、凋亡和分化。
Human embryonic stem cells (hESCs) can be maintained in a fully defined niche on extracellular matrix substrates, to which they attach through integrin receptors. However, the underlying integrin signaling mechanisms, and their contribution to hESC behavior, are largely unknown. Here, we show that focal adhesion kinase (FAK) transduces integrin activation and supports hESC survival, substrate adhesion, and maintenance of the undifferentiated state. After inhibiting FAK kinase activity we show that hESCs undergo cell detachment-dependent apoptosis or differentiation. We also report deactivation of FAK downstream targets, AKT and MDM2, and upregulation of p53, all key players in hESC regulatory networks. Loss of integrin activity or FAK also induces cell aggregation, revealing a role in the cell-cell interactions of hESCs. This study provides insight into the integrin signaling cascade activated in hESCs and reveals in FAK a key player in the maintenance of hESC survival and undifferentiated state. Integrin activation in hESCs is transduced by FAK kinase FAK protects hESCs from anoikis upstream of the AKT/MDM2/p53 cascade FAK is required for maintenance of low contractility and attachment of hESCs Prolonged inhibition of FAK induces non-biased hESCs differentiation In this research, Kimber and colleagues reveal the critical role of the extracellular matrix-dependent signaling in controlling human embryonic stem cell behavior. Such cues are principally mediated by focal adhesion kinase signaling, which links to intrinsic pluripotent stem cell regulators, such as AKT and p53, preventing detachment, apoptosis, and differentiation.