Laminin 411 mediates endothelial specification via multiple signaling axes that converge on β-catenin.
Laminin 411 mediates endothelial specification via multiple signaling axes that converge on β-catenin.
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DOI：
10.1016/j.stemcr.2022.01.005
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发表时间：
2022-03-08
影响因子：
5.9
通讯作者：
Ogle, Brenda M.
中科院分区：
文献类型：
--
作者：
Hall, Mikayla L.;Givens, Sophie;Santosh, Natasha;Iacovino, Michelina;Kyba, Michael;Ogle, Brenda M.
细胞外基质(ECM)在体内组织发育过程中为促进内皮细胞的规范提供必要的线索；相应地，ECM被认为是体外血管内皮细胞分化所必需的。然而，还没有进行系统的研究来评估单个ECM蛋白对内皮分化的确切贡献。此外，分化协议的多组分性质使得研究ECM对细胞命运的影响的潜在机制变得具有挑战性。在这项研究中，我们确定层粘连蛋白411单独促进诱导的多能干细胞在I型胶原或Matrigel上的内皮分化。ECM的作用不依赖于血管内皮生长因子(VEGF)的结合能力。我们还发现，细胞外基质诱导的内皮细胞分化依赖于粘着斑激酶(FAK)、整合素连接激酶(ILK)、Notch和β-连环蛋白通路的激活。我们的结果表明，细胞外基质通过多个途径促进内皮细胞分化，这些途径集中在活性β-连环蛋白的表达上。层粘连蛋白411诱导人和小鼠肺间充质干细胞内皮细胞分化FAK、ILK和Notch作用于层粘连蛋白411下游诱导内皮细胞分化单靠细胞外基质吸收血管内皮生长因子不能诱导内皮细胞分化β-catenin信号转导是细胞外基质诱导内皮细胞分化所必需的。层粘连蛋白411诱导的分化依赖于粘着斑激酶、整合素连接激酶、Notch和β-连环蛋白，而不依赖于细胞外基质对血管内皮生长因子吸收的差异。
The extracellular matrix (ECM) provides essential cues to promote endothelial specification during tissue development in vivo; correspondingly, ECM is considered essential for endothelial differentiation outside of the body. However, systematic studies to assess the precise contribution of individual ECM proteins to endothelial differentiation have not been conducted. Further, the multi-component nature of differentiation protocols makes it challenging to study the underlying mechanisms by which the ECM contributes to cell fate. In this study, we determined that Laminin 411 alone increases endothelial differentiation of induced pluripotent stem cells over collagen I or Matrigel. The effect of ECM was shown to be independent of vascular endothelial growth factor (VEGF) binding capacity. We also show that ECM-guided endothelial differentiation is dependent on activation of focal adhesion kinase (FAK), integrin-linked kinase (ILK), Notch, and β-catenin pathways. Our results indicate that ECM contributes to endothelial differentiation through multiple avenues, which converge at the expression of active β-catenin. Laminin 411 induces endothelial differentiation in human and mouse iPSCs FAK, ILK, and Notch act downstream of laminin 411-induced endothelial differentiation VEGF absorption by ECM alone does not induce endothelial differentiation β-catenin signaling is necessary for ECM-induced endothelial differentiation In this article, Ogle and colleagues demonstrate that the ECM protein laminin 411 induces a significant level of endothelial differentiation in both human and mouse iPSCs. Laminin 411-induced differentiation is dependent on focal adhesion kinase, integrin-linked kinase, Notch, and β-catenin, but not on differences in VEGF absorption into the ECM substrate.
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通讯作者：
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