Laminin 411 mediates endothelial specification via multiple signaling axes that converge on β-catenin

• Published in: Stem cell reports 2022-03, Vol.17 (3), p.569-583
• Main Authors: Hall, Mikayla L., Givens, Sophie, Santosh, Natasha, Iacovino, Michelina, Kyba, Michael, Ogle, Brenda M.
• Format: Article
• Language: English
• Subjects: beta catenin; beta Catenin - metabolism; cell signaling; differentiation; endothelial cells; extracellular matrix; Extracellular Matrix - metabolism; focal adhesion; laminin; Laminin - metabolism; signal transduction; Signal Transduction - physiology; stem cells; vascular; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2022.01.005

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. [Display omitted] •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.