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Jiagang Zhao, Peng-Yu Yang, Weijun Shen, Peter G. Schultz, Natalie A Afshari; Effects of YAP small molecule activators on human neural crest stem cells and corneal endothelial cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1420.
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© ARVO (1962-2015); The Authors (2016-present)
To probe whether Hippo-YAP pathway is a potential drug target for treating cell loss of corneal endothelium and to investigate novel small molecule activators of YAP for use in corneal endothelial regenerative medicine.
The novel, potent, selective YAP small molecule activators were tested in the cultured hiPSC-derived neural crest stem cells (NCSCs), NCSC-derived corneal endothelial cells (CECs) and human primary CECs. Alterations in cell proliferation, morphology, expression of cell markers and Hippo-Yap signaling pathway have been examined.
Previously, we found that subcellular localization of YAP is correlated with growth capacity of human corneal endothelial cells. The small molecular activators of YAP were initially identified by a screening a library of drug-like compounds in non-corneal tissue cell types. These compounds increase YAP dephosphorylation and nuclear localization, and activate YAP target gene expression and prevent cell-cell contact inhibition. In human corneal endothelial cell cultures, the presence of YAP small molecular activator increased numbers of Ki-67+ cells without promoting endothelial-to-mesenchymal transition. In addition, we tested the effect of compound on hiPSC-derived NCSC, the precursor of corneal endothelial cells. The treatment suppressed spontaneous cell differentiation and enriched SOX2 positive NCSCs in the culture.
Previous studies by us and others suggested that Hippo-Yap pathway may play an important role in cell-cell contact inhibition and preventing cell reentry of mitosis in corneal endothelium. Our current work demonstrates the potential of using a small molecular activator of YAP to promote the proliferation of human corneal endothelial cells as well as to expand their precursors -ocular NCSCs.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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