Abstract
Purpose :
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.
Methods :
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.
Results :
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.
Conclusions :
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.