WNT10B Enhances Proliferation Through β-catenin and RAC1 GTPase in Human Corneal Endothelial Cells

Abstract The cornea is the anterior, transparent tissue of the human eye that serves as its main refractive element. The corneal endothelial cells are arranged as a monolayer on the posterior surface of the cornea and function as a pump to counteract the leakiness of its basement membrane. Maintaining the cornea in a slightly dehydrated state is critical for maintenance of corneal transparency. Adult human corneal endothelial cells are G1 arrested, even in response to injury, leading to an age-dependent decline in the endothelial cell density. Corneal edema and subsequent vision loss ensues when the endothelial cell density decreases below a critical threshold. Vision loss secondary to corneal endothelial dysfunction is a common indication for transplantation in developed nations. An impending increase in demand for and a current global shortage of donor corneas will necessitate development of treatments for vision loss due to endothelial dysfunction that does not rely on donor corneas. Wnt ligands regulate many critical cellular functions such as proliferation, making them attractive candidates for modulation in corneal endothelial dysfunction. We show WNT10B causes nuclear transport and binding of RAC1 and β-catenin in human corneal endothelial cells, leading to activation of Cyclin D1 expression and proliferation. Our findings indicate WNT10B promotes proliferation in human corneal endothelial cells by simultaneously utilizing both β-catenin dependent and independent pathways, and suggest that its modulation could be used to treat vision loss secondary to corneal endothelial dysfunction.