The corneal endothelium (CE) is vital for maintaining the water balance and clarity of the cornea. The CE is a cell layer that is particularly susceptible to aging because of its postmitotic arrest, high metabolic activity involving pumping of ions, and lifelong exposure to ultraviolet light. Despite gradual age-related cell loss, a sufficient number of CE cells are preserved during the lifespan of an individual. However, in conditions such as Fuchs endothelial corneal dystrophy (FECD), permanent loss of CE cells leads to corneal edema and loss of vision requiring corneal transplantation. FECD is a genetic and oxidative stress disorder manifested by abnormal cell–matrix interactions and expedited cellular aging culminating in cellular death. Because the endothelium has minimal replicative capacity in vivo and an inability to replace its genome, it is particularly prone to cumulative DNA damage acquired throughout life. In FECD, the underlying genetic defects make the CE genome even more vulnerable to this damage, to the point of causing mitochondrial dysfunction, mitochondrial membrane potential loss, and excessive mitophagy activation. Endogenous and exogenous intracellular stressors alter the synthetic footprint of CE cells, leading to endothelial–mesenchymal transition and secretion of aberrant extracellular matrix (in the form of guttae), resembling scar formation in other organs. In turn, the guttae or endothelial scars contribute to a vicious cycle of FECD pathogenesis and, by further inducing endothelial–mesenchymal transition and oxidant–antioxidant imbalance, perpetuate the molecular changes of the degenerating endothelium.
Department of Ophthalmology, Harvard Medicial School, and Schepens Eye Research Institute, Massachusetts Eye and Ear, Boston, MA
Correspondence: Ula V. Jurkunas, MD, Department of Ophthalmology, Harvard Medical School, and Schepens Eye Research Institute, Massachusetts Eye and Ear, 20 Staniford St, Room 245, Boston, MA 02114 (e-mail: firstname.lastname@example.org).
U. V. Jurkunas has received grants from the NEI/NIH (R01 EY020581), Santen Pharmaceutical Co, Ltd, and the Eversight Foundation; has received travel support from Santen Pharmaceutical Co, Ltd; and has received consultancy fees from Chiesi and a grant from Intellia.
Received June 29, 2018
Accepted August 21, 2018