Exploring novel modulators for rescuing cigarette smoke-induced corneal edema and examining iPSC-derived corneal endothelial cells as a treatment modality

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Project Summary Cigarette smoke (CS) is a complex mixture of toxins (e.g., nicotine, carbon monoxide) that affects multiple tissues of the eye including the cornea, the outermost tissue of the eye. The cornea is at high risk due to its proximity to the burning end of the cigarette and flying ash. Corneal endothelium (CE) is the innermost layer of the cornea responsible for corneal hydration. CS results in progressive corneal endothelial cell (CEC) loss leading to corneal edema and vision loss if remains untreated. The severity of CS-induced corneal edema is further compounded with preexisting morbidities such as corneal endothelial dystrophies and diabetes. Our preliminary studies of proteome profiling have demonstrated that CS triggers CEC loss and disruption of critical structural proteins in Descemet’s membrane (DM). We further identified elevated levels of oxidative stress-associated indicators and decreased levels of CE-associated markers in response to cigarette smoke extract (CSE) treatment in human induced pluripotent stem cell (iPSC)-derived CEC monolayer cultures. In parallel, we have shown that human embryonic stem cell (hESC)-derived CECs can form a functional CE on denuded DM (DM without CE) in rabbits and monkeys. Moreover, we have also shown that injected hESC-derived CECs can form a functional CE on denuded stroma (stroma without CE and DM). In this application, we will build on these datasets through large-scale screening of cellular pathway modulators to establish a non-invasive topical eye drop approach. In parallel, we will demonstrate the efficacy of the iPSC-derived CECs injection technique as a minimally invasive, donor tissue-independent, treatment modality. Taken together, the combined knowledge gained from identifying modulators and cell therapy will make a paradigm by offering an unlimited source for the treatment of oxidative stress-induced CE disorders.