The retinal pigmented epithelium (RPE) is a monolayer of highly specialized pigmented cells residing between the photoreceptors and Bruch's membrane. This layer of cells is essential for maintaining the physiological environment in the subretinal space. It is believed that degeneration of RPE cells is the root cause of the age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly population in the western world. To this regard, strenuous efforts have been spent to identify possible causes of RPE degeneration. To date, more than fifty risk factors have been linked to AMD, including both environmental and genetic elements; however, the pathogenesis of this devastating disease is still elusive.

Maintaining tissue homeostasis is achieved by preventing cell death, repairing damaged cells, or replenishing functional cells. Since it is challenging to prevent every potential pathological pathway associating with RPE degeneration, tipping the balance in the flavor of homeostasis by replenishing with new functional cells may be a more efficacious tactic for treating AMD. Indeed, this concept was proved to be feasible in recent years; it was showed that transplantation of stem cell-derived RPE cells could restore the vision loss in animal studies. Human clinical trials are ongoing.

The goal of my Ph.D. research is to advance the field further toward direct in vivo RPE regeneration by investigating the underlying mechanisms of RPE repair and regeneration. The work presented in this dissertation elucidates several fundamental principles of RPE regeneration. The first chapter provides an in-depth review of pathogenic elements of AMD as well as current knowledge on RPE regeneration. One obstacle of RPE regeneration is the limited differentiation capability of human RPE cells, mechanisms of which are revealed in the second chapter. Additionally, a novel reprogramming method was developed to restore and maintain the differentiation capability of RPE cells by expressing OTX2 and MYCN in conjunction with TGF? signaling pathway inhibition. In the third chapter, the wound healing response of bystander RPE cells was investigated, and its association with AMD pathogenesis is revealed. Finally, building upon our novel discoveries, strategies and challenges of in vivo RPE regeneration are discussed. Together, work presented in this dissertation provides novel insights and foundations of developing potential treatments for AMD using regenerative medicine.