Elucidating the Molecular Underpinnings of Endogenous RPE Regeneration

University Of Texas At Austin, Austin TX

Investigators

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Abstract

SUMMARY: Diseases resulting in degeneration of the retinal pigment epithelium (RPE) are among the leading causes of blindness worldwide, and no therapies exist that can replace RPE or restore lost vision. Age-related macular degeneration (AMD) is one such disease, and is the third leading cause of blindness in the world. Transplantation of stem-cell derived RPE has emerged as a possibility for treating AMD and clinical trials are underway. An intriguing alternative approach to treat RPE disease is to develop therapies focused on stimulating endogenous RPE regeneration. Indeed, strategies targeting endogenous retinal regeneration are gaining traction as potential therapeutic approaches to treat a number of retinal degenerations. For this to become possible for the RPE, we must first gain a deeper understanding of the molecular and cell biological mechanisms underlying RPE regeneration. In mammals, RPE regeneration is extremely limited; small lesions can be repaired by the expansion of adjacent RPE cells, but remaining RPE are unable to functionally replace lost cells when the lesions are large. In some injury paradigms, RPE cells proliferate but do not regenerate a morphologically normal monolayer. Moreover, RPE cells often overproliferate after injury, such as during proliferative vitreoretinopathy, where proliferative RPE cells invade the subretinal space and lead to blindness. A subpopulation of quiescent human RPE stem cells has been identified which can be induced to proliferate in vitro and differentiate into RPE or mesenchymal cell types. This discovery is exciting because it suggests that the human RPE contains a population of cells that could be induced to regenerate. Despite these studies, little is known about the process by which RPE cells respond to injury to elicit a regenerative, rather than pathological, response. There are also few models in which to study intrinsic RPE regeneration. This knowledge gap is a major barrier to developing effective strategies to restore RPE lost to disease or injury. To overcome this barrier, we developed a unique transgenic zebrafish model to study RPE injury and regeneration and leveraged this model to begin to identify the molecular and cellular mechanisms facilitating RPE regeneration. Our work to date supports our central hypothesis that injury-adjacent RPE cells proliferate in response to RPE damage to generate RPE daughter cells that then regenerate RPE lost to injury. Experiments in this proposal further test this hypothesis by i) determining how RPE heterogeneity influences RPE regeneration and identify the source of regenerated RPE; ii) determining the cell biological mechanisms underlying RPE regeneration; and iii) determining how the nrg1/ErbB pathway facilitates RPE regeneration. Understanding how injury-responsive RPE cells proliferate in vivo and the signals/pathways active during the injury response holds significant promise to identify strategies to stimulate or reactivate this ability in the human eye, which would be transformational for treating AMD and other diseases that affect the RPE.