Zachary I. Richards

 Introduction. Age-related macular degeneration (AMD) is the top cause of vision loss for those over 70.¹ The disease presents with central photoreceptor loss and irreversible central blindness.¹ Two types of AMD predominate, wet and dry. Wet AMD is a disease of neovascularization in the choroid, while dry AMD presents with geographic photoreceptor atrophy and drusen on ophthalmic exam. Unlike wet AMD, there remains no treatment for dry AMD, so an urgent need for one exists.¹ Recent studies have implanted a stem cell-derived sheet of retinal pigment epithelium (RPE) with reported preservation of photoreceptors in a genetically susceptible mouse model.² The purpose of this study was to investigate the importance of the RPE and the mechanism causing its demise in AMD, as well as why maintaining photoreceptor outer segment (POS) phagocytosis is critical to photoreceptor health.² Loss of POS phagocytosis kick-starts a pathway to free-radical damage, senescence, and complement activation, presenting a plausible mechanism discussed here. Methods. One work performed siRNA knockdown of RB1CC1 and examined photoreceptor survival as a function of autophagy.³ Two additional studies examined free radical formation caused by photodegrading POS waste products such as A2E, a key component of lipofuscin.^4,5 The next work examined the effect of cysteine starvation on senescence-associated β-galactosidase activity (a senescence marker) in the RPE.⁶ The effect that RPE senescence has on VEGF and complement factor H (a complement inhibitor) was investigated with Western blot.⁷ Stem cell-derived RPE cells were transplanted into AMD-prone mice to examine POS phagocytosis and photoreceptor survival.² Results. Knockdown of RB1CC1 inhibited LC3-mediated phagocytosis, which prevented POS from being degraded by the RPE.⁴ The resulting photodegradation of A2E resulted in significant production of reactive oxygen species.⁴ Glutathione depletion led to RPE senescence, as visualized by the increase of senescence-associated beta-galactosidase.⁶ Senescent phenotypes showed increased expression of VEGF and decreased expression of CFH.⁷ Stem cell-derived RPE demonstrated POS phagocytosis in vitro and prevented outer nuclear layer thinning.² Conclusion. These studies illustrate the importance of POS phagocytosis in the RPE and why accumulation of waste products leads to toxic levels of reactive oxygen species that force RPE senescence and photoreceptor death. Transplanted mouse stem cells improve the breakdown of POS, thereby saving photoreceptors from demise.

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