The retinal pigment epithelium: Development, injury responses, and regenerative potential in mammalian and non-mammalian systems

George, Stephanie M.; Lu, Fangfang; Rao, Mishal; Leach, Lyndsay L.; Gross, Jeffrey M.

doi:10.1016/j.preteyeres.2021.100969

Cited by 52 publications

(34 citation statements)

References 321 publications

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“…Currently, there are few options for treating AMD (66); however, an innovative potential direction for therapeutic development is the stimulation of intrinsic regeneration of the RPE (8). Previously, our lab established a genetic RPE ablation paradigm in zebrafish and demonstrated that zebrafish are capable of regenerating a functional RPE monolayer, thus providing a model through which the molecular underpinnings of the RPE regenerative response can be identified (13).…”

Section: Discussionmentioning

confidence: 99%

“…A complementary reparative strategy to explore for use in human patients is to stimulate intrinsic RPE regeneration. However, in mammals, the RPE shows an extremely limited capacity to regenerate after injury (5)(6)(7)(8). RPE cells terminally differentiate during the early stages of eye development and remain mitotically inactive in adults, under most conditions.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to mammals, zebrafish possess remarkable regenerative capacity after injury in multiple tissues (8,12), including the RPE (13,14). Previous work from our laboratory established a transgenic zebrafish RPE ablation model (rpe65a:nfsB-eGFP) and demonstrated that RPE could intrinsically regenerate into a functional monolayer after widespread genetic ablation (13).…”

Section: Introductionmentioning

confidence: 99%

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mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

Leach

Gross

2021

Preprint

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The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is necessary and sufficient for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity in the RPE is required for recruitment of macrophages/microglia to the injury site. In turn, these macrophages/microglia reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

Leach

Gross

2021

Preprint

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“…The biochemical processes within PRs require extensive metabolic activity, largely mediated by their interactions with the retinal pigment epithelium (RPE). 3 Together with Müller glia (MG), the RPE plays a crucial role in supporting PRs to maintain outer retinal structure, function, and homeostasis. 3 – 5 …”

Section: Introductionmentioning

confidence: 99%

“… 3 Together with Müller glia (MG), the RPE plays a crucial role in supporting PRs to maintain outer retinal structure, function, and homeostasis. 3 – 5 …”

Section: Introductionmentioning

confidence: 99%

Outer Retinal Cell Replacement: Putting the Pieces Together

Ludwig

Gamm

2021

Trans. Vis. Sci. Tech.

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CYLD Maintains Retinal Homeostasis by Deubiquitinating ENKD1 and Promoting the Phagocytosis of Photoreceptor Outer Segments

Yang,

Yu,

Yang

et al. 2024

Advanced Science

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Phagocytosis of shed photoreceptor outer segments by the retinal pigment epithelium (RPE) is essential for retinal homeostasis. Dysregulation of the phagocytotic process is associated with irreversible retinal degenerative diseases. However, the molecular mechanisms underlying the phagocytic activity of RPE cells remain elusive. In an effort to uncover proteins orchestrating retinal function, the cylindromatosis (CYLD) deubiquitinase is identified as a critical regulator of photoreceptor outer segment phagocytosis. CYLD‐deficient mice exhibit abnormal retinal structure and function. Mechanistically, CYLD interacts with enkurin domain containing protein 1 (ENKD1) and deubiquitinates ENKD1 at lysine residues K141 and K242. Deubiquitinated ENKD1 interacts with Ezrin, a membrane‐cytoskeleton linker, and stimulates the microvillar localization of Ezrin, which is essential for the phagocytic activity of RPE cells. These findings thus reveal a crucial role for the CYLD‐ENKD1‐Ezrin axis in regulating retinal homeostasis and may have important implications for the prevention and treatment of retinal degenerative diseases.

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The retinal pigment epithelium: Development, injury responses, and regenerative potential in mammalian and non-mammalian systems

Cited by 52 publications

References 321 publications

mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

mTOR activity is essential for retinal pigment epithelium regeneration in zebrafish

Outer Retinal Cell Replacement: Putting the Pieces Together

CYLD Maintains Retinal Homeostasis by Deubiquitinating ENKD1 and Promoting the Phagocytosis of Photoreceptor Outer Segments

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