Investigative ophthalmology & visual science · 2025
Small-Molecule Inhibition of the Hippo Pathway Induces Regeneration of Retinal Pigment Epithelium.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Souverein Erik A, Oak Sanyukta, Fouladian Zachary, Reid Mark W, Fernandez G Esteban, Salas Andrew, Aparicio Jennifer G, Nagiel Aaron, Gnedeva Ksenia
Аннотация
PURPOSE: To investigate whether Hippo pathway inhibition via a novel Lats kinase inhibitor (LKI) induces regeneration of retinal pigment epithelium (RPE).
METHODS: An in vitro scratch "injury" on confluent RPE monolayers was produced using the Woundmaker Tool. A 6×6 grid of laser spots was delivered to the central retinae of Dutch Belted rabbits via indirect laser. Following laser injury, eyes received 50 µL intravitreal LKI or vehicle. Fundus photography and optical coherence tomography (OCT) were performed prior to sacrifice for immunohistological analyses.
RESULTS: In vitro RPE demonstrated accelerated wound healing 24 to 96 hours after injury with LKI versus control treatment (P < 0.0001). In the in vivo rabbit model of retinal degeneration, laser spots in LKI-injected eyes demonstrated hyperpigmentation and RPE layer thickening with shadowing on OCT beginning at 1 week after treatment. There was a marked increase in RPE cross-sectional area (P < 0.0001) and percentage of Ki67+ RPE and Müller glia (P < 0.001), specifically at the laser spots. At 4 weeks, the increase in RPE cross-sectional area persisted (P < 0.001), but Ki67+ cells were no longer observed within the RPE (P = 0.36) or Müller glia (P = 0.48). The response was limited to the damaged regions, and there was no proliferation seen in the intact retina in either control or LKI-treated eyes.
CONCLUSIONS: Hippo pathway inhibition via a novel LKI promotes wound healing and RPE proliferation in RPE monolayers in vitro. In a rabbit model of geographic atrophy, LKI treatment facilitated robust RPE regeneration and Müller glia proliferation specifically at the sites of injury.
METHODS: An in vitro scratch "injury" on confluent RPE monolayers was produced using the Woundmaker Tool. A 6×6 grid of laser spots was delivered to the central retinae of Dutch Belted rabbits via indirect laser. Following laser injury, eyes received 50 µL intravitreal LKI or vehicle. Fundus photography and optical coherence tomography (OCT) were performed prior to sacrifice for immunohistological analyses.
RESULTS: In vitro RPE demonstrated accelerated wound healing 24 to 96 hours after injury with LKI versus control treatment (P < 0.0001). In the in vivo rabbit model of retinal degeneration, laser spots in LKI-injected eyes demonstrated hyperpigmentation and RPE layer thickening with shadowing on OCT beginning at 1 week after treatment. There was a marked increase in RPE cross-sectional area (P < 0.0001) and percentage of Ki67+ RPE and Müller glia (P < 0.001), specifically at the laser spots. At 4 weeks, the increase in RPE cross-sectional area persisted (P < 0.001), but Ki67+ cells were no longer observed within the RPE (P = 0.36) or Müller glia (P = 0.48). The response was limited to the damaged regions, and there was no proliferation seen in the intact retina in either control or LKI-treated eyes.
CONCLUSIONS: Hippo pathway inhibition via a novel LKI promotes wound healing and RPE proliferation in RPE monolayers in vitro. In a rabbit model of geographic atrophy, LKI treatment facilitated robust RPE regeneration and Müller glia proliferation specifically at the sites of injury.