Laminin-defined Mechanical Status Modulates Retinal Pigment Epithelium Functionality

Abstract

Epithelial cells are highly interconnected, whereby they acquire mesoscale mechanical properties to accomplish specific tissue functions. In homeostasis, this mechanical status can be summarised as mechanical homeostasis, regulated by the balance of intercellular tension and extracellular matrix adhesion forces. In the outer retina, the significance of these forces in defining its mechanical homeostasis and consequences for vision remains poorly understood. The retinal pigmented epithelium (RPE) is located at the base of the retina and supports vision by ensuring the light sensitivity and lifespan of photoreceptor cells. Given the varying photoreceptor densities along the visual angle, this functional demand on the RPE varies from the most illuminated macula to the less illuminated retinal periphery and corresponds to a significant difference in monolayer organisation. In this work, we hypothesised that extracellular matrix cues define the relation between RPE organisation, mechanical status and functional capacity. We found that the density of basement membrane laminins modulates the level of RPE contractility, which directly controls the efficiency of the epithelium in phagocytosing photoreceptor outer segments. In vivo, the density gradient of laminin α5 and 332 follow retinal functional demand, thus supporting the physiological role of laminins in controlling RPE mechanical homeostasis. Our data suggest that laminin density and isoforms can differentially engage integrins β1 and β4, the ratio of which, in turn, determines the contribution of actin vs keratin cytoskeleton in balancing tissue mechanics. ECM-defined mechanical status of the RPE provides a novel parameter for visual function. It opens new paths of investigation and treatment for sight-threatening diseases such as high myopia and age-related macular degeneration.