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 this force balance and its consequences for vision remains poorly understood. We found that the density of basement membrane laminins modulates the level of retinal pigmented epithelium contractility, which directly controls its efficiency in phagocytosing photoreceptor outer segments. In vivo, the density gradient of laminins follows retinal functional demand, supporting the physiological role of laminins in controlling epithelial mechanical homeostasis. Our data suggest that laminin density and isoform heterogeneity can differentially engage integrins {beta}1 and {beta}4, the ratio of which determines the contribution of actin vs keratin cytoskeleton in balancing tissue mechanics. With this work, we suggest that the extracellular matrix-defined mechanical status of retinal pigmented epithelium is a novel parameter for visual function. SignificanceIn the retina, the retinal pigmented epithelium (RPE) is responsible for the daily phagocytosis of photoreceptor cell fragments, a process vital for visual function. Along the visual axis, there is a natural decrease in the ratio of photoreceptors to RPE cells, indicating a decrease in RPE functional demand. This study reveals that the density of laminins in RPE basement membrane also diminishes along this axis, critically influencing RPE function by regulating its contractility. For the first time, we demonstrate the presence of a laminin- defined mechanical gradient within the RPE, which determines its capacity to support photoreceptor cells. Our findings highlight the importance of mechanical properties as a key factor in visual function, offering new insights into retinal health and disease.