Lens Stretching Modulates Lens Epithelial Cell Proliferation via YAP Regulation

PURPOSE: The continuous growth of the lens throughout life may contribute to the onset of age-related conditions in the lens (i.e., presbyopia and cataract). Volumetric growth is the result of continuous proliferation of lens epithelial cells (LECs). The driving factors controlling LEC proliferation are not well understood. This study tested the hypothesis that mechanical stretching modulates LEC proliferation. METHODS: Biomechanical regulation of LEC proliferation was investigated by culturing whole porcine lenses and connective tissues ex vivo under varying physiologically relevant stretching conditions using a bespoke lens stretching device. Additionally, some lenses were treated with a YAP function inhibitor to determine the Hippo signaling pathway's role in regulating lens growth. Resulting changes in LEC labeling index were analyzed using EdU incorporation and flow cytometry for each lens. RESULTS: LEC proliferation was found to be modulated by mechanical strain. Increasing both the magnitude of static stretching and the stretching frequency in cyclic stretching resulted in a proportional increase in the labeling indices of the LECs. Additionally, treatment with the YAP function inhibitor effectively eliminated this relationship. CONCLUSIONS: These data demonstrate that LEC proliferation is regulated in part, by the mechanotransduction of stresses induced in the lens capsule and that YAP plays an important role in mechanosensing. These results have important implications for understanding lens growth and morphogenesis. The model may also be used to identify and evaluate targets for modulating lens growth.