The Influence of Capsule Composition on Lens Biology

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Extracapsular cataract surgery is a marvel of modern medicine that has greatly reduced the global burden of cataract-related blindness. However, optimal implantation of a replacement intraocular lens requires preservation of most of the lens capsule, the basement membrane surrounding the lens. Since lens epithelial cells (LECs) are tightly attached to the lens capsule, it is not possible to remove all LECs during cataract surgery, and these cells undergo robust wound healing responses characterized by cell proliferation and the transdifferentiation of LECs to scar producing myofibroblasts. While modern intraocular lens implants can sequester myofibroblasts away from the ocular axis short term, these cells can survive long term at the periphery of the capsular bag, and often escape years after surgery, migrating into the visual axis, where they can proliferate, wrinkle the capsule, and produce fibrotic extracellular matrix molecules, leading to the onset of posterior capsular opacification (PCO) years after the initial cataract surgery. Thus, understanding the mechanisms by which myofibroblasts differentiate post lens injury, and maintain their phenotype long term is of great importance. During the last grant cycle, we discovered that fibronectin produced by lens cells after surgery was critical for the maintenance of the fibrotic phenotype of LECs post fiber cell removal while RNAseq profiling revealed that numerous inhibitors of protease activity upregulate their expression dramatically in LECs following lens injury suggesting a key role for fibrotic ECM in establishing and sustaining fibrotic PCO. This proposal seeks to investigate the molecular mechanisms by which fibronectin regulates the fibrotic phenotype of lens epithelial cells and the role of matrix regulators in this process.