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Alhanoof A Alnwibit, Brigid Bleaken, A Sue Menko, Janice L Walker; α9 Integrin-Vimentin Linked Pathways are Positioned for Important Roles in the Regulation of Wound Healing and Fibrosis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3190.
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© ARVO (1962-2015); The Authors (2016-present)
While vimentin intermediate filaments and the α9 integrin receptor have been linked to pathways that are involved either in regulating wound healing or promoting fibrosis, the cooperative function of these molecules in these processes has not been studied. We investigated this possibility in a physiologically relevant ex vivo mock cataract surgery culture model of wound healing and fibrosis.
Our mock cataract surgery ex vivo cultures are a clinically relevant model of tissue injury. The epithelial wound created in the center of the endogenous basement membrane of the lens capsule by removal of the lens fiber cells, termed the Central Migration Zone (CMZ), is repaired within 3 days in culture. This repair process is directed by a population of mesenchymal leader cells. At the outside edge of the explants mesenchymal leader cells also direct lens epithelial cells to migrate off of the capsule onto the culture substrate, the ExtraCapsular Zone (ECZ), a rigid environment that promotes emergence of myofibroblasts and fibrosis. This model recapitulates the major features the lens fibrotic disease Posterior Capsule Opacification (PCO). Expression and localization of α9 integrin and vimentin and their potential relationship in both the CMZ and ECZ were determined by co-immunofluorescence staining. To determine whether there was an interaction between α9 integrin and vimentin and where that occurred, we used the Polymerase Ligation Assay (PLA). PLA is a highly sensitive and specific assay that reveals whether protein-protein interactions occur in close proximity, within 30-40nm, in situ.
Our studies revealed that the leader cell population that directs wound healing in the CMZ and transitions to a myofibroblast phenotype in the ECZ is enriched for both vimentin and α9 integrin. These molecules are linked in the leader cells during the process of wound repair in the CMZ, but not after the wound closes. α9 integrin became linked to vimentin in leader cells as they differentiate to myofibroblasts in the ECZ, a property maintained in the expanding myofibroblast population at the wound edge.
Our studies reveal for the first time that α9 linkage to vimentin could regulate leader cell function in migration following wounding and play a role in myofibroblast emergence in fibrotic disease.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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