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Tara Tovar-Vidales, Navita Lopez, Rajiv Rangan, Abbot F Clark; miRNA Expression in Glaucomatous and TGFβ2 Treated Lamina Cribrosa Cells. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2372.
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During glaucoma, there is a remodeling of the extracellular matrix (ECM) in the optic nerve head (ONH), the site of initial ON damage. ONH derived lamina cribrosa (LC) cells synthesize ECM proteins to support the ONH. However, LC cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing expression of the profibrotic cytokine transforming growth factor-beta 2 (TGFβ2) and ECM proteins, including collagen. Moreover, microRNAs (miRNAs) regulate ECM gene and protein expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to remodeling of the glaucomatous optic nerve head. We want to understand the epigenetic regulation of the ECM in the optic nerve head. The purpose of this study was to determine whether modulation of anti-fibrotic miRNAs alters the expression of ECM in human LC cells.
Primary human normal (n=3 strains) and glaucoma (n=3 strains) LC cells were derived from human donor eyes. Normal and glaucomatous LC cells were grown to confluency and treated with or without TGFβ2 (5ng/ml) for 24 hours. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. Primary LC cells were transfected with candidate miRNA mimics, inhibitors, or non-targeting siRNA (10nM) to determine ECM expression levels for collagens I and IV in human LC cells, using immunocytochemistry.
miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFβ2 treatment significantly downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated the expression of ECM proteins as seen by immunocytochemistry.
TGFβ2 modulates the expression of several miRNAs in cultured human LC cells that appear to stimulate a profibrotic environment and may be responsible for pathogenic remodeling of the optic nerve head in glaucoma. New therapeutic targets for miRNAs within the ONH could be identified that stop or slow the pathogenesis of glaucoma, preserving ONH structure and function.
This is a 2021 ARVO Annual Meeting abstract.
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