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Mahbubul Shihan, Erin Jackson, Yan Wang, Melinda K Duncan; Regulation of BMP and TGFβ signaling in Posterior Capsular Opacification (PCO). Invest. Ophthalmol. Vis. Sci. 2018;59(9):1602.
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© ARVO (1962-2015); The Authors (2016-present)
Posterior capsular opacification (PCO) is the major complication of cataract surgery. Transforming growth factor beta (TGFβ) signaling mediates PCO pathogenesis. However, the factors regulating TGFβ pathway activation and influencing the onset of PCO post cataract surgery (PCS) are not well understood. To overcome this, an unbiased approach was taken to identify all genes whose expression levels change in lens epithelial cells (LECs) by 48 hrs. PCS, the first time when canonical TGFβ signaling is first detected concomitant with elevated protein levels of α smooth muscle actin (αSMA), the most commonly used fibrotic marker in PCO.
Lens fiber cells were removed from adult wild type (WT) mice to model cataract surgery. RNA was isolated from 0 hr. & 48 hrs. PCS samples of LECs. Sequencing, bioinformatics analysis and filtering for significant changes were performed. Immunostaining was done to further validate transcriptome analysis.
A total of 2015 genes exhibited altered expression levels in LECs by 48 hrs. PCS (1134 genes were upregulated and 971 genes were downregulated (0.05 < P, Fold Change- FC ≥ 2, RPKM ≥ 2)). As expected, these include many common fibrotic markers including fibronectin (up 53.2 fold), Collagen I (up 50.3 fold), and αSMA (up 5.2 fold). Interestingly, some of the identified DEGs are implicated in fibrosis in other systems but either have not been reported or are only poorly described in PCO. One of these is gremlin-1 (up 309 fold), a profibrotic gene and bone morphogenetic protein (BMP) signaling antagonist. Immunostaining found that gremlin-1 protein levels upregulate sharply in LECs by 6 hrs. PCS, while this upregulation increases further through 5 days PCS. This gremlin-1 upregulation correlates with a decrease in BMP signaling in LECs first detected at 48 hrs PCS. This downregulation of BMP signaling in LECs occurs simultaneously with an activation of canonical TGFβ signaling and the onset of fibrotic marker expression.
For the first time, these data provide a comprehensive analysis of LECs remodeling at the onset of PCO, providing new insight into the mechanisms underlying the fibrotic response that LECs undergo PCS. Upregulation of gremlin-1 expression in LECs PCS may be a critical factor for the inhibition of BMP signaling which may lead to loss of LE markers and the activation of TGFβ signaling necessary for the fibrotic response leading to PCO.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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