Smad3 Signaling Is Required for Epithelial-Mesenchymal Transition of Lens Epithelium after Injury

Abstract

Lens epithelial cells undergo epithelial-mesenchymal transition (EMT) after injury as in cataract extraction, leading to fibrosis of the lens capsule. Fibrosis of the anterior capsule can be modeled in the mouse by capsular injury in the lens, which results in EMT of the lens epithelium and subsequent deposition of extracellular matrix without contamination of other cell types from outside the lens. We have previously shown that signaling via Smad3, a key signal-transducing element downstream of transforming growth factor (TGF)-beta and activin receptors, is activated in lens epithelial cells by 12 hours after injury and that this Smad3 activation is blocked by administration of a TGF-beta 2-neutralizing antibody in mice. We now show that EMT of primary lens epithelial cells in vitro depends on TGF-beta expression and that injury-induced EMT in vivo depends, more specifically, on signaling via Smad3. Loss of Smad3 in mice blocks both morphological changes of lens epithelium to a mesenchymal phenotype and expression of the EMT markers snail, alpha-smooth muscle actin, lumican, and type I collagen in response to injury in vivo or to exposure to exogenous TGF-beta in organ culture. The results suggest that blocking the Smad3 pathway might be beneficial in inhibiting capsular fibrosis after injury and/or surgery.

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

“…Numerous studies have implicated the TGFβ/Smad signaling pathway in PCO (Saika et al ., 2004; Wormstone et al ., 2004). αSMA, MMP2, CTGF, integrin αV, integrin α5, integrin β1, miR4279, and miR1469 have been shown to be upregulated by TGFβ2 during the EMT of HLE cells (Dawes et al ., 2007; Wang et al ., 2013; Mamuya et al ., 2014).…”

Smad3 Is a Key Nonredundant Mediator of Transforming Growth Factor β Signaling in Nme Mouse Mammary Epithelial Cells

“…Several studies in different cell types have already aimed at distinguishing between the specific roles of Smad2 and Smad3, which share biochemical properties, in TGFβ signaling. The majority of these data were obtained from the assessment of transcriptional responses in Smad2 and Smad3 knockout cells, including fibroblasts, hepatocytes, as well as epithelial cells from lens and renal tubules (19)(20)(21)(22)(23)(24). Both of these latter types of epithelial cell also undergo EMT in response to TGFβ, which has been proposed to contribute to fibrosis in the kidney or in the lens after injury.…”

Lumican, a small leucine‐rich proteoglycan

“…Previously, obligatory involvement of Smad signaling in EMT induction was demonstrated, allowing one to hypothesize that lumican modulates TGF-b2-pathway restricted, Smad downstream signaling in EMT (52,53). The Fas-Fas ligand (FasL) signaling, a key cellular pathway, was found to be disrupted in Lum 2/2 stromal keratocytes (43).…”