Transforming Growth Factor-β-Induced Epithelial-Mesenchymal Transition in the Lens: A Model for Cataract Formation

Abstract

The vertebrate lens has a distinct polarity and structure that are regulated by growth factors resident in the ocular media. Fibroblast growth factors, in concert with other growth factors, are key regulators of lens fiber cell differentiation. While members of the transforming growth factor (TGFβ) superfamily have also been implicated to play a role in lens fiber differentiation, inappropriate TGFβ signaling in the anterior lens epithelial cells results in an epithelial-mesenchymal transition (EMT) that bears morphological and molecular resemblance to forms of human cataract, including anterior subcapsular (ASC) and posterior capsule opacification (PCO; also known as secondary cataract or after-cataract), which occurs after cataract surgery. Numerous in vitro and in vivo studies indicate that this TGFβ-induced EMT is part of a wound healing response in lens epithelial cells and is characterized by induced expression of numerous extracellular matrix proteins (laminin, collagens I, III, tenascin, fibronectin, proteoglycans), intermediate filaments (desmin, α-smooth muscle actin) and various integrins (α2, α5, α7B), as well as the loss of epithelial genes [Pax6, Cx43, CP49, α-crystallin, E-cadherin, zonula occludens-1 protein (ZO-1)]. The signaling pathways involved in initiating the EMT seem to primarily involve the Smad-dependent pathway, whereby TGFβ binding to specific high affinity cell surface receptors activates the receptor-Smad/Smad4 complex. Recent studies implicate other factors [such as fibroblast growth factor (FGFs), hepatocyte growth factor, integrins], present in the lens and ocular environment, in the pathogenesis of ASC and PCO. For example, FGF signaling can augment many of the effects of TGFβ, and integrin signaling, possibly via ILK, appears to mediate some of the morphological features of EMT initiated by TGFβ. Increasing attention is now being directed at the network of signaling pathways that effect the EMT in lens epithelial cells, with the aim of identifying potential therapeutic targets to inhibit cataract, particularly PCO, which remains a significant clinical problem in ophthalmology.

Matrix metalloproteinases as mediators of primary and secondary cataracts

“…Together, these changes are thought to promote cellular migration and scatter [16]. Additionally, as is found in other fibroses, the EMT of LECs in ASC and PCO is followed by excessive deposition of extracellular matrix proteins, such as laminin, collagen types I and III, fibronectin and tenascin [15]. Finally, another commonality that has recently been identified between ASC and PCO with other fibrotic disorders is the involvement of the matrix-degrading enzymes, the MMPs [17][18][19].…”

“…EMT is a feature of a number of fibrotic pathologies, such as pulmonary fibrosis, renal fibrosis, metastatic cancers [12][13][14] and lenticular fibroses [15]. In addition to pathological conditions, EMT is also an essential biological process involved in many aspects of development.…”

Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression

“…Similar genetic and molecular players are involved in pathological EMT as in development but appear to lack the intricate coordination. Dysregulated responses such as diabetic nephropathy (Kalluri and Neilson, 2003) and cataracts (de Iongh et al, 2005) involve the over production of fibroblasts which overtake functioning tissue-these bear the signature of EMT. Many epithelial tumors hijack EMT to become metastatic (Thiery and Sleeman, 2006), and examples of this in various carcinoma contexts will be discussed in the following sections.…”

The murine lens: A model to investigate in vivo epithelial–mesenchymal transition

“…Myofibroblasts are involved in tissue fibrosis in lung (Willis et al, 2006), liver (Albanis and Friedman, 2001; Friedman, 2004), kidney (Sato et al, 2003; Zeisberg and Kalluri, 2004), skin (Darby et al, 2014), eye (retina [Bochaton‐Piallat et al, 2000; Saika et al, 2004a,2007a], lens [Saika et al, 2001; de Iongh et al, 2005; Shirai et al, 2006]) to name a few. Myofibroblasts that appear in the fibrotic lesion are considered to be a mixture of cells derived from either fibroblasts (Gabbiani, 2003; Hinz and Gabbiani, 2003; Micallef et al, 2012; Willis et al, 2006;), local epithelial cells (Kalluri and Neilson, 2003; Zeisberg and Kalluri, 2004), and bone‐marrow‐derived cells (Quan et al, 2006) (Fig.…”

“…2A), indicating the effectiveness of exogenous factors on EMT on cells in their native setting. This work was nicely reviewed by de Iongh et al (2005), with the procedure subsequently applied to investigating the intact lens of genetically modified mice displaying cataract. For example, adding TGFβ to the culture medium produces EMT‐type cataract in a rat lens in culture (Hales et al, 1995).…”