Dual function of TGFβ in lens epithelial cell fate: implications for secondary cataract

Boswell, Bruce A.; Korol, Anna; West‐Mays, Judith A.; Musil, Linda S.

doi:10.1091/mbc.e16-12-0865

Cited by 44 publications

(66 citation statements)

References 112 publications

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“…Future studies will be needed to address the following questions: a) Do β/γ-crystallin regulatory regions contain AP-1 and Ets binding sites? [189]; b) BMP signaling is known to regulate the expression of αA-crystallin gene [190, 191] and maybe other crystallins. Are crystallin genes regulated by Smad proteins?…”

Section: Lens Morphogenesis and Gene Regulatory Networkmentioning

confidence: 99%

Signaling and Gene Regulatory Networks in Mammalian Lens Development

2017

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Ocular lens development represents an advantageous system to study regulatory mechanisms governing cell fate decisions, extracellular signaling, cell and tissue organization, and underlying gene regulatory networks. Spatiotemporaly regulated domains of BMP, FGF, and other signaling molecules in the late gastrula-early neurula stage embryos generate the border region between the neural plate and non-neural ectoderm from which multiple cell types, including lens progenitor cells, emerge and undergo initial tissue formation. Extracellular signaling and DNA-binding transcription factors govern lens and optic cup morphogenesis. Pax6, c-Maf, Hsf4, Prox1, Sox1, and a few additional factors regulate expression of the lens structural proteins, the crystallins. A multitude of cross-talks between a diverse array of signaling pathways control the complexity and order of the lens morphogenetic processes and its transparency.

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Section: Lens Morphogenesis and Gene Regulatory Networkmentioning

confidence: 99%

Signaling and Gene Regulatory Networks in Mammalian Lens Development

2017

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“…It is known that TGFβ signaling is increased during cataract surgery, presumably as part of the wound-healing response (Sponer et al, 2005;Saika et al, 2002). It has long been proposed, and experimentally supported in primary culture systems, that TGFβ signaling contributes to myofibroblast differentiation in PCO, as it does in many fibrotic conditions in other organs (Meacock et al, 2000;Wormstone et al, 2002Wormstone et al, , 2006Wormstone et al, , 2009Saika, 2004;de Iongh et al, 2005;Vasavada and Praveen, 2014;Nibourg et al, 2015;Boswell et al, 2017). We have recently shown that TGFβ induces some epithelial cells in primary embryonic chick lens cultures (DCDMLs) to differentiate into myofibroblasts, and other cells in the same wells to form immature lens fiber cells.…”

Section: Introductionmentioning

confidence: 99%

“…We have recently shown that TGFβ induces some epithelial cells in primary embryonic chick lens cultures (DCDMLs) to differentiate into myofibroblasts, and other cells in the same wells to form immature lens fiber cells. The latter process is distinct from induction of fiber differentiation by FGF in that it does not require BMP signaling and is only partially reduced by fibroblast growth factor receptor (FGFR) inhibition (Boswell et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Fibronectin regulates growth factor signaling and cell differentiation in primary lens cells

VanSlyke

Boswell

Musil

2018

Journal of Cell Science

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Lens epithelial cells are bound to the lens extracellular matrix capsule, of which laminin is a major component. After cataract surgery, surviving lens epithelial cells are exposed to increased levels of fibronectin, and so we addressed whether fibronectin influences lens cell fate, using DCDML cells as a serum-free primary lens epithelial cell culture system. We found that culturing DCDMLs with plasma-derived fibronectin upregulated canonical TGFβ signaling relative to cells plated on laminin. Fibronectin-exposed cultures also showed increased TGFβ signalingdependent differentiation into the two cell types responsible for posterior capsule opacification after cataract surgery, namely myofibroblasts and lens fiber cells. Increased TGFβ activity could be identified in the conditioned medium recovered from cells grown on fibronectin. Other experiments showed that plating DCDMLs on fibronectin overcomes the need for BMP in fibroblast growth factor (FGF)-induced lens fiber cell differentiation, a requirement that is restored when endogenous TGFβ signaling is inhibited. These results demonstrate how the TGFβfibronectin axis can profoundly affect lens cell fate. This axis represents a novel target for prevention of late-onset posterior capsule opacification, a common but currently intractable complication of cataract surgery.

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“…Many lens models have been developed to study PCO (Liu et al, ; West‐Mays et al, ; Wormstone and Eldred, ; Boswell et al, ). The classic model is the human capsular bag cultures, which have been used to study wound repair and fibrosis (Liu et al, ).…”

Section: Lessons Learned From the Study Of The Lensmentioning

confidence: 99%

“…Thus, an imbalance in TGFβ signaling can lead to fibrotic disease progression. In the lens, TGFβ signaling has been linked to the development of PCO (Wormstone et al, ; Wormstone et al, ; West‐Mays et al, ; Eldred et al, ; Boswell et al, ). The latent form of TGFβ is bound within the extracellular matrix and its activation involves integrin receptors, particularly αvβ6.…”

Section: Lessons Learned From the Study Of The Lensmentioning

confidence: 99%

Fibrosis: Shared Lessons From the Lens and Cornea

Menko

Walker

Stepp

2019

The Anatomical Record

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Regenerative repair in response to wounding involves cell proliferation and migration. This is followed by the reestablishment of cell structure and organization and a dynamic process of remodeling and restoration of the injured cells' extracellular matrix microenvironment and the integration of the newly synthesized matrix into the surrounding tissue. Fibrosis in the lungs, liver, and heart can lead to loss of life and in the eye to loss of vision. Learning to control fibrosis and restore normal tissue function after injury repair remains a goal of research in this area. Here we use knowledge gained using the lens and the cornea to provide insight into how fibrosis develops and clues to how it can be controlled. The lens and cornea are less complex than other tissues that develop life-threatening fibrosis, but they are well characterized and research using them as model systems to study fibrosis is leading toward an improved understanding of fibrosis. Here we summarize the current state of the literature and how it is leading to promising new treatments.

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Dual function of TGFβ in lens epithelial cell fate: implications for secondary cataract

Cited by 44 publications

References 112 publications

Signaling and Gene Regulatory Networks in Mammalian Lens Development

Signaling and Gene Regulatory Networks in Mammalian Lens Development

Fibronectin regulates growth factor signaling and cell differentiation in primary lens cells

Fibrosis: Shared Lessons From the Lens and Cornea

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