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Fibronectin has multifunctional roles in posterior capsular opacification (PCO).

ABSTRACT: Fibrotic posterior capsular opacification (PCO), one of the major complications of cataract surgery, occurs when lens epithelial cells (LCs) left behind post cataract surgery (PCS) undergo epithelial to mesenchymal transition, migrate into the optical axis and produce opaque scar tissue. LCs left behind PCS robustly produce fibronectin, although its roles in fibrotic PCO are not known. In order to determine the function of fibronectin in PCO pathogenesis, we created mice lacking the fibronectin gene (FN conditional knock out -FNcKO) from the lens. While animals from this line have normal lenses, upon lens fiber cell removal which models cataract surgery, FNcKO LCs exhibit a greatly attenuated fibrotic response from 3 days PCS onward as assessed by a reduction in surgery-induced cell proliferation, and fibrotic extracellular matrix (ECM) production and deposition. This is correlated with less upregulation of Transforming Growth Factor β (TGFβ) and integrin signaling in FNcKO LCs PCS concomitant with sustained Bone Morphogenetic Protein (BMP) signaling and elevation of the epithelial cell marker E cadherin. Although the initial fibrotic response of FNcKO LCs was qualitatively normal at 48 h PCS as measured by the upregulation of fibrotic marker protein αSMA, RNA sequencing revealed that the fibrotic response was already quantitatively attenuated at this time, as measured by the upregulation of mRNAs encoding molecules that control, and are controlled by, TGFβ signaling, including many known markers of fibrosis. Most notably, gremlin-1, a known regulator of TGFβ superfamily signaling, was upregulated sharply in WT LCs PCS, while this response was attenuated in FNcKO LCs. As exogenous administration of either active TGFβ1 or gremlin-1 to FNcKO lens capsular bags rescued the attenuated fibrotic response of fibronectin null LCs PCS including the loss of SMAD2/3 phosphorylation, this suggests that fibronectin plays multifunctional roles in fibrotic PCO development.

SUBMITTER: Shihan MH

PROVIDER: S-EPMC7321929 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Posterior capsule opacification (PCO) is a significant complication of intraocular lens (IOL) implantation in cataract surgery, in which the adhesion and proliferation of lens epithelial cells (LECs) on the implanted IOL surface play an important role. The surface modification of IOL to prevent LEC adhesion and proliferation is a practical way to reduce the incidence of PCO. In this study, a multifunctional binary copolymer of poly(ethylene glycol) methacrylate (PEGMA) and glycidyl methacrylate (GMA) was synthesized (poly(PEGMA-co-GMA), PPG) and chemically grafted onto the aminolyzed IOL surface, utilizing the coupling reaction of epoxy and amino groups. Doxorubicin (DOX) was subsequently immobilized on the surface coating via the reaction of epoxy and amino groups as well. Taking advantages of the hydrophilicity of the PEG segments in the copolymer coating and the anti-proliferative effects of the DOX, a multifunctional surface coating was easily established by the synthesized copolymer PPG. Such anti-proliferative drug immobilized hydrophilic coating modification may effectively reduce the cell adhesion and proliferation and thus it is hypothesized to have great potential in PCO inhibition. The synthesis of PPG was confirmed by proton nuclear magnetic resonance spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy (FTIR). The surface coating immobilization was demonstrated by X-ray photoelectron spectroscopy (XPS). The in vitro drug release profiles and the cell behaviors were also investigated to validate the multifunctional coating inhibition effect on cellular adhesion and antiproliferation. Finally, the in vivo ocular implantation was carried out on rabbit eyes to evaluate the effect of the coating modified IOL on the inhibition of postoperative PCO. It followed that such multifunctional coating modification can effectively inhibit the adhesion and proliferation of LECs and significantly reduce the incidence of PCO. All these results reveal that such PPG copolymer modification provides a facile yet effective way to inhibit PCO formation after IOL implantation.

Project description:Cataract is the leading cause of visual impairment, and posterior capsular opacification (PCO) is the most common long-term complication of modern cataract surgery, which can cause severe visual impairment after surgery. The proliferation, migration, and epithelial-mesenchymal transition (EMT) of residual lens epithelial cells (LECs) stimulated by growth factors and cytokines, are the key pathological mechanisms involved in the development of PCO. This study demonstrated that non-steroidal anti-inflammatory drug (NSAID), bromfenac, was capable of effectively inhibiting cell migration, overexpression of EMT markers, such as fibronectin (FN), matrix metalloproteinase 2 (MMP2), α-smooth muscle actin (α-SMA), and transcription factor Snail, and extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3β (GSK-3β) signaling induced by transforming growth factor-β2 (TGF-β2) in vitro. The inhibitory effect of bromfenac on TGF-β2-induced EMT was also verified on a primary lens epithelial cell model using human anterior capsules. Furthermore, based on ultrasonic spray technology, we developed a drug-eluting intraocular lens (IOL) using poly (lactic-co-glycolic acid) (PLGA) with sustained bromfenac release ability for the prevention of PCO development. In the rabbit models of cataract surgery, bromfenac-eluting IOL exhibited remarkable PCO prevention and inflammation suppression effects with excellent biocompatibility. In conclusion, bromfenac can inhibit TGF-β2-induced cell migration and the EMT of LECs via ERK/GSK-3β/Snail signaling. The present study offers a novel approach for preventing PCO through PLGA-based drug sustained-release IOLs. Graphical abstract TGF-β2 promoted migration and EMT of lens epithelial cells (LECs) through activation of ERK/GSK-3β/Snail signaling, which could be suppressed by bromfenac. Novel bromfenac-based drug-eluting IOLs exhibited excellent PCO prevention in vivo.Image 1 Highlights • Bromfenac inhibited TGF-β2-induced migration and EMT of LECs through ERK/GSK-3β/Snail signaling.• Drug-eluting IOLs with sustained bromfenac release were developed based on ultrasonic spray technology.• Bromfenac-eluting IOLs exhibited remarkable PCO prevention and inflammation suppression effects in vivo.• Bromfenac-eluting IOLs hold great potential for clinical application of PCO prevention.

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Fibronectin has multifunctional roles in posterior capsular opacification (PCO).

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