Targeting the Fibronectin Type III Repeats in Tenascin-C Inhibits Epithelial-Mesenchymal Transition in the Context of Posterior Capsular Opacification

Tiwari, Anil; Ram, Jagat; Luthra-Guptasarma, Manni

doi:10.1167/iovs.14-14934

Cited by 23 publications

(20 citation statements)

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“…Myofibroblasts furthermore overexpress fibronectin, which allows them to bind to extracellular matrix. Fibronectin modulates and stabilizes the extracellular matrix in wound healing processes [29]. Fibronectin was present in the expected location extracellularly and enhanced below the IOLs and in the capsular folds, where increased fibrotic cell activity is suspected [21].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of posterior capsule opacification of the Alcon Clareon IOL vs the Alcon Acrysof IOL using a human capsular bag model

et al. 2020

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Background: Posterior capsule opacification (PCO) after cataract surgery is influenced by intraocular lens (IOL) design and material. The following is an ex vivo comparison of PCO between the Clareon vs. the AcrySof IOL in human capsular bags. Methods: Twenty cadaver capsular bags from 10 human donors were used, with the novel hydrophobic IOL (Clareon, CNA0T0) being implanted in one eye and the other eye of the same donor receiving the AcrySof IOL (SN60WF) following phacoemulsification cataract surgery. Five capsular bags of 3 donors served as controls without IOL. Cellular growth of lens epithelial cells was photo-documented daily. The primary endpoint was the time until full coverage of the posterior capsule by cells. Furthermore, immunofluorescence staining of capsular bags for the fibrotic markers f-actin, fibronectin, alpha smooth muscle actin, and collagen type 1 were performed. Results: The new Clareon IOL did not show any disadvantages in terms of days until full cell coverage of the posterior capsule in comparison to the AcrySof (p > 0.99). Both, the Clareon (p = 0.01, 14.8 days) and the AcrySof IOL (p = 0.005, 15.7 days) showed a slower PCO development in comparison to the control (8.6 days). The fibrotic markers f-actin, fibronectin, alpha smooth muscle actin, and collagen type 1 were equally distributed between the two IOLs and differed from the control. Conclusions: A comparable performance has been found in the ex vivo formation of PCO between the two IOLs. Long-term clinical studies are necessary to reach final conclusions.

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Section: Discussionmentioning

confidence: 99%

Evaluation of posterior capsule opacification of the Alcon Clareon IOL vs the Alcon Acrysof IOL using a human capsular bag model

et al. 2020

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“…Estudo realizado anteriormente em humanos evidenciou que há aumento na expressão de proteínas na membrana extracelular das cápsulas colhidas de pacientes diabéticos, quando comparados às colhidas de pacientes sadios que apresentavam apenas cataratas do tipo corticais, o que supostamente poderia alterar a composição dos proteoglicanos nessa estrutura e, por consequência, sua função nestes pacientes (Tiwari et al 2014). Outros estudos referem que há uma maior produção de colágeno na presença de catarata e/ou diabete e que a alteração é ainda maior no grupo dos diabéticos, quando também comparados a pacientes sadios (Glover & Constantinescu 1997, Bras et al 2006, Pot et al 2009, Wormstone et al 2009, Chandler et al 2012.…”

Section: Discussionunclassified

Avaliação da composição molecular da cápsula anterior da lente de cães idosos com catarata de alto risco

et al. 2016

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Resumo: Atualmente, a cápsula anterior e o epitélio da lente tem sido cada vez mais estudados, com o intuito de reduzir as possíveis complicações do pós-operatório da remoção da catarata, tal como a opacidade da cápsula posterior, alteração ocasionada principalmente pela diferenciação e migração das células do epitélio lenticular para a cápsula posterior da lente. O objetivo deste estudo foi analisar a composição molecular da cápsula anterior da lente pela técnica histoquímica de PAS (avaliação de proteoglicanos) e picrosirius red (avaliação de colágeno IV), em cães idosos com catarata diabética e não diabética do tipo hipermadura, submetidos ao uso ou não de azul de tripano a 0,1 % durante a facoemulsificação. Vinte e sete cães foram estudados, incluindo 21 fêmeas e 6 machos, de 8 a 12 anos de idade (média = 9,6 anos), de diversas raças e divididos em 2 grupos: GC (catarata hipermadura) e GCD (catarata diabética). Os resultados das análises realizadas mostraram que ambas as amostras, tanto as provenientes das cataratas hipermaduras, quanto das diabéticas, apresentam semelhante composição molecular de proteoglicanos e colágeno IV e isto independente da utilização de azul de tripano a 0,1 %. Conclui-se, portanto, que se os resultados obtidos forem decorrentes de alterações provocadas pelo rápido metabolismo da catarata diabética e pela cronicidade da catarata hipermadura sugere-se que o comprometimento da estrutura capsular seja de intensidade equivalente e, por consequência, que isto também possa prejudicar o metabolismo das células do epitélio anterior da lente, diminuindo assim a incidência da opacidade da cápsula posterior de cães com catarata diabética e hipermadura submetidos à facoemulsificação.

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“…In addition to studying such behavior under ordinary culture conditions, we also use protein-engineered versions of ECM components, and examine the effects of these in comparison with non-protein-engineered components. One aspect that we commonly examine is the presence and activation status of metalloproteases such as MMP-2 and MMP-9, as a function of cell type and the presence of different factors including protein-engineered factors (Sharma et al, 2013;Tiwari et al, 2015;Tiwari et al, 2016;Mehta et al, 2018).…”

Section: Supplementarymentioning

confidence: 99%

Sustained exposure to trypsin causes cells to transition into a state of reversible stemness that is amenable to transdifferentiation

Sharma

Kumar

Sharma

et al. 2019

Preprint

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During cell culture, trypsin, a serine protease, is applied to cells for 5-10 minutes to separate them from each other and from the underlying substratum so that they can be transferred to a different vessel, for re-plating, after growth medium containing 10 % serum has been added to the cells, in a well-known technique known as 'passaging'. The serum in the growth medium contains alpha-1 antitrypsin, which is a potent inhibitor of trypsin, elastase and other serine proteases.Although what is used is bovine serum in which levels of proteins could be different from levels seen in humans, normal human serum contains A1AT (> 1 mg/ml; > ~18 µmol/L) as well as trypsin itself (< 460 ng/ml, or ~0.02 µmol/L), with the former in a ~900-fold molar excess over the latter. Thus, it may be assumed there is also enough A1AT in the bovine serum added during passaging, to neutralize the trypsin (~100 μM) present in the small volume of trypsin-EDTA solution used to separate cells. What are the consequences of not adding serum, when growth medium is added, or of maintaining cells for a few tens of hours in the presence of trypsin, in a serum-free growth medium? What does such sustained exposure to trypsin during cell culture do to cells? More generally, what are the responses of cells within an organism to the balance of trypsin and A1AT in the serum that bathes them constantly? We know that excesses and deficiencies in the levels of either trypsin or A1AT are associated with disease. We know that cellular metabolism can be influenced through signaling involving protease activated membrane GPCR receptors (PAR1-4). In particular, we know of a receptor called PAR2, which is specifically activated by trypsin, expressed by cells at baseline levels, and upregulated through some feedback involving trypsin-activation. We also know that cells at sites of injury or inflammation produce and secrete trypsin, and that this trypsin can act locally upon cells in a variety of ways, all of which have probably not yet been elucidated. Here, we show that sustained exposure to trypsin induces cells to de-differentiate into a stem-like state. We show that if serum is either not added at all, or added and then washed away (after confluency is attained), during cell culture, all cells exposed to exogenously-added trypsin undergo changes in morphology, transcriptome, secretome, and developmental potential, and transition into a state of stemness, in minimal essential medium (MEM). Regardless of their origins, i.e., independent of whether they are derived from primary cultures, cell lines or cancer cell lines, and regardless of the original cell type used, exposure to trypsin (~10 µM; ~250 µg/ml) at a concentration 10-fold lower than that used to separate cells during passaging (~100 μM), over a period of 24-48 hours, causes cells to (1) become rounded, (2) cluster together, (3) get arrested in the G0/G1 stage of the cell cycle, (4) display increased presence of 5-hydroxymethyl cytosine in their nuclei (indicative of reprogramming), (5) display increased...

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Targeting the Fibronectin Type III Repeats in Tenascin-C Inhibits Epithelial-Mesenchymal Transition in the Context of Posterior Capsular Opacification

Abstract: Our data suggest that the TNfnIII 1-5 repeats play an important role in PCO pathology. The inhibition of EMT by TN64 is mediated by SMAD-independent, integrin-β-catenin-FAK signaling pathway, and is therefore proposed as a novel antifibrotic therapeutic candidate.

Cited by 23 publications

References 54 publications

Evaluation of posterior capsule opacification of the Alcon Clareon IOL vs the Alcon Acrysof IOL using a human capsular bag model

Evaluation of posterior capsule opacification of the Alcon Clareon IOL vs the Alcon Acrysof IOL using a human capsular bag model

Avaliação da composição molecular da cápsula anterior da lente de cães idosos com catarata de alto risco

Sustained exposure to trypsin causes cells to transition into a state of reversible stemness that is amenable to transdifferentiation

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