Involvement of P38MAPK in human corneal endothelial cell migration induced by TGF-β2

Joko, Takeshi; Shiraishi, Atsushi; Akune, Yoko; Tokumaru, Sho; Kobayashi, Takeshi; Miyata, Kazunori; Ohashi, Yuichi

doi:10.1016/j.exer.2012.11.018

Cited by 43 publications

(40 citation statements)

References 28 publications

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“…These findings correspond with our results, and support the supposition that enlargement may be a major factor in early CEC recovery. Though several in-vitro studies have revealed molecular biologic findings in corneal [13,[39][40][41], this does not mean that migration is a main pattern in early CEC recovery. Instead, cellular migration seems to act on CEC recovery in the long term.…”

Section: Discussionmentioning

confidence: 76%

“…To our knowledge, there has been no study to investigatewhich mechanism (cellular migration or enlargement) has the major effect on early CEC recovery after cataract surgery in humans. A lot of results from animal in-vivo studies and human invitro studies seem to have made people think that cellular migration or enlargement can be taken for granted as recovery patterns after cataract surgery in humans [6][7][8][9][10][11][12][13][14][15][16]. Because it is uncertain which of migration or enlargement have the major effect on early CEC recovery after cataract surgery in humans, this study could be meaningful as a human in-vivo study.…”

Section: Discussionmentioning

confidence: 97%

“…Recovery mechanism for corneal endothelial cell (CEC) have been studied for several decades, and most subjects of in-vivo studies about the CEC recovery mechanism following endothelial damages have been animals, including rabbit, rat, and monkey [6][7][8][9]. The human CEC recovery mechanism has been studied mostly in vitro or ex vivo because human in-vivo study is very difficult to perform [10][11][12][13][14][15][16][17]. Human in-vivo studies concerning the CEC recovery mechanism following endothelial damage have been rare.…”

Section: Introductionmentioning

confidence: 99%

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The pattern of early corneal endothelial cell recovery following cataract surgery: cellular migration or enlargement?

Kim

Wee

Hyon

2015

Graefes Arch Clin Exp Ophthalmol

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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The pattern of early corneal endothelial cell recovery following cataract surgery: cellular migration or enlargement?

Kim

Wee

Hyon

2015

Graefes Arch Clin Exp Ophthalmol

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“…There have been many attempts to overcome the cell cycle arrest using various approaches including the use of growth factors such as FGF, EGF, and TGF-β, the use of endothelial cell growth supplements (5)(6)(7)(8)(9), and disruption of contact inhibition using EDTA (10). Moreover, severely injured CEC can undergo mesenchymal transition through which they lose their polarity and assume a fibroblastic phenotype.…”

mentioning

confidence: 99%

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

Lee

Jung

Heur

2018

Journal of Biological Chemistry

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Investigating stimulation of endogenous wound healing in corneal endothelial cells (CECs) may help address the global shortage of donor corneas by decreasing the number of transplants performed for blindness due to endothelial dysfunction. We previously reported that IL-1β stimulation leads to fibroblast growth factor (FGF2) expression, enhancing migration and proliferation of mammalian CECs. However, FGF2 also promotes the endothelial-mesenchymal transition, which can lead to retrocorneal membrane formation and blindness. This prompted us to investigate downstream FGF2 signaling targets that could be manipulated to prevent retrocorneal membrane formation. FGF2 stimulation altered cell morphology and induced expression of mesenchymal transition marker genes such as snail family transcriptional repressor 1 (SNAI1), SNAI2, zinc finger E-boxbinding homeobox 1 (ZEB1), and ZEB2. This, in turn, induced expression of fibronectin, vimentin and, type I collagen and suppressed E-cadherin in CECs in vitro and ex vivo. siRNA-mediated SNAI1 knockdown revealed that SNAI1 induces ZEB1 expression, in turn inducing expression of type I collagen, the major component of retrocorneal membranes, and of cyclin-dependent kinase 2 (CDK2) and cyclin E1, promoting cell proliferation. siRNA-mediated knockdown of SNAI1 or ZEB1, but not of CDK2, inhibited FGF2-dependent expression of fibronectin, vimentin, and type I collagen and of suppression of E-cadherin expression. We conclude that SNAI1 is a key regulator of FGF2-dependent mesenchymal transition in human ex vivo corneal endothelium, with ZEB1 regulating type I collagen expression and CDK2 regulating cell proliferation. These results suggest that SNAI1 promotes fibrosis and cell proliferation in human corneal endothelium through ZEB1 and CDK2.The cornea is the anterior, transparent tissue of the human eye and consists of epithelium, stroma and endothelium. The corneal endothelium is composed of a monolayer of cells and plays a critical role in maintaining corneal transparency that is critical for sharp vision through its pump function (1,2). Adult human corneal endothelial cells (CEC) are usually mitotically inactive and arrested at the G 1 phase of the cell cycle (3,4). Because of the cell cycle arrest, there is a progressive decline in CEC density that can be further accelerated by injury, such as intraocular surgery or infection. When the density decreases below a critical threshold, corneal edema ensues, leading to loss of transparency and vision. Vision loss secondary to endothelial dysfunction is a common indication for corneal transplantation in developed nations.There have been many attempts to overcome the cell cycle arrest using various approaches including the use of growth factors such as FGF, EGF, and TGF-β, the use of endothelial cell growth supplements (5-9), and disruption of contact inhibition using EDTA (10). Moreover, severely injured CEC can undergo mesenchymal transition through which they lose their polarity and assume a fibroblastic phenotype. These CEC a...

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“…In PPCD, aberrant cells exhibit proliferative activity and increased migration [1, 21]. Interestingly, here we have found that in PPCD the proliferation of aberrant cells is not associated with lower, but rather significantly higher TGF-β2 levels in AH compared to the control group; however, in 81% of samples the levels of TGF-β2 do not exceed 500 pg/ml, a concentration that was able to reduce the proliferation of cultured human corneal endothelial cells [43]. The responses of corneal endothelial cells in healthy endothelium and aberrant cells present in PPCD to TGF-β2 could differ.…”

Section: Discussionmentioning

confidence: 85%

Active transforming growth factor-β2 in the aqueous humor of posterior polymorphous corneal dystrophy patients

et al. 2017

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PurposePosterior polymorphous corneal dystrophy (PPCD) is characterized by abnormal proliferation of corneal endothelial cells. It was shown that TGF-β2 present in aqueous humor (AH) could help maintaining the corneal endothelium in a G1-phase-arrest state. We wanted to determine whether the levels of this protein are changed in AH of PPCD patients.MethodsWe determined the concentrations of active TGF-β2 in the AH of 29 PPCD patients (42 samples) and 40 cadaver controls (44 samples) by ELISA. For data analysis the PPCD patients were divided based on either the molecular genetic cause of their disease as PPCD1 (37 samples), PPCD3 (1 sample) and PPCDx (not linked to a known PPCD loci, 4 samples) or on the presence (17 samples) or absence (25 samples) of secondary glaucoma or on whether they had undergone penetrating keratoplasty (PK, 32 samples) or repeated PK (rePK, 7 samples).ResultsThe level of active TGF-β2 in the AH of all PPCD patients (mean ± SD; 386.98 ± 114.88 pg/ml) in comparison to the control group (260.95 ± 112.43 pg/ml) was significantly higher (P = 0.0001). Compared to the control group, a significantly higher level of active TGF-β2 was found in the PPCD1 (P = 0.0005) and PPCDx (P = 0.0022) groups. Among patients the levels of active TGF-β2 were not significantly affected by gender, age, secondary glaucoma or by the progression of dystrophy when one or repeated PK were performed.ConclusionThe levels of active TGF-β2 in the AH of PPCD patients are significantly higher than control values, and thus the increased levels of TGF-β2 could be a consequence of the PPCD phenotype and can be considered as another feature characterizing this disease.

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Involvement of P38MAPK in human corneal endothelial cell migration induced by TGF-β2

Cited by 43 publications

References 28 publications

The pattern of early corneal endothelial cell recovery following cataract surgery: cellular migration or enlargement?

The pattern of early corneal endothelial cell recovery following cataract surgery: cellular migration or enlargement?

Fibroblast growth factor 2 induces proliferation and fibrosis via SNAI1-mediated activation of CDK2 and ZEB1 in corneal endothelium

Active transforming growth factor-β2 in the aqueous humor of posterior polymorphous corneal dystrophy patients

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