Interleukin-1β-Induced Wnt5a Enhances Human Corneal Endothelial Cell Migration through Regulation of Cdc42 and RhoA

Lee, Jung Goo; Heur, Martin

doi:10.1128/mcb.01572-13

Cited by 41 publications

(38 citation statements)

References 66 publications

(82 reference statements)

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“…Rho family proteins play important roles in regulating proliferation and/or migration (32), and Wnt5a has been reported to activate Rac1 and RhoA in other cell types (33,34). We observed that Wnt5a induced activation of Rac1 and RhoA within 30 minutes ( Figure 1D and Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 48%

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

Yu¹,

Chen²,

Cui³

et al. 2015

Journal of Clinical Investigation

154

211

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Section: Resultsmentioning

confidence: 48%

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

Yu¹,

Chen²,

Cui³

et al. 2015

Journal of Clinical Investigation

154

211

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“…Gene Knockdown by siRNA -For gene knockdown by siRNA, Accell SMARTpool system was used as previously reported (43). Corneal endothelial cells at 70% confluence or ex vivo corneal endothelium were transfected on 6-well plate with 1.5 µM Accell SMARTpool of siRNA targeting SNAI1, ZEB1 or CDK2 (Dharmacon, Pittsburgh, PA) in Accell delivery medium according to the manufacturer's instructions.…”

Section: Methodsmentioning

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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“…48,51 Moreover, both stimuli induce the activation of MAPK signaling, implicated in the activation of Runx2 and other transcription factors, such as the NF-kB, 13e15,46,52 which also induce the expression of Wnt. 53,54 Therefore, we can hypothesize that IL-1b and 45-kDa Fn-fs induce aggrecanases expression by activation of the transcription factor Runx2, mainly through the ERK-MAPK signaling. Moreover, these stimuli specifically induce the Wnt/b-catenin signaling in OA-SF, with the consequent therapeutic value.…”

Section: Q18mentioning

confidence: 99%

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Pérez‐García

Gutiérrez‐Cañas

Seoane

et al. 2016

The American Journal of Pathology

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Current description of osteoarthritis includes the involvement of synovial inflammation. Studies contributing to understanding the mechanisms of cross-talk and feedback among the joint tissues could be relevant to the development of therapies that block disease progression. During osteoarthritis, synovial fibroblasts exposed to anomalous mechanical forces and an inflammatory microenvironment release factors such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) metalloproteinases that mediate tissue damage and perpetuate inflammation. We therefore studied the production of ADAMTS by synovial fibroblasts and their contribution to cartilage degradation. Moreover, we analyzed the implication of two mediators present in the osteoarthritis joint, IL-1b as proinflammatory cytokine, and 45-kDa fibronectin fragments as products of matrix degradation. We reported that synovial fibroblasts constitutively express and release ADAMTS 4, 5, 7, and 12. Despite the contribution of both mediators to the stimulation of Runx2 and Wnt/b-catenin signaling pathways, as well as to ADAMTS expression, promoting the degradation of aggrecan and cartilage oligomeric matrix protein from cartilage, fibronectin fragments rather than IL-1b played the major pathological role in osteoarthritis, contributing to the maintenance of the disease. Moreover, higher levels of ADAMTS 4 and 7 and a specific regulation of ADAMTS-12 were observed in osteoarthritis, suggesting them as new potential therapeutic targets. Therefore, synovial fibroblasts provide the biochemical tools to the chronicity and destruction of the osteoarthritic joints. (Am J Pathol 2016, -: 1e13; http:// dx

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Interleukin-1β-Induced Wnt5a Enhances Human Corneal Endothelial Cell Migration through Regulation of Cdc42 and RhoA

Cited by 41 publications

References 66 publications

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation

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

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

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