Role of CD44 in Epithelial Wound Repair

Kikuchi, Shojiro; Griffin, Courtney T.; Wang, Shao-Shean; Bissell, D. Montgomery

doi:10.1074/jbc.m414048200

Cited by 48 publications

(25 citation statements)

References 25 publications

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“…Previous studies have shown that OPN binds to the family of αVβ integrins, and the cell surface adhesion molecule CD44, to initiate cellular signals that enable tumor progression [19], [54]. The interaction of OPN with integrins is dependent on the OPN Arg-Gly-Asp (RGD) motif and on a high activation state of the integrin receptors, αVβ1, αVβ3 and αVβ5 [55].…”

Section: Discussionmentioning

confidence: 99%

Role of Hepatitis C Virus Induced Osteopontin in Epithelial to Mesenchymal Transition, Migration and Invasion of Hepatocytes

et al. 2014

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Osteopontin (OPN) is a secreted phosphoprotein which has been linked to tumor progression and metastasis in a variety of cancers including hepatocellular carcinoma (HCC). Previous studies have shown that OPN is upregulated during liver injury and inflammation. However, the role of OPN in hepatitis C virus (HCV)-induced liver disease pathogenesis is not known. In this study, we determined the induction of OPN, and then investigated the effect of secreted forms of OPN in epithelial to mesenchymal transition (EMT), migration and invasion of hepatocytes. We show the induction of OPN mRNA and protein expression by HCV-infection. Our results also demonstrate the processing of precursor OPN (75 kDa) into 55 kDa, 42 kDa and 36 kDa forms of OPN in HCV-infected cells. Furthermore, we show the binding of secreted OPN to integrin αVβ3 and CD44 at the cell surface, leading to the activation of downstream cellular kinases such as focal adhesion kinase (FAK), Src, and Akt. Importantly, our results show the reduced expression of epithelial marker (E-cadherin) and induction of mesenchymal marker (N-cadherin) in HCV-infected cells. We also show the migration and invasion of HCV-infected cells using wound healing assay and matrigel coated Boyden chamber. In addition, we demonstrate the activation of above EMT markers, and the critical players involved in OPN-mediated cell signaling cascade using primary human hepatocytes infected with Japanese fulminant hepatitis (JFH)-1 HCV. Taken together, these studies suggest a potential role of OPN in inducing chronic liver disease and HCC associated with chronic HCV infection.

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Section: Discussionmentioning

confidence: 99%

Role of Hepatitis C Virus Induced Osteopontin in Epithelial to Mesenchymal Transition, Migration and Invasion of Hepatocytes

et al. 2014

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“…This was also observed in our system as exposure of MTs to TGF-β1 led to an increase in the number of αSMA-positive cells and the induction of ECM components (collagen I, IV, fibronectin, CD44, and MMP2). CD44 (hyaluronic acid receptor) is usually upregulated in stellate cells of injured liver and it is also correlated to their activated and migratory phenotype [32]. Also MMP2 upregulation in the supernatant confirms the remodelling of the ECM, as previously published [33].…”

Section: Discussionmentioning

confidence: 60%

Pro-fibrotic compounds induce stellate cell activation, ECM-remodelling and Nrf2 activation in a human 3D-multicellular model of liver fibrosis

et al. 2017

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Background & AimsCurrently most liver fibrosis research is performed in vivo, since suitable alternative in vitro systems which are able to recapitulate the cellular events leading to liver fibrosis are lacking. Here we aimed at generating a system containing cells representing the three key players of liver fibrosis (hepatocyte, Kupffer cells and stellate cells) and assess their response to pro-fibrotic compounds such as TGF-β1, methotrexate (MTX) and thioacetamide (TAA).MethodsHuman cell lines representing hepatocytes (HepaRG), Kupffer cell (THP-1 macrophages) and stellate cells (hTERT-HSC) were co-cultured using the InSphero hanging drop technology to generate scaffold-free 3D microtissues, that were treated with pro-fibrotic compounds (TGF-β1, MTX, TAA) for up to 14 days. The response of the microtissues was evaluated by determining the expression of cytokines (TNF-α, TGF-β1 and IL6), the deposition and secretion of ECM proteins and induction of gene expression of fibrosis biomarkers (e.g. αSMA). Induction of Nrf2 and Keap1, as key player of defence mechanism, was also evaluated.ResultsWe could demonstrate that the multicellular 3D microtissue cultures could be maintained in a non-activated status, based on the low expression levels of activation markers. Macrophages were activated by stimulation with LPS and hTERT-HSC showed activation by TGF-β1. In addition, MTX and TAA elicited a fibrotic phenotype, as assessed by gene-expression and protein-deposition of ECM proteins such as collagens and fibronectin. An involvement of the antioxidant pathway upon stimulation with pro-fibrotic compounds was also observed.ConclusionHere, for the first time, we demonstrate the in vitro recapitulation of key molecular and cellular events leading to liver fibrosis: hepatocellular injury, antioxidant defence response, activation of Kupffer cells and activation of HSC leading to deposition of ECM.

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“…Among various biodegradable synthetic and natural polymers, hyaluronic acid (HA), a glycosaminoglycan (GAG) component richly present in connective tissues, has been reported to mediate its activity in cell signaling [7], cell migration [8], wound repair [9], and morphogenesis [10]. HA based hydrogels are thus widely used as wound healing dressing, tissue engineering scaffolds, and cell/molecule delivery carriers [11, 12].…”

Section: Introductionmentioning

confidence: 99%

Stiffness and adhesivity control aortic valve interstitial cell behavior within hyaluronic acid based hydrogels

et al. 2013

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Bioactive and biodegradable hydrogels that mimic the extracellular matrix and regulate valve interstitial cells (VIC) behavior are of great interest as three dimensional (3D) model systems for understanding mechanisms of valvular heart disease pathogenesis in vitro and the basis for regenerative templates for tissue engineering. However, the role of stiffness and adhesivity of hydrogels in VIC behavior remains poorly understood. This study reports synthesis of oxidized and methacrylated hyaluronic acid (Me-HA and MOHA) and subsequent development of hybrid hydrogels based on modified HA and methacrylated gelatin (Me-Gel) for VIC encapsulation. The mechanical stiffness and swelling ratio of the hydrogels were tunable with molecular weight of HA and concentration/composition of precursor solution. The encapsulated VIC in pure HA hydrogels with lower mechanical stiffness showed more spreading morphology comparing to stiffer counterparts and dramatically upregulated alpha smooth muscle actin expression indicating more activated myofibroblast properties. The addition of Me-Gel in Me-HA facilitated cell spreading, proliferation and VIC migration from encapsulated spheroids and better maintained VIC fibroblastic phenotype. The VIC phenotype transition during migration from encapsulated spheroids in both Me-HA and Me-HA/Me-Gel hydrogel matrix was also observed. These findings are important for the rational design of hydrogels for controlling VIC morphology, and for regulating VIC phenotype and function. The Me-HA/Me-Gel hybrid hydrogels accommodated with VIC are promising as valve tissue engineering scaffolds and 3D model for understanding valvular pathobiology.

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Role of CD44 in Epithelial Wound Repair

Cited by 48 publications

References 25 publications

Role of Hepatitis C Virus Induced Osteopontin in Epithelial to Mesenchymal Transition, Migration and Invasion of Hepatocytes

Role of Hepatitis C Virus Induced Osteopontin in Epithelial to Mesenchymal Transition, Migration and Invasion of Hepatocytes

Pro-fibrotic compounds induce stellate cell activation, ECM-remodelling and Nrf2 activation in a human 3D-multicellular model of liver fibrosis

Stiffness and adhesivity control aortic valve interstitial cell behavior within hyaluronic acid based hydrogels

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