Increased Expression of Integrin αvβ5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts

Asano, Yoshihide; Ihn, Hironobu; Yamane, Kunio; Jinnin, Masatoshi; Tamaki, Kunihiko

doi:10.2353/ajpath.2006.041306

Cited by 159 publications

(130 citation statements)

References 49 publications

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“…36 TbRII association with avb5-integrin was also found in sclerodermal fibroblasts, and subsequent FAK activity is required for myofibroblastic differentiation. 37 These reports strongly suggest the involvement of tenascin C integrin binding might exert a specific effect on Smad signal. Further in vitro study is needed to uncover this point.…”

Section: Discussionmentioning

confidence: 95%

Impaired cornea wound healing in a tenascin C-deficient mouse model

Sumioka

Kitano

Flanders

et al. 2013

Laboratory Investigation

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We investigated the effects of loss of tenascin C on the healing of the stroma using incision-injured mice corneas. Tenascin C was upregulated in the stroma following incision injury to the cornea. Wild-type (WT) and tenascin C-null (knockout (KO)) mice on a C57BL/6 background were used. Cell culture experiments were also conducted to determine the effects of the lack of tenascin C on fibrogenic gene expression in ocular fibroblasts. Histology, immunohistochemistry and real-time reverse transcription PCR were employed to evaluate the healing process in the stroma. The difference in the incidence of wound closure was statistically analyzed in hematoxylin and eosin-stained samples between WT and KO mice in addition to qualitative observation. Healing of incision injury in corneal stroma was delayed, with less appearance of myofibroblasts, less invasion of macrophages and reduction in expression of collagen Ia1, fibronectin and transforming growth factor b1 (TGFb1) in KO mice compared with WT mice. In vitro experiments showed that the loss of tenascin C counteracted TGFb1 acceleration of mRNA expression of TGFb1, and of collagen Ia1 and of myofibroblast conversion in ocular fibroblasts. These results indicate that tenascin C modulates wound healing-related fibrogenic gene expression in ocular fibroblasts and is required for primary healing of the corneal stroma.

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Section: Discussionmentioning

confidence: 95%

Impaired cornea wound healing in a tenascin C-deficient mouse model

Sumioka

Kitano

Flanders

et al. 2013

Laboratory Investigation

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“…Integrins are known to regulate TGF-b1 signaling through trans-activation of TGF-b1 receptors and downstream signaling (43)(44)(45). CCN1 binds to integrin a avb3 and avb5, which are known to enhance TGF-b signaling by physical association with TGF-bRII (46)(47)(48)(49). We speculate that CCN1 binding to these integrins may be necessary for enhanced TGF-b1/SMAD3 signaling.…”

Section: Discussionmentioning

confidence: 99%

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Kurundkar

Rangarajan

et al. 2016

FASEB j.

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Matricellular proteins mediate pleiotropic effects during tissue injury and repair. CCN1 is a matricellular protein that has been implicated in angiogenesis, inflammation, and wound repair. In this study, we identified CCN1 as a gene that is differentially up-regulated in alveolar mesenchymal cells of human subjects with rapidly progressive idiopathic pulmonary fibrosis (IPF). Elevated levels of CCN1 mRNA were confirmed in lung tissues of IPF subjects undergoing lung transplantation, and CCN1 protein was predominantly localized to fibroblastic foci. CCN1 expression in ex vivo IPF lung fibroblasts correlated with gene expression of the extracellular matrix proteins, collagen (Col)1a1, Col1a2, and fibronectin as well as the myofibroblast marker, a-smooth muscle actin. RNA interference (RNAi)-mediated knockdown of CCN1 down-regulated the constitutive expression of these profibrotic genes in IPF fibroblasts. TGF-b1, a known mediator of tissue fibrogenesis, induces gene and protein expression of CCN1 via a mothers against decapentaplegic homolog 3 (SMAD3)-dependent mechanism. Importantly, endogenous CCN1 potentiates TGF-b1-induced SMAD3 activation and induction of profibrotic genes, supporting a positive feedback loop leading to myofibroblast activation. In vivo RNAi-mediated silencing of CCN1 attenuates fibrogenic responses to bleomycin-induced lung injury. These studies support previously unrecognized, cooperative interaction between the CCN1 matricellular protein and canonical TGF-b1/SMAD3 signaling that promotes lung

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“…Before TGF-b1 can exert its biological effects, LAP and LTBP have to be dissociated. This can occur by conformational changes (Murphy-Ullrich and Poczatek, 2000; Annes et al, 2003;Asano et al, 2006), proteolytic cleavage (Lyons et al, 1990;Taipale et al, 1992;Dallas et al, 2002;Wang et al, 2006), irradiation (Barcellos-Hoff et al, 1994;Ehrhart et al, 1997) or by an acid environment (Jullien et al, 1989). The complex release mechanism of TGF-b1 might implicate that high total TGF-b1 has no biological consequences without the presence of appropriate activation mechanisms in the tumour microenvironment.…”

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confidence: 99%

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

et al. 2007

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Transforming growth factor-b1 (TGF-b1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-b1 activation and localisation of TGF-b1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-b1 staining by immunohistochemistry. Active TGF-b1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-b1. Active TGF-b1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-b1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGFb1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGFb1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-b1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-b1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-b1 activity levels in gastric cancer.

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Increased Expression of Integrin αvβ5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts

Cited by 159 publications

References 49 publications

Impaired cornea wound healing in a tenascin C-deficient mouse model

Impaired cornea wound healing in a tenascin C-deficient mouse model

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

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