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Simultaneous deactivation of FAK and Src improves the pathology of hypertrophic scar.

ABSTRACT: Hypertrophic scar (HS) is a serious fibrotic skin condition with currently no satisfactory therapy due to undefined molecular mechanism. FAK and Src are two important non-receptor tyrosine kinases that have been indicated in HS pathogenesis. Here we found both FAK and Src were activated in HS vs. normal skin (NS), NS fibroblasts treated with TGF-?1 also exhibited FAK/Src activation. Co-immunoprecipitation and dual-labelled immunofluorescence revealed an enhanced FAK-Src association and co-localization in HS vs. NS. To examine effects of FAK/Src activation and their interplay on HS pathogenesis, site-directed mutagenesis followed by gene overexpression was conducted. Results showed only simultaneous overexpression of non-phosphorylatable mutant FAK Y407F and phosphomimetic mutant Src Y529E remarkably down-regulated the expression of Col I, Col III and ?-SMA in cultured HS fibroblasts, alleviated extracellular matrix deposition and made collagen fibers more orderly in HS tissue vs. the effect from single transfection with wild-type or mutational FAK/Src. Glabridin, a chemical found to block FAK-Src complex formation in cancers, exhibited therapeutic effects on HS pathology probably through co-deactivation of FAK/Src which further resulted in FAK-Src de-association. This study suggests FAK-Src complex could serve as a potential molecular target, and FAK/Src double deactivation might be a novel strategy for HS therapy.

SUBMITTER: Su L

PROVIDER: S-EPMC4867599 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Simultaneous deactivation of FAK and Src improves the pathology of hypertrophic scar.

Su Linlin L Li Xiaodong X Wu Xue X Hui Bo B Han Shichao S Gao Jianxin J Li Yan Y Shi Jihong J Zhu Huayu H Zhao Bin B Hu Dahai D

Scientific reports 20160516

Hypertrophic scar (HS) is a serious fibrotic skin condition with currently no satisfactory therapy due to undefined molecular mechanism. FAK and Src are two important non-receptor tyrosine kinases that have been indicated in HS pathogenesis. Here we found both FAK and Src were activated in HS vs. normal skin (NS), NS fibroblasts treated with TGF-β1 also exhibited FAK/Src activation. Co-immunoprecipitation and dual-labelled immunofluorescence revealed an enhanced FAK-Src association and co-locali ...[more]

PMID: 27181267

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Project description:Background: As a fibrotic disease with a high incidence, the pathogenesis of hypertrophic scarring is still not fully understood, and the treatment of this disease is also challenging. In recent years, human adipose-derived mesenchymal stem cells (AD-MSCs) have been considered an effective treatment for hypertrophic scars. This study mainly explored whether the therapeutic effect of AD-MSCs on hypertrophic scars is associated with oxidative-stress-related proteins. Methods: AD-MSCs were isolated from adipose tissues and characterized through flow cytometry and a differentiation test. Afterwards, coculture, cell proliferation, apoptosis, and migration were detected. Western blotting and a quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect oxidative stress-related genes and protein expression in hypertrophic scar fibroblasts (HSFs). Flow cytometry was used to detect reactive oxygen species (ROS). A nude mouse animal model was established; the effect of AD-MSCs on hypertrophic scars was observed; and hematoxylin and eosin staining, Masson's staining, and immunofluorescence staining were performed. Furthermore, the content of oxidative-stress-related proteins, including nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), B-cell lymphoma 2(Bcl2), Bcl2-associated X(BAX) and caspase 3, was detected. Results: Our results showed that AD-MSCs inhibited HSFs' proliferation and migration and promoted apoptosis. Moreover, after coculture, the expression of antioxidant enzymes, including HO-1, in HSFs decreased; the content of reactive oxygen species increased; and the expression of Nrf2 decreased significantly. In animal experiments, we found that, at 14 days after injection of AD-MSCs into human hypertrophic scar tissue blocks that were transplanted onto the dorsum of nude mice, the weight of the tissue blocks decreased significantly. Hematoxylin and eosin staining and Masson's staining demonstrated a rearrangement of collagen fibers. We also found that Nrf2 and antioxidant enzymes decreased significantly, while apoptotic cells increased after AD-MSC treatment. Conclusions: Our results demonstrated that AD-MSCs efficiently cured hypertrophic scars by promoting the apoptosis of HSFs and by inhibiting their proliferation and migration, which may be related to the inhibition of Nrf2 expression in HSFs, suggesting that AD-MSCs may provide an alternative therapeutic approach for the treatment of hypertrophic scars.

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Simultaneous deactivation of FAK and Src improves the pathology of hypertrophic scar.

Publications

Simultaneous deactivation of FAK and Src improves the pathology of hypertrophic scar.

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