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Updated: Mar 21, 2026
In Vitro Model of Human Cutaneous Hypertrophic Scarring using Macromolecular Crowding
Published on: May 1, 2020
Simultaneous deactivation of FAK and Src improves the pathology of hypertrophic scar
Linlin Su1, Xiaodong Li2, Xue Wu1
1Department of Burns and Cutaneous Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
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-β1 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 α-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.
Insights
Targeting the FAK-Src complex shows promise for treating hypertrophic scars (HS). Simultaneous deactivation of focal adhesion kinase (FAK) and Src kinases in HS fibroblasts reduced fibrotic markers and improved collagen structure.
Area of Science:
- Biochemistry
- Dermatology
- Molecular Biology
Background:
- Hypertrophic scarring (HS) is a fibrotic skin condition lacking effective treatments due to poorly understood mechanisms.
- Focal adhesion kinase (FAK) and Src kinases are implicated in HS pathogenesis.
Purpose of the Study:
- To investigate the role of FAK and Src activation and their interplay in hypertrophic scar formation.
- To explore FAK-Src complex as a potential therapeutic target for HS.
Main Methods:
- Analysis of FAK and Src activation in HS versus normal skin (NS) and TGF-β1 treated NS fibroblasts.
- Co-immunoprecipitation and immunofluorescence to assess FAK-Src association.
- Site-directed mutagenesis and gene overexpression in HS fibroblasts.
- Treatment with Glabridin to evaluate therapeutic effects.
Main Results:
- FAK and Src were activated in HS tissues and TGF-β1 stimulated fibroblasts.
- Enhanced FAK-Src association and co-localization were observed in HS.
- Simultaneous overexpression of FAK Y407F and Src Y529E mutants significantly reduced fibrotic markers (Col I, Col III, α-SMA) and improved collagen organization.
- Glabridin demonstrated therapeutic effects on HS, likely via FAK-Src co-deactivation and de-association.
Conclusions:
- The FAK-Src complex plays a critical role in hypertrophic scar pathogenesis.
- Targeting the FAK-Src complex, specifically through co-deactivation, represents a novel therapeutic strategy for HS.
