Dataset Information

Targeting Nuclear Mechanics Mitigates the Fibroblast Invasiveness in Pathological Dermal Scars Induced by Matrix Stiffening.

ABSTRACT: Pathological dermal scars such as keloids present significant clinical challenges lacking effective treatment options. Given the distinctive feature of highly stiffened scar tissues, deciphering how matrix mechanics regulate pathological progression can inform new therapeutic strategies. Here, it is shown that pathological dermal scar keloid fibroblasts display unique metamorphoses to stiffened matrix. Compared to normal fibroblasts, keloid fibroblasts show high sensitivity to stiffness rather than biochemical stimulation, activating cytoskeletal-to-nuclear mechanosensing molecules. Notably, keloid fibroblasts on stiff matrices exhibit nuclear softening, concomitant with reduced lamin A/C expression, and disrupted anchoring of lamina-associated chromatin. This nuclear softening, combined with weak adhesion and high contractility, facilitates the invasive migration of keloid fibroblasts through confining matrices. Inhibiting lamin A/C-driven nuclear softening, via lamin A/C overexpression or actin disruption, mitigates such invasiveness of keloid fibroblasts. These findings highlight the significance of the nuclear mechanics of keloid fibroblasts in scar pathogenesis and propose lamin A/C as a potential therapeutic target for managing pathological scars.

SUBMITTER: Fu X

PROVIDER: S-EPMC11022731 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Targeting Nuclear Mechanics Mitigates the Fibroblast Invasiveness in Pathological Dermal Scars Induced by Matrix Stiffening.

Fu Xiangting X Taghizadeh Ali A Taghizadeh Mohsen M Li Cheng Ji CJ Lim Nam Kyu NK Lee Jung-Hwan JH Kim Hye Sung HS Kim Hae-Won HW

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240214 15

Pathological dermal scars such as keloids present significant clinical challenges lacking effective treatment options. Given the distinctive feature of highly stiffened scar tissues, deciphering how matrix mechanics regulate pathological progression can inform new therapeutic strategies. Here, it is shown that pathological dermal scar keloid fibroblasts display unique metamorphoses to stiffened matrix. Compared to normal fibroblasts, keloid fibroblasts show high sensitivity to stiffness rather t ...[more]

PMID: 38353381

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Project description:Controlling fibrosis is an essential part of regenerating the post-ischemic heart. In the post-ischemic heart, fibroblasts differentiate to myofibroblasts that produce collagen-rich matrix to physically stabilize the infarct area. Infarct models in adult mice result in permanent scarring unlike newborn animals which fully regenerate. Decellularized extracellular matrix (dECM) hydrogels derived from early-aged hearts have been shown to be a transplantable therapy that preserves heart function and stimulates cardiomyocyte proliferation and vascularization. In this study, we investigate the anti-fibrotic effects of injectable dECM hydrogels in a cardiac explant model in the context of age-associated tissue compliance. Treatments with adult and fetal dECM hydrogels were tested for molecular effects on cardiac fibroblast activation and fibrosis. Altered sensitivity of fibroblasts to the mechanosignaling of the remodeling microenvironment was evaluated by manipulating the native extracellular matrix in explants and also with elastomeric substrates in the presence of dECM hydrogels. The injectable fetal dECM hydrogel treatment decreases fibroblast activation and contractility and lowers the stiffness-mediated increases in fibroblast activation observed in stiffened explants. The anti-fibrotic effect of dECM hydrogel is most observable at highest stiffness. Experiments with primary cells on elastomeric substrates with dECM treatment support this phenomenon. Transcriptome analysis indicated that dECM hydrogels affect cytoskeleton related signaling including Macrophage capping protein (CAPG) and Leupaxin (LPXN). CAPG was down-regulated by the fetal dECM hydrogel. LPXN expression was decreased by stiffening the explants; however, this effect was reversed by dECM hydrogel treatment. Pharmacological disruption of cytoskeleton polymerization lowered fibroblast activation and CAPG levels. Knocking down CAPG expression with siRNA inhibited fibroblast activation and collagen deposition. Collectively, fibroblast activation is dependent on cooperative action of extracellular molecular signals and mechanosignaling by cytoskeletal integrity.

Project description:IntroductionThe propagation of mechanochemical signals from the extracellular matrix to the cell nucleus has emerged as a central feature in regulating cellular differentiation and de-differentiation. This process of outside-in signaling and the associated mechanotransduction pathways have been well described in numerous developmental and pathological contexts. However, it remains less clear how mechanotransduction influences the activity of chromatin modifying enzymes that direct gene expression programs.ObjectivesThe primary objective of this study was to explore how matrix mechanics and geometric confinement influence histone deacetylase (HDAC) activity in fibroblast culture.MethodsPolyacrylamide hydrogels were formed and functionalized with fibronectin patterns using soft lithography. Primary mouse embryonic fibroblasts (MEFs) were cultured on the islands until confluent, fixed, and immunolabeled for microscopy.ResultsAfter 24 h MEFs cultured on soft hydrogels (0.5 kPa) show increased expression of class I HDACs relative to MEFs cultured on stiff hydrogels (100 kPa). A member of the class II family, HDAC4 shows a similar trend; however, there is a pronounced cytoplasmic localization on soft hydrogels suggesting a role in outside-in cytoplasmic signaling. Pharmacological inhibitor studies suggest that the opposing activities of extracellular related kinase 1/2 (ERK) and protein phosphatase 2a (PP2a) influence the localization of HDAC4. MEFs cultured on the soft hydrogels show enhanced expression of markers associated with a fibroblast-myofibroblast transition (Paxillin, αSMA).ConclusionsWe show that the phosphorylation state and cellular localization of HDAC4 is influenced by matrix mechanics, with evidence for a role in mechanotransduction and the regulation of gene expression associated with fibroblast-myofibroblast transitions. This work establishes a link between outside-in signaling and epigenetic regulation, which will assist efforts aimed at controlling gene regulation in engineered extracellular matrices.

Dataset Information

Targeting Nuclear Mechanics Mitigates the Fibroblast Invasiveness in Pathological Dermal Scars Induced by Matrix Stiffening.

Publications

Targeting Nuclear Mechanics Mitigates the Fibroblast Invasiveness in Pathological Dermal Scars Induced by Matrix Stiffening.

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