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Hyperosmolar potassium inhibits myofibroblast conversion and reduces scar tissue formation.

ABSTRACT: Scar formation is a natural result of almost all wound healing in adult mammals. Unfortunately, scarring disrupts normal tissue function and can cause significant physical and psychological distress. In addition to improving surgical techniques to limit scar formation, several therapies are under development towards the same goal. Many of these treatments aim to disrupt transforming growth factor ?1 (TGF?1) signaling, as this is a critical control point for fibroblast differentiation into myofibroblasts; a contractile cell that organizes synthesized collagen fibrils into scar tissue. The present study aimed to examine the role of hyperosmolar potassium gluconate (KGluc) on fibroblast function in skin repair. KGluc was first determined to negatively regulate fibroblast proliferation, metabolism, and migration in a dose-dependent manner in vitro. Increasing concentrations of KGluc also inhibited differentiation into myofibroblasts, suggesting that local KGluc treatment might reduce fibrosis. KGluc delivery was confirmed via loading into collagen hydrogels and used to treat a full thickness skin wound in mice. KGluc qualitatively slowed initial closure of the wounds and resulted in tissue that more closely resembled mature, healthy skin (epidermal thickness and dermal-epidermal morphology) when compared to unloaded collagen hydrogels. KGluc treatment significantly reduced the number of myofibroblasts within the dermis while upregulated blood vessel density with respect to unloaded hydrogels, likely a result of disruption of TGF?1 signaling. Taken together, these data demonstrate the effectiveness of KGluc treatment on skin wound healing and suggest that this may be an efficient treatment to limit scar formation.

SUBMITTER: Grasman JM

PROVIDER: S-EPMC7241611 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Hyperosmolar potassium inhibits myofibroblast conversion and reduces scar tissue formation.

Grasman Jonathan M JM Williams Marisa D MD Razis Constantine G CG Bonzanni Mattia M Golding Anne S AS Cairns Dana M DM Levin Michael M Kaplan David L DL

ACS biomaterials science & engineering 20190918 10

Scar formation is a natural result of almost all wound healing in adult mammals. Unfortunately, scarring disrupts normal tissue function and can cause significant physical and psychological distress. In addition to improving surgical techniques to limit scar formation, several therapies are under development towards the same goal. Many of these treatments aim to disrupt transforming growth factor β1 (TGFβ1) signaling, as this is a critical control point for fibroblast differentiation into myofib ...[more]

PMID: 32440531

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Project description:: Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2-34.9) vs. 12.6% (IQR 8.3-27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

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Hyperosmolar potassium inhibits myofibroblast conversion and reduces scar tissue formation.

Publications

Hyperosmolar potassium inhibits myofibroblast conversion and reduces scar tissue formation.

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