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TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts

ABSTRACT: We established a hypertrophic scar-like animal model using traction force in C57BL/6J mice to demonstrate the crucial mechanistic effect of TEM1 on pathological scarring. Samples from scar areas in sham and traction groups of Tem1WT/WT and Tem1lacZ/lacZ mice were subjected to RNA sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE207284 | GEO | 2024/02/09

REPOSITORIES: GEO

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High-salt diet promotes hypertrophic scarring through TRPC3-mediated mitochondrial Ca2+ homeostasis dysfunction

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Project description:Injury in mammals induces a connective tissue response to either regenerate as before, or to scar. The fibroblastic actions and mechanisms that underlie these connective tissue responses remain obscure, as direct observation in animals is too difficult and current assays do not faithfully reproduce physiology. Here, we developed a skin explant technique termed scar-in-a-dish (SCAD) that faithfully recapitulates uniform scars with contraction and reveals how scarring occurs in unprecedented detail. By growing mouse SCADs, with a traceable scar-progenitor fibroblast lineage, we observed previously unseen intercellular connections form between scar-progenitors that then collectively swarm into the nascent wound in highly regular periodic movements that progressively contract the skin and form scars. Swarming is exclusive to scar progenitors and absent from oral cavity fibroblasts that regenerate scarless. By testing a panel of adhesion molecules that might instigate intercellular connections, we found swarming was induced by the upregulation of N-cadherin in scar progenitors. Impeding N-cadherin binding inhibited swarming and contraction, and led to reduced scarring in SCAD and in mice. Blocking N-cadherin and scar-progenitor swarming thus provides a novel therapeutic space to curtail pathological fibrotic responses across a range of medical settings.

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JUN promotes hypertrophic skin scarring via CD36

Project description:JUN promotes hypertrophic skin scarring via CD36

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TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts.

Project description:BackgroundPathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars.MethodsTo investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-β-mediated responses in pathologic scars.ResultsThe levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids.ConclusionsOur data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-β signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars.

| S-EPMC10804696 | biostudies-literature

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Project description:We hypothesize that, the mTOR pathway is a dominant pathway in cultured keloid and hypertrophy scar fibriblasts compared to normal skin cells. Certain pathway changes can be detected after medication treatment. Global gene expression in RNA samples from rapamycin and tacrolimus treated fibroblasts (from normal skin and hypertrophic scars, keloid scars) is assayed to study the possibility to use mTOR inhibitors as potential drug to treat abnormal scarring. We investigated the difference between normal wound healing and hypertrophic scars and keloids as well.

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TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts

Project description:TEM1/endosialin/CD248 promotes pathologic scarring and TGF-β activity through its receptor stability in dermal fibroblasts

| PRJNA854626 | ENA

In vivo analysis of injury sites presenting full or attenuated pericyte-derived scarring after spinal cord injury (SCI)

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