Identification of a myofibroblast-specific expression signature in skin wounds

Bergmeier, Vera; Etich, Julia; Pitzler, Lena; Frie, Christian; Koch, Manuel; Fischer, Matthias; Rappl, Gunter; Abken, Hinrich; Tomasek, James J.; Brachvogel, Bent

doi:10.1016/j.matbio.2017.07.005

Cited by 69 publications

(61 citation statements)

References 60 publications

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“…In this context, downregulation of the ALDH1A1 and SOD3 genes, encoding antioxidant enzymes, could facilitate oxidative stress‐induced damage. Similar expression changes in ALDH1A1 were recently described as part of the myofibroblast‐specific expression profile in mouse skin wounds . In fact, an in silico comparison of our 186 dysregulated genes disclosed 41 overlapping genes included in the transcriptomic signature of mouse wound myofibroblasts.…”

Section: Discussionsupporting

confidence: 78%

“…However, these specific expression changes were not the focus of this study and should be considered separately. All in all, the common genetic signature in fibroblasts of the three genodermatoses shares some similarities with that found in myofibroblasts, wound‐activated fibroblasts and cutaneous CAFs . The common mechanisms of the three diseases would allow consideration of symptom‐relief therapies currently tested in RDEB to be used also in XPC and KS.…”

Section: Discussionmentioning

confidence: 87%

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Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer‐prone genodermatoses

et al. 2019

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SummaryBackgroundRecessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer‐prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.ObjectivesTo investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.MethodsWe conducted RNA‐Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.ResultsInterdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA‐Seq data. In addition, enzyme‐linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.ConclusionsOur results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury‐sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development.Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix‐synthetic capacity.This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor‐β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention.It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 87%

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer‐prone genodermatoses

et al. 2019

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“…The fibrotic reaction leads to increased production of extracellular matrix proteins including collagens, as well as the activation of local fibroblasts to differentiate into myofibroblasts [45]. TGF stimulates COL11A1 expression in dermal fibroblasts [46], while novel myofibroblast-specific expression of COL24A1 is a signature of skin wounds [47]. Together with associations at IL6R and IL10R, our GWAS results support the complex interplay between fibrotic and inflammatory processes in determining pathologies associated with CL caused by L. braziliensis.…”

Section: Discussionsupporting

confidence: 65%

A genome-wide association study highlights a regulatory role forIFNG-AS1contributing to cutaneous leishmaniasis in Brazil

Almeida

Cherlin

et al. 2020

Preprint

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Background. Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis remains animportant public health problem in Brazil. The goal of this study was to identify genetic risk factors for CL.Methods. Genome-wide analysis was undertaken using DNAs from 956 CL cases and 868 controls (phase 1) and 1110 CL cases and 1178 controls (phase 2) genotyped using Illumina HumanCoreExome BeadChips. Imputation against 1000G data provided 4,498,586 qualitycontrolled single nucleotide variants (SNVs) common across phase 1 and phase 2 samples.Linear mixed models in FastLMM were used to take account of genetic diversity/ethnicity/admixture. Cellular cytokines were measured using flow cytometry.

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“…It has been shown recently that Lox family members are differentially expressed during wound healing in murine myofibroblasts. While Loxl2 and Loxl3 are significantly up regulated, expression of Loxl4 is decreased, suggesting that different crosslinking enzymes are needed to stabilise the granulation tissue in a wound [ 39 ]. However, wound healing is not affected in the different Loxl2 mice genotypes (F Salvador, A Martin & A Cano, unpublished observation), suggesting that LOXL2 is dispensable.…”

Section: Discussionmentioning

confidence: 99%

Loxl2 is dispensable for dermal development, homeostasis and tumour stroma formation

et al. 2018

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Lysyl oxidase-like 2 (LOXL2) is a copper-dependent monoamine oxidase that contributes to the remodelling of the extracellular matrix (ECM) by cross linkage of collagen and elastin fibres and has emerged as a potential therapeutic target in cancer and fibrosis. In the skin, LOXL2 is essential for epidermal cell polarity and differentiation. However, its role in the dermis has not been evaluated. We found that Loxl2 is dispensable for mouse dermal development, maturation and homeostasis, yet affects dermal stiffness. Neither loss of Loxl2 nor increased Loxl2 expression affected dermal architecture following treatment with the phorbol ester TPA. Furthermore, Loxl2 expression did not alter the stroma of DMBA-TPA-induced tumours. We conclude that, although Loxl2 is expressed in both dermis and epidermis, its function appears largely confined to the epidermis.

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Identification of a myofibroblast-specific expression signature in skin wounds

Cited by 69 publications

References 60 publications

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer‐prone genodermatoses

Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer‐prone genodermatoses

A genome-wide association study highlights a regulatory role forIFNG-AS1contributing to cutaneous leishmaniasis in Brazil

Loxl2 is dispensable for dermal development, homeostasis and tumour stroma formation

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