miR-145-5p regulates fibrotic features of recessive dystrophic epidermolysis bullosa skin fibroblasts

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Abstract

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder caused by mutations in the COL7A1 gene encoding type VII collagen, a cutaneous basement membrane component essential for epidermal-dermal adhesion. Hallmarks of the disease are unremitting blistering and chronic wounds with severe inflammation and fibrosis. microRNAs are post-transcriptional regulators of gene expression also implicated in fibrotic processes. However, the role of microRNAs in RDEB fibrosis is almost unexplored.

OBJECTIVES: Our study aimed at identifying microRNAs deregulated in primary RDEB skin fibroblasts (RDEBFs) and at characterizing their function in RDEB fibrosis.

METHODS: qRT-PCR was used to screen RDEBFs for the expression levels of a group of microRNAs deregulated in hypertrophic scars and keloids, pathological conditions with abnormal wound healing and fibrosis. Contractility, proliferation and migration rate were evaluated by different in vitro assays in RDEBFs transfected with a miR-145-5p inhibitor. qRT-PCR and western blot analysis provided the expression levels of fibrotic markers and miR-145-5p targets.

RESULTS: The miR-143/145 cluster was up-regulated in RDEBFs with respect to fibroblasts from healthy subjects. RDEBFs transfected with a miR-145-5p inhibitor showed attenuated fibrotic traits, i.e. contraction, proliferation and migration, accompanied by reduced expression of the contractile proteins α-smooth muscle actin and transgelin. These effects were associated with the up-regulation of kruppel like factor 4 transcriptional repressor and the down-regulation of Jagged 1, a known inducer of fibrosis.

CONCLUSIONS: Our results highlight the pro-fibrotic role of miR-145-5p and its regulatory networks in RDEB, shedding light on novel disease pathomechanisms and targets for future therapeutic approaches. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalBritish Journal of Dermatology
DOIs
Publication statusPublished - Nov 2019

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