Exosomes with overexpressed miR 147a suppress angiogenesis and infammatory injury in an experimental model of atopic dermatitis

Abstract

Atopic dermatitis is defined as an intensely systemic inflammation among skin diseases. Exosomes derived from adipose-derived stem cells may be a novel cell-free therapeutic strategy for atopic dermatitis treatment. This study aims to elucidate the possible underlying mechanism of adipose-derived stem cells-exosomes harboring microRNA-147a in atopic dermatitis pathogenesis. BALB/c mice treated with Dermatophagoides farinae extract/2,4-dinitrochlorobenzene were defined as a mouse model of atopic dermatitis, either with inflamed HaCaT cells and HUVECs exposed with TNF-α/IFN-γ stimulation were applied for a cell model of atopic dermatitis. The concentrations of IL-1β and TNF-α in the supernatants were examined by ELISA. Cell viability and migration were assessed by MTT and Transwell assay. The apoptosis was examined using flow cytometry and TUNEL staining. The tube formation assay was employed to analyzed angiogenesis. The molecular regulations among miR-147a, MEF2A, TSLP and VEGFA were confirmed using luciferase reporter assay, either with ChIP. microRNA-147a was markedly downregulated in the serum and skin samples of atopic dermatitis mice, of which overexpression remarkably promoted HaCaT cell proliferation, meanwhile inhibiting inflammatory response and cell apoptosis. microRNA-147a in adipose-derived stem cells was subsequently overexpressed, and exosomes (Exos-miR-147a mimics) were collected. Functionally, exos-microRNA-147a mimics attenuated TNF-α/IFN-γ-induced HaCaT cell inflammatory response and apoptosis, and suppressed HUVECs angiogenesis. Encouraging, molecular interaction experiments revealed that exosomal microRNA-147a suppressed TNF-α/IFN-γ-induced HUVECs angiogenesis by targeting VEGFA, and exosomal microRNA-147a repressed HaCaT cells inflammatory injury through the MEF2A-TSLP axis. Mechanistically, exosomal microRNA-147a repressed pathological angiogenesis and inflammatory injury during atopic dermatitis progression by targeting VEGFA and MEF2A-TSLP axis. microRNA-147a-overexpressing adipose-derived stem cells-derived exosomes suppressed pathological angiogenesis and inflammatory injury in atopic dermatitis by targeting VEGFA and MEF2A-TSLP axis.

Hypoxic conditioning induced by CoCl2 enhanced the therapeutic effects of mesenchymal stem cell-derived exosomes on oxazolone-induced atopic dermatitis-like skin lesions

“…A disrupted epidermal barrier in AD is restored by the de novo synthesis of ceramides induced by the MSC-derived exosomes [44]. It has also been shown that exosomes in which miR 147a was overexpressed suppressed in ammatory injury in an AD mouse model [45].…”

Exosomes: The emerging mechanisms and potential clinical applications in dermatology

“…Meanwhile, deep RNA sequencing analysis of skin lesions demonstrated that ADSC-exos normalized the expression of genes altered during AD pathogenesis, which involved skin barrier, lipid metabolism, cell cycle, and inflammatory response. Shi et alreported that miR-147a-overexpressing ADSC-exos inhibited inflammatory response, cell apoptosis, and angiogenesis in the DNCB-induced AD mouse model via targeting VEGF-A and MEF2A-TSLP axis 41 . In addition, exosomes based on skin component cells or other stem cells, such as dermal fibroblasts and iPSC-derived MSCs (iMSCs), possess outstanding advantages in modulating inflammation and promoting tissue regeneration and repair and are expected to be candidates for AD therapy.…”

Exosomal microRNA-Based therapies for skin diseases

“…For AD mice induced by Dermatophagoides farinae extract and 2,4-dinitrochlorobenzene, Shi et al. [ 92 ] found that miR-147a levels decreased markedly in the serum and skin lesions, meanwhile thymic stromal lymphopoietin (TSLP, a cytokine involved in the angiogenic phenotype and AD pathogenesis) and VEGFA (a key regulator of angiogenesis) increased markedly. These observations revealed that miR-147a correlated negatively with the expression levels of VEGFA and TSLP in AD lesions.…”