Abstract
Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes’ effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD.
Highlights
Atopic dermatitis (AD) is a chronic, relapsing, and highly pruritic inflammatory skin disease that significantly reduces the quality of life [1,2] for patients
The results of this study indicate that treatment of Adipose Tissue-Derived MSCs (ASCs)-exosomes lead to a significant improvement in epidermal barrier functions by de-repressing synthesis of ceramides and dihydroceramides carrying long acyl chains (Figure 5) and inducing the formation and secretion of lamellar bodies at the stratum granulosum (SG)-stratum corneum (SC) interface (Figure 6)
The skin barrier disruption has been known to play a role in the progression of AD, linking the structural changes with severe skin inflammation as it triggers the easy access of pathogens, allergens, and toxic environmental pollutants [59]
Summary
Atopic dermatitis (AD) is a chronic, relapsing, and highly pruritic inflammatory skin disease that significantly reduces the quality of life [1,2] for patients. The pathogenesis and development of AD have been mostly attributed to the T helper (Th) type 1/Th type 2 immune dysregulation (inside–outside hypothesis). The relationship between the epidermal barrier defect and immunological abnormalities in the pathogenesis of AD still needs to be elucidated, recent studies have shown the strong synergism between dysregulation of immune response such as elevated Th2 cytokine levels and abnormal expression of genes responsible for epidermal barrier functions to increase susceptibility to AD [6]. The data indicate that both defective skin barrier and abnormal immune responses are crucial factors in the development of AD and the multi-pronged approach, which involves repair of leaky skin barriers as well as suppression of skin inflammation, is essential for the effective treatment of AD
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