Abstract
The skin is a multilayered and primary defensive organ. Intimate intercellular communication in the skin is necessary to ensure effective surveillance. Extracellular vesicles (EVs) are being explored for their involvement in intercellular skin communication. The aim of this study was to evaluate how human dermal fibroblasts (HDFs) accelerate EV production during senescence and the effects of senescence-associated EVs on epidermal homeostasis. Replicative senescent HDFs were assessed with senescence-associated β-galactosidase staining and the expression of senescence-related markers. Isolated EVs were characterized by dynamic light scattering and EV marker expression. EVs secreted from untreated young or senescent HDFs, or from those treated with a nSMase inhibitor, antioxidant, and lysosomal activity regulators, were determined by sandwich ELISA for CD81. Human epidermal keratinocytes were treated with young- and senescent HDF-derived EVs. Compared to young HDFs, senescent HDFs produced relatively high levels of EVs due to the increased nSMase activity, oxidative stress, and altered lysosomal activity. The nSMase inhibitor, antioxidant, and agents that recovered lysosomal activity reduced EV secretion in senescent HDFs. Relative to young HDF-derived EVs, senescent HDF-derived EVs were less supportive in keratinocyte differentiation and barrier function but increased proinflammatory cytokine IL-6 levels. Our study suggests that dermis-derived EVs may regulate epidermal homeostasis by reflecting cellular status, which provides insight as to how the dermis communicates with the epidermis and influences skin senescence.
Highlights
Skin is a primary defensive organ and comprises various cell types that intercommunicate to make it an effective barrier [1]
Exosomes are generated by the fusion of multivesicular bodies (MVBs) with plasma membranes and microvesicles are formed from plasma membranes by evagination and fission [6]
human dermal fibroblasts (HDFs) were derived primarily from adult human skin. Their growth was maintained until the population doubling level (PDL) 10 for young HDFs
Summary
Skin is a primary defensive organ and comprises various cell types that intercommunicate to make it an effective barrier [1]. Skin cells form cytokine cascades from the epidermis to the dermis, activate vascular endothelial cells, and recruit circulating immune cells. EVs, lipid bilayer-enclosed spherical vesicles ~30–1000 nm in diameter, are either constitutively or actively produced by most organisms and harbor various biomolecules originating from parent cells, which they deliver to neighboring cells [3,4,5]. Based on their mechanism of biogenesis, EVs are classified as exosomes and microvesicles. While adipose-, endothelial cell- or mesenchymal stem cell-derived EVs influence wound healing, pathogen-derived EVs are involved in the pathogenesis of skin disorders such as acne vulgaris and atopic dermatitis [7,11,12]
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