Extracellular vesicles modulate skin aging biomarkers in a 3D reconstructed full-thickness skin model.

Extracellular vesicles (EVs) are lipid-enveloped nanovesicles rich in microRNAs, proteins and lipids, that serve as potent mediators of intercellular communication. While EVs have demonstrated pro-regenerative potential in 2D and preclinical models, their impact on skin regeneration and aging processes in 3D reconstructed skin models has remained less explored. In this study, EVs from adipose-derived stem cells and umbilical cord-derived mesenchymal stem cells (UC-MSCs) were evaluated using both 2D primary skin cells and 3D full-thickness reconstructed skin models. EVs stimulated fibroblast and keratinocyte proliferation, increased epidermal thickness, and enhanced the presence of collagen IV in the dermal-epidermal junction (DEJ) and fibrillin 1 in the extracellular matrix. Bulk transcriptomic analysis of the 3D reconstructed skin revealed gene expression profiles impacted by the addition of EVs. Additionally, miRNA-seq and proteomics of extracellular vesicle contents revealed miRNAs and proteins that may be drivers of the biological activities observed in 3D models, suggesting EVs activate processes associated with skin regeneration. This holistic approach demonstrated that EVs previously linked to pro-regenerative behaviors also modulate biomarkers associated with cutaneous aging in full-thickness 3D reconstructed models. This work not only provides mechanistic insights but also paves the way for the development of next-generation regenerative skincare active ingredients.