Integrated evaluation of umbilical cord mesenchymal stromal cell-derived extracellular vesicles across skin-related cellular and zebrafish models

Abstract

Introduction Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have shown biological effects in skin-related models, particularly in oxidative injury, wound repair, and photoaging. However, previous studies have used different MSC sources, EVs preparations, and experimental systems, and the activity of a defined EVs preparation across multiple skin-related processes has rarely been examined within a single study. Effects on sebocyte lipid metabolism and androgen-related responses are particularly poorly characterized. Methods Human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (UC-MSC-EVs) were characterized and evaluated across complementary cellular and zebrafish models assessing oxidative injury, keratinocyte migration and barrier-related proteins, UVB-induced fibroblast senescence and extracellular matrix responses, sebocyte lipid and androgen metabolism, melanogenesis, and dermal papilla cell function. Results UC-MSC-EVs reduced UVB- and tert-butyl hydroperoxide-induced injury in HaCaT keratinocytes, decreased oxidative stress, and restored antioxidant enzyme activities. They also promoted keratinocyte migration, increased filaggrin and aquaporin-3 expression, and enhanced zebrafish tail-fin regeneration, increasing relative regenerated length from 60.24 ± 4.01% in the model group to 84.10 ± 5.82% at 48 h post-amputation. In UVB-exposed human skin fibroblasts, UC-MSC-EVs reduced cellular senescence and modulated extracellular matrix, inflammatory, and antioxidant responses. In oleic acid-stimulated SZ95 sebocytes, UC-MSC-EVs reduced lipid accumulation and lipid peroxidation and attenuated 5α-reductase activity and dihydrotestosterone production. In B16F10 cells stimulated with α-MSH, melanin content decreased from 147.60 ± 15.98% to 99.70 ± 7.98% of the untreated control at the highest tested UC-MSC-EVs concentration, accompanied by reduced tyrosinase activity and melanogenic gene expression. Pigmentation intensity was also reduced in zebrafish. In human dermal papilla cells, UC-MSC-EVs enhanced migration and increased alkaline phosphatase activity to 148.22 ± 4.72% of the control level, while increasing expression of hair growth factors and reducing androgen metabolism. Discussion These results characterize the biological activity of a single UC-MSC-EVs preparation across multiple skin-related experimental systems and provide a basis for further investigation of its bioactive components and dose-response relationships.