Protective Effect of Multifloral Honey on Stem Cell Aging in a Dynamic Cell Culture Model

Natural compounds, as honey-derived flavonoids and phenolic compounds, are increasingly investigated for their potential to mitigate skin aging and prevent oxidative stress-induced cellular damages. In this context, a dynamic cell culture model was employed to assess the protective influence of honey pre-treatment on stem cell-associated genes and the Wingless-related integration site (Wnt) signaling pathway following ultraviolet (UV)-induced aging. Using a bioreactor, skin stem cells (SSCs) derived from healthy skin biopsies and human skin fibroblasts (HFF1) were pre-treated with 1% honey for 48 h and then exposed to UV. Real-time quantitative polymerase chain reaction (RT-qPCR) analyses were performed on Wnt signaling and anti-aging molecular responses. Honey pre-treatment enhanced the expression of pluripotency markers (Octamer-binding transcription factor 4 (Oct4); SRY-box transcription factor 2 (Sox2)) and reduced senescence-related cell cycle regulators (cyclin-dependent kinase inhibitor 2A (p16); cyclin-dependent kinase inhibitor 1A (p21); tumor protein 53 (p53)) in SSCs. In UV-damaged SSCs, honey also significantly increased Wnt3a expression. In fibroblasts, honey pre-treatment upregulated Heat shock protein 70 (Hsp70) and Hyaluronan synthase 2 (HAS2) expression, while downregulating caspase-8 (CASP8), indicating a protective role against UV-mediated cellular stress. We also analyzed nitric oxide release and the total antioxidant capacity of cells after treatment. Collectively, these findings suggest that honey may safeguard skin stem cells from UV-induced aging by modulating pluripotency and senescence-associated genes and regulating differentiation through alterations in Wnt signaling. Furthermore, Hsp70 upregulation in fibroblasts appears to strengthen cellular stress responses and support homeostatic stability.