Remodeling of dermal collagen in photoaged skin using low-dose 5-aminolevulinic acid photodynamic therapy occurs via the transforming growth factor-β pathway

5-Aminolevulinic acid photodynamic therapy (ALA-PDT) is known to be effective in the treatment of photoaged skin. However, the molecular mechanisms still remain elusive. Protoporphyrin IX (PpIX) fluorescence is primarily located in the epidermis while ALA-PDT affects the dermal collagen, presumably by an indirect mechanism. This study aimed to investigate the molecular communication in low-dose ALA-PDT occurring between epidermal keratinocytes and dermal fibroblasts. Western blotting and enzyme-linked immunosorbent assays were performed to evaluate collagen expression and transforming growth factor-beta (TGF-beta) signaling in human keratinocytes and dermal fibroblasts. The impact on fibroblast proliferation was assessed by morphology and proliferating cell nuclear antigen immunofluorescence. Skin biopsies from mice were used to analyze the histological changes in dermal collagen and PpIX distribution. When fibroblasts were cocultured with keratinocytes treated with low-dose ALA-PDT, collagen synthesis and fibroblast proliferation were enhanced. Low-dose ALA-PDT stimulated TGF-1 expression in keratinocytes. Fibroblasts cocultured with low-dose ALA-PDT-treated keratinocytes also showed activation of the TGF-beta pathway. In vivo, PpIX fluorescence was densely distributed in photoaged mouse epidermis while collagen in the mouse dermis underwent remodeling. This study suggests that low-dose ALA-PDT can stimulate keratinocytes to release TGF-1, activating the TGF-beta pathway in dermal fibroblasts to remodel collagen in the dermis.