Divergent effects of vitamin D₃ on human dermal fibroblasts and keratinocytes in wound repair: Implications for therapeutic targeting in tissue remodelling and scarring.

Abstract

Vitamin D is known to regulate inflammation and immunity, suggesting it may play a role in wound healing. However, its mechanism of action in key skin cell types-keratinocytes and fibroblasts-involved in wound repair is poorly understood. This study aimed to elucidate the impact of vitamin D₃ and its precursors on keratinocyte and fibroblast behaviour during wound healing using human ex vivo skin explant and primary cell culture models. The rate of closure of incisional wounds made on human ex vivo skin explants treated with the vitamin D₃ precursor, cholecalciferol, or the active form 1,25(OH)₂D₃ was measured over 6 days in culture. Primary cultures of human keratinocytes and dermal fibroblasts were propagated from female facial skin, and changes in gene expression and physiological responses to cholecalciferol or 1,25(OH)₂D₃ were assessed using various techniques, including scratch wound assays, quantitative reverse transcription polymerase chain reaction, zymography, and immunocytochemistry. 1,25(OH)₂D₃ significantly increased the early wound closure rate in ex vivo human skin explants, while cholecalciferol had no effect. 1,25(OH)₂D₃ accelerated keratinocyte migration but inhibited fibroblast migration and their transition into pro-fibrotic myofibroblasts, reducing extracellular matrix remodelling. Using small interfering RNA, it was established that responses were mediated by vitamin D receptor signalling. This study highlighted the divergent effects of vitamin D on keratinocyte and fibroblast wound responses, i.e., promoting re-epithelialisation, while potentially suppressing aberrant fibrosis. Optimising vitamin D status may facilitate wound repair while minimising scarring, which has implications for treating non-healing wounds and excessive scarring disorders.