The multifaceted properties of manna in skin wound healing include the enhancement of cell motility and differentiation, and antioxidant and anti-inflammatory actions

Manna is a natural substance exuded from the trunk and branches of certain Fraxinus species, primarily from Fraxinus ornus L. and Fraxinus angustifolia Vahl. The manna here used was predominantly obtained from F. angustifolia . It has gained attention for its potential pharmaceutical applications mainly for its antioxidant and anti-inflammatory effects. This in vitro study investigates the talented properties of manna in promoting skin regeneration. We used HaCaT, BJ, HUVEC and THP-1 cells to evaluate manna's effects on cell activation in terms of motility, differentiation with oxidative and inflammatory responses. In detail, we demonstrated that manna enhanced the migration and invasion of keratinocytes, fibroblasts, and endothelial cells, as key players in the wound healing process. Manna also exerted significant antioxidant activity on all these cells, by protecting them from hydrogen peroxide stress. Additionally, it induced angiogenesis by activating endothelial cells. The beneficial effects of manna are further promoted by favoring the differentiation of the analyzed cells through the regulation of levels of protein markers as cytokeratin 10 and involucrin on keratinocytes, vinculin and fibroblasts activated protein-1α on fibroblasts and CD31 on endothelial cells. It was also revealed that manna retained anti-inflammatory effects, by reducing the polarization of human macrophages in M1 pro-inflammatory phenotype and inhibiting the phosphorylation of NF-kB after stimulation with lipopolysaccharide/interferon-γ, thus further supporting the healing process. These findings provide valuable insights into the complex role of manna in the different stages intervening in the skin wound healing, highlighting its potential as a therapeutic agent in regenerative medicine.