Metformin Promotes Mechanical Stretch-Induced Skin Regeneration by Improving the Proliferative Activity of Skin-Derived Stem Cells

Abstract

BackgroundSkin expansion by mechanical stretch is an essential and widely used treatment for tissue defects in plastic and reconstructive surgery; however, the regenerative capacity of mechanically stretched skin limits clinical treatment results. Here, we propose a strategy to enhance the regenerative ability of mechanically stretched skin by topical application of metformin.MethodsWe established a mechanically stretched scalp model in male rats (n = 20), followed by their random division into two groups: metformin-treated (n = 10) and control (n = 10) groups. We measured skin thickness, collagen volume fraction, cell proliferation, and angiogenesis to analyze the effects of topical metformin on mechanically stretched skin, and immunofluorescence staining was performed to determine the contents of epidermal stem cells and hair follicle bulge stem cells in mechanically stretched skin. Western blot was performed to detect the protein expression of skin-derived stem cell markers.ResultsCompared with the control group, metformin treatment was beneficial to mechanical stretch-induced skin regeneration by increasing the thicknesses of epidermis (57.27 ± 10.24 vs. 31.07 ± 9.06 μm, p < 0.01) and dermis (620.2 ± 86.17 vs. 402.1 ± 22.46 μm, p < 0.01), number of blood vessels (38.30 ± 6.90 vs. 17.00 ± 3.10, p < 0.01), dermal collagen volume fraction (60.48 ± 4.47% vs. 41.28 ± 4.14%, p < 0.01), and number of PCNA+, Aurora B+, and pH3+ cells. Additionally, we observed significant elevations in the number of proliferating hair follicle bulge stem cells [cytokeratin (CK)15+/proliferating cell nuclear antigen (PCNA)+] (193.40 ± 35.31 vs. 98.25 ± 23.47, p < 0.01) and epidermal stem cells (CK14+/PCNA+) (83.00 ± 2.38 vs. 36.38 ± 8.96, p < 0.01) in the metformin-treated group, and western blot results confirmed significant increases in CK14 and CK15 expression following metformin treatment.ConclusionTopical application of metformin enhanced the regenerative capacity of mechanically stretched skin, with the underlying mechanism possibly attributed to improvements in the proliferative activity of skin-derived stem cells.

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

“…Additionally, resveratrol treatment has been shown to reduce markers of cellular senescence and restore SIRT1 activity in MSCs exposed to high levels of oxidative stress (Haramizu et al., 2017). Metformin as another well‐known pro‐longevity compound has demonstrated promising activity in enhancing hematopoiesis and the function of hair follicle stem cells in young mice, although it may have deleterious effects on muscle stem cells (S. Xiong et al., 2022). Oxytocin and activin receptor‐like kinase 5 (Alk5) inhibitors have both exhibited efficacy in improving muscle regenerative function and neurogenesis in aged mice (Yousef et al., 2015).…”