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Published on: February 17, 2021
Fisetin-Mediated Topical Modulation of Senescent Cells in Skin Improves Wound Healing Dynamics in Diabetic Mice
Asfia Numani1, Margarita Carrasco-Jeldres2, Barbara Hernandez-Rovira2
1Mayo Clinic Alix School of Medicine, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota.
Objective:
Diabetes mellitus affects over 25% of adults aged 65+ in the United States and is associated with a heightened risk of developing diabetic foot ulcers. Accumulation of senescent cells within the wound microenvironment can impair cutaneous repair, and senolytic therapies offer a promising approach to accelerate wound healing.
Approach:
In this study, topical fisetin, a flavonoid that promotes apoptosis of senescent cells, was evaluated for its impact on diabetic wound repair. Full-thickness excisional wounds were created on the dorsal skin of diabetic (db/db) mice. Animals were randomized to receive either topical vehicle (n = 12) or fisetin (n = 12) for three consecutive days per week, and wound healing outcomes were longitudinally assessed.
Results:
Topical fisetin significantly increased the ratio of healthy dermis to granulation by day 7 (p = 0.04) and reduced dermal fibrosis by day 21 (p = 0.03). Fisetin decreased p16+ cells (p = 0.01) but increased p21+ cells (p = 0.02) at day 7 in the dermis, indicating varied effects on senescent cells. M1 macrophages (CD80+) were decreased in the fisetin-treated group (p = 0.05) at day 21, accompanied by a decrease in pro-inflammatory senescence-associated secretory phenotype cytokines, tumor necrosis factor alpha (p = 0.03), and interleukin-1beta (p = 0.01) at day 7.
Innovation:
Fisetin is the first topical seno-modulatory agent shown to enhance wound repair when administered after injury onset. Its favorable safety and efficacy in both modulating senescence and inflammation highlight its potential as a novel therapy for diabetic wounds.
Conclusion:
Topical fisetin enhances diabetic wound healing by reducing fibrosis and promoting healthy dermal regeneration through senescence and inflammation modulation. [Figure: see text].
Insights
Topical fisetin accelerates diabetic wound healing by reducing fibrosis and inflammation. This senolytic therapy promotes healthy skin regeneration, offering a promising new treatment for diabetic foot ulcers.
Area of Science:
- Wound Healing Research
- Diabetic Complications
- Senotherapeutics
Background:
- Diabetes mellitus affects over 25% of US adults aged 65+, increasing diabetic foot ulcer risk.
- Accumulated senescent cells in wounds impede healing; senolytic therapies show promise.
Purpose of the Study:
- To evaluate topical fisetin, a senolytic flavonoid, for enhancing diabetic wound repair.
- To assess fisetin's impact on wound healing outcomes in diabetic mice.
Main Methods:
- Diabetic (db/db) mice received topical fisetin or vehicle for wound repair assessment.
- Wound healing outcomes were longitudinally monitored over 21 days.
Main Results:
- Fisetin significantly improved the healthy dermis to granulation ratio by day 7 and reduced dermal fibrosis by day 21.
- Fisetin modulated senescent cell markers (p16+, p21+) and decreased M1 macrophages and pro-inflammatory cytokines (TNF-α, IL-1β).
Conclusions:
- Topical fisetin enhances diabetic wound healing by modulating senescence and inflammation.
- Fisetin promotes healthy dermal regeneration and reduces fibrosis, indicating potential as a novel diabetic wound therapy.
