PURPOSE: Radiation therapy for cancer often results in tissue damage, including fibrosis and fat loss. Existing treatments for tissue regeneration tend to be invasive and necessitate frequent physician visits. Systemic administration of rosiglitazone, a PPARγ agonist, has been shown to promote adipogenesis and reduce fibrosis in wounds, but it carries the risk of systemic toxicity. Our research focuses on developing a topical formulation of rosiglitazone to reduce skin fibrosis and promote adipogenesis, specifically targeting radiation-induced skin injury while minimizing the risk of systemic side effects.
METHODS: Ex Vivo model: Skin samples from 6-8-week-old C57BL/6 mice and from human patients (n=3/treatment) undergoing surgery were excised and sectioned into 1cm*1cm pieces. Samples were placed in transwell plates, with one plate receiving radiation (15Gy). Samples were treated with either topical rosiglitazone (10mg/mL) or control solution daily to the epidermis for 7 days. Tissues were sectioned and processed for flow cytometry, histology and immunofluorescence (IF).
In Vivo model: 6-8-week-old C57BL/6 mice (n=3/treatment) received radiation at 15Gy to the dorsum of the back (1cm*1cm shaved area). Mice then received either 50µL of topical rosiglitazone (10mg/ml) or control solution to the irradiated area daily for 7 days. Tissues were sectioned and processed for flow cytometry, histology and immunofluorescence (IF).
RESULTS: Topical rosiglitazone significantly increased adipose layer thickness in irradiated ex vivo (p<0.05*) and in vivo mouse skin samples compared to controls. Additionally, topical rosiglitazone treatment decreased total fibrosis area in ex vivo and in vivo (p<0.05*) irradiated mouse skin samples compared to controls. In ex vivo irradiated human skin samples, rosiglitazone enhanced subdermal adipose deposits, as shown by H&E staining, and increased mature adipocyte expression, evidenced by perilipin-1 staining on IF, compared to controls. Dashed lines and boxes: areas of fibrosis. Arrows: adipose layer. Solid box: adipose deposits. Yellow lines: start of epidermis. TC: topical control. TR: topical rosiglitazone.
CONCLUSIONS: Topical rosiglitazone enhances skin quality by promoting adipogenesis in both mouse and human skin samples. Additionally, in irradiated mouse skin, daily application of rosiglitazone for one week significantly reduces fibrosis. These findings suggest that topical PPARγ agonism may be a promising and safe therapeutic approach for radiation-induced skin damage. Future studies will focus on optimizing the topical formulation and evaluating its effects over longer time periods and in response to higher radiation doses.