Exosomes derived from adipose-derived stem cells alleviate acute radiation-induced dermatitis through up-regulating hyaluronic acid synthase 1 expression

Abstract

Abstract Background Acute radiation-induced dermatitis refers to skin lesions that usually appear within 90 days of the start of radiotherapy. Although various treatments are available, none have proven fully effective. Exosomes produced by adipose-derived stem cells play crucial roles in enhancing cell regeneration, promoting angiogenesis, regulating inflammation and remodeling the extracellular matrix. Hyaluronic acid, a major extracellular matrix component, is synthesized by hyaluronic acid synthase, with hyaluronic acid synthase 1 being particularly critical for skin repair. This study aimed to investigate whether exosomes derived from adipose-derived stem cells can protect against radiation-induced acute skin damage and to elucidate the underlying mechanisms involving hyaluronic acid synthase 1. Methods Thirty-six male adult SD rats were randomly divided into a negative control group, an irradiation group (90 Gy), and a radiation + exosomes group (90 Gy + 100 ug exosomes). Three groups of fibroblasts were assigned: one for control, one for radiation (6 Gy), and one for radiation plus exosomes (6 Gy + 4 ug exosomes). The effect of ADSC-exos transplantation was evaluated using skin damage score, histopathological analysis, electron microscopy, immunohistochemical staining, immunofluorescence staining, and immunoblotting analysis. Furthermore, small interfering RNA-mediated knockdown of hyaluronic acid synthase 1 was performed to explore its regulatory role in the TGF-β/Smad2/3 signaling pathway. Results After irradiation, the ADSC-exos intervention significantly increased the levels of stromal cell-derived factor-1, matrix metalloproteinases, transforming growth factor, basic fibroblast growth factor, platelet-derived growth factor, vascular endothelial growth factor, interleukin 10, interleukin 12, and reduced the expression of the pro-inflammatory factor interleukin 6. Notably, exosomes treatment markedly upregulated hyaluronic acid synthase 1 expression, and small interfering RNA-mediated knockdown of hyaluronic acid synthase 1 resulted in reduced phosphorylation of TGF-β/Smad2/3 signaling components, indicating that hyaluronic acid synthase 1 is a critical mediator of this pathway. Conclusion Exosomes derived from adipose-derived stem cells alleviate acute radiation-induced dermatitis by enhancing hyaluronic acid synthase 1 expression and activating the TGF-β/Smad2/3 pathway, thereby promoting skin regeneration and repair. These findings suggest that exosomes derived from adipose-derived stem cells may serve as a promising cell-free therapeutic strategy for the prevention and treatment of acute radiation-induced dermatitis. Graphical abstract

Keywords

• Adipose-derived stem cell exosomes
• Hyaluronic acid
• Hyaluronic acid synthase
• Acute radiation-induced dermatitis
• Mesenchymal stem cells