Tian Chenyang, Xu Huan, Li Chunli, Gao Jiaxue, Zhang Hao, Wang Peng, Wang Yuhang, Liu Dongyang, Jing Lan, Wang Bingang, Liu Wenjun, Liao Dongfa, Li Junjie, Shen Kuo, Hu Dahai
Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Western Theater General Hospital of the Chinese People's Liberation Army, Chengdu, Sichuan 610083, China.
Cell Signal. 2025 Oct;134:111936. doi: 10.1016/j.cellsig.2025.111936. Epub 2025 Jun 10.
Diabetic foot ulcer (DFU) is a common and challenging chronic disease that can lead to non-traumatic amputation. Studies have indicated that complex cellular environments in DFU often lead to the dysfunction of several cells at the wound site; however, the mechanism of this injury is still difficult to elucidate.
DFU and normal skin tissue from patients were analyzed by pathological examination using hematoxylin and eosin (H&E), Masson, myeloperoxidase (MPO) and 8-Oxo-2'-deoxyguanosine (8OHdG) immunohistochemical staining. Extract and identify adipose-derived stem cell (ADSC) exosomes from ADSC culture medium. A diabetic wound healing model and a high-glucose-induced fibroblast cell model were used to analyze the effects of ADSC exosomes on DFU wound healing. In addition, collagen synthesis and fibrosis-related molecules as well as oxidative stress-related indices were detected in the cell model. To uncover the underlying mechanism, we further detected the expression of antioxidant related molecules, including Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4).
Pathological examination confirmed that DFU tissue displayed increased inflammatory cell infiltration and cell injury compared to normal skin. We confirmed that ADSC exosomes accelerated DFU wound healing and improved collagen synthesis and deposition. ADSC exosomes could reverse high glucose induced fibroblast damage, as well as the ability of collagen synthesis. Furthermore, our results indicated that ADSC exosomes improved HG-induced oxidative stress injury by regulating the expression of the Keap1/Nrf2 axis.
This study revealed that ADSC exosomes alleviated HG-induced fibroblast injury and accelerated diabetic wound healing by regulating the expression of the Keap1/Nrf2 axis.
糖尿病足溃疡（DFU）是一种常见且具有挑战性的慢性疾病，可导致非创伤性截肢。研究表明，DFU中复杂的细胞环境常导致伤口部位多种细胞功能障碍；然而，这种损伤的机制仍难以阐明。
采用苏木精-伊红（H&E）、Masson、髓过氧化物酶（MPO）和8-氧代-2'-脱氧鸟苷（8OHdG）免疫组织化学染色对患者的DFU和正常皮肤组织进行病理检查分析。从脂肪干细胞（ADSC）培养基中提取并鉴定ADSC外泌体。使用糖尿病伤口愈合模型和高糖诱导的成纤维细胞模型分析ADSC外泌体对DFU伤口愈合的影响。此外，在细胞模型中检测胶原合成和纤维化相关分子以及氧化应激相关指标。为揭示潜在机制，我们进一步检测了抗氧化相关分子的表达，包括 Kelch样ECH相关蛋白1（Keap1）、核因子红细胞2相关因子2（Nrf2）、血红素加氧酶-1（HO-1）和谷胱甘肽过氧化物酶4（GPX4）。
病理检查证实，与正常皮肤相比，DFU组织炎症细胞浸润增加且细胞损伤加重。我们证实ADSC外泌体加速了DFU伤口愈合，并改善了胶原合成和沉积。ADSC外泌体可逆转高糖诱导的成纤维细胞损伤以及胶原合成能力。此外，我们的结果表明，ADSC外泌体通过调节Keap1/Nrf2轴的表达改善了高糖诱导的氧化应激损伤。
本研究表明，ADSC外泌体通过调节Keap1/Nrf2轴的表达减轻了高糖诱导的成纤维细胞损伤，并加速了糖尿病伤口愈合。
