Department of Plastic and Reconstructive Surgery, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Guangzhou, Guangdong Province 510317, China.
Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou North Road, Guangzhou, Guangdong Province 510515, China.
J Leukoc Biol. 2024 Apr 29;115(5):882-892. doi: 10.1093/jleuko/qiad116.
Adipose-derived stem cells (ADSCs) have been proven to promote healing in diabetic wounds, which are one of the most serious chronic refractory wounds. However, reactive oxygen species (ROS) induced by high glucose (HG) lead to oxidative stress and aging in ADSCs, which limits the therapeutic effect of ADSCs. In this study, we investigated the role of GKT137831, a NOX1/4 inhibitor that can reduce ROS production, in protecting ADSCs from hyperglycemia and in diabetic wound healing. In vitro, ROS levels and NOX4 expression were increased after HG treatment of ADSCs, while the oxidative stress marker malondialdehyde was increased; mitochondrial membrane potential was decreased; inflammatory aging-related indicators such as p16, p21, matrix metalloproteinase-1 (MMP1), MMP3, interleukin-6, and β-galactosidase were increased; and migration was weakened. In vivo, we constructed a diabetic mouse wound model and found that the combination of ADSCs and GKT137831 synergistically promoted the 21-day wound healing rate, increased the expression of collagen and hydroxyproline, increased the number of blood vessels and the expression of CD31, and reduced the expression of interleukin-6, MMP1, MMP3, and p21. These results suggest that GKT137831 could protect ADSCs from oxidative stress and aging induced by HG and enhance the therapeutic effect of ADSCs on diabetic wounds.
脂肪干细胞（ADSCs）已被证明可促进糖尿病伤口的愈合，糖尿病伤口是最严重的慢性难愈性伤口之一。然而，高糖（HG）诱导的活性氧（ROS）导致 ADSCs 发生氧化应激和衰老，从而限制了 ADSCs 的治疗效果。在这项研究中，我们研究了 NOX1/4 抑制剂 GKT137831 的作用，该抑制剂可减少 ROS 的产生，从而保护 ADSCs 免受高血糖和糖尿病伤口愈合的影响。在体外，HG 处理 ADSCs 后 ROS 水平和 NOX4 表达增加，而氧化应激标志物丙二醛增加；线粒体膜电位降低；p16、p21、基质金属蛋白酶-1（MMP1）、MMP3、白细胞介素-6 和β-半乳糖苷酶等炎症性衰老相关指标增加；迁移能力减弱。在体内，我们构建了糖尿病小鼠伤口模型，发现 ADSCs 和 GKT137831 的联合使用协同促进了 21 天的伤口愈合率，增加了胶原蛋白和羟脯氨酸的表达，增加了血管数量和 CD31 的表达，并降低了白细胞介素-6、MMP1、MMP3 和 p21 的表达。这些结果表明，GKT137831 可以保护 ADSCs 免受 HG 诱导的氧化应激和衰老，并增强 ADSCs 对糖尿病伤口的治疗效果。
