Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Both the authors contributed equally to this article.
Cell Transplant. 2019 Dec;28(12):1652-1663. doi: 10.1177/0963689719885076. Epub 2019 Nov 5.
Adipose-derived stem cells (ADSCs) have the ability to migrate to injury sites and facilitate tissue repair by promoting angiogenesis. However, the therapeutic effect of ADSCs from patients with diabetes is impaired due to oxidative stress. Given that diabetes is a group of metabolic disorders and mitochondria are a major source of reactive oxygen species (ROS), it is possible that mitochondrial ROS plays an important role in the induction of diabetic ADSC (dADSC) dysfunction. ADSCs isolated from diabetic mice were treated with mitoTEMPO, a mitochondrial ROS scavenger, or TEMPO, a universal ROS scavenger, for three passages. The results showed that pretreatment with mitoTEMPO increased the proliferation, multidifferentiation potential, and the migration and proangiogenic capacities of dADSCs to levels similar to those of ADSCs from control mice, whereas pretreatment with TEMPO showed only minor effects. Mechanistically, mitoTEMPO pretreatment enhanced the mitochondrial antioxidant capacity of dADSCs, and knockdown of superoxide dismutase reduced the restored mitochondrial antioxidant capacity and attenuated the proangiogenic effects induced by mitoTEMPO pretreatment. In addition, mitoTEMPO pretreatment improved the survival of dADSCs in diabetic mice with critical limb ischemia, showing protective effects similar to those of control ADSCs. Pretreatment of dADSCs with mitoTEMPO decreased limb injury and improved angiogenesis in diabetic mice with critical limb ischemia. These findings suggested that short-term pretreatment of dADSCs with a mitochondrial ROS scavenger restored their normal functions, which may be an effective strategy for improving the therapeutic effects of ADSC-based therapies in patients with diabetes.
脂肪干细胞（ADSCs）具有迁移到损伤部位的能力，并通过促进血管生成来促进组织修复。然而，由于氧化应激，糖尿病患者的 ADSC 的治疗效果受损。鉴于糖尿病是一组代谢紊乱，线粒体是活性氧（ROS）的主要来源，因此线粒体 ROS 可能在诱导糖尿病 ADSC（dADSC）功能障碍中发挥重要作用。用线粒体 ROS 清除剂 mitoTEMPO 或通用 ROS 清除剂 TEMPO 处理来自糖尿病小鼠的 ADSC 进行三个传代。结果表明，mitoTEMPO 的预处理增加了 dADSC 的增殖、多向分化潜能以及迁移和促血管生成能力，使其达到与来自对照小鼠的 ADSC 相似的水平，而 TEMPO 的预处理仅显示出较小的作用。从机制上讲，mitoTEMPO 预处理增强了 dADSCs 的线粒体抗氧化能力，而过表达超氧化物歧化酶降低了恢复的线粒体抗氧化能力，并减弱了 mitoTEMPO 预处理诱导的促血管生成作用。此外，mitoTEMPO 预处理提高了糖尿病伴有严重肢体缺血小鼠中 dADSCs 的存活率，表现出与对照 ADSC 相似的保护作用。dADSCs 的 mitoTEMPO 预处理减少了糖尿病伴有严重肢体缺血小鼠的肢体损伤并改善了血管生成。这些发现表明，用线粒体 ROS 清除剂对 dADSCs 进行短期预处理可以恢复其正常功能，这可能是改善糖尿病患者基于 ADSC 治疗的治疗效果的有效策略。
