Pretreatment of Diabetic Adipose-derived Stem Cells with mitoTEMPO Reverses their Defective Proangiogenic Function in Diabetic Mice with Critical Limb Ischemia
Pretreatment of Diabetic Adipose-derived Stem Cells with mitoTEMPO Reverses their Defective Proangiogenic Function in Diabetic Mice with Critical Limb Ischemia
复制标题
用 mitoTEMPO 预处理糖尿病脂肪干细胞可逆转糖尿病小鼠严重肢体缺血的促血管生成功能缺陷
DOI：
10.1177/0963689719885076
复制
发表时间：
2019-11-05
影响因子：
3.3
通讯作者：
Li, Chengxiang
中科院分区：
文献类型：
--
作者：
Lian, Kun;Wang, Qin;Li, Chengxiang
脂肪源性干细胞（ADSCs）具有迁移到损伤部位并通过促进血管生成促进组织修复的能力。然而，来自糖尿病患者的ADSCs的治疗效果由于氧化应激而受损。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，线粒体ROS可能在诱导糖尿病ADSC （dADSC）功能障碍中起重要作用。用线粒体活性氧清除剂mitoTEMPO或通用活性氧清除剂TEMPO处理糖尿病小鼠ADSCs三代。结果表明，mitoTEMPO预处理使ADSCs的增殖、多分化潜能、迁移和促血管生成能力提高到与对照小鼠ADSCs相似的水平，而TEMPO预处理仅显示出轻微的影响。在机制上，mitoTEMPO预处理增强了dADSCs的线粒体抗氧化能力，而超氧化物歧化酶的下调降低了修复后的线粒体抗氧化能力，减弱了mitoTEMPO预处理诱导的促血管生成作用。此外，mitoTEMPO预处理可提高重度肢体缺血糖尿病小鼠dADSCs的存活率，显示出与对照ADSCs相似的保护作用。用mitoTEMPO预处理dADSCs可减轻糖尿病小鼠重度肢体缺血的肢体损伤，促进血管生成。这些发现表明，使用线粒体ROS清除剂对dADSCs进行短期预处理可以恢复其正常功能，这可能是提高基于adsc的糖尿病患者治疗效果的有效策略。
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.