Pretreatment of Diabetic Adipose-derived Stem Cells with mitoTEMPO Reversestheir Defective Proangiogenic Function in Diabetic Mice with Critical LimbIschemia

摘要

Adipose-derived stem cells (ADSCs) have the ability to migrate to injury sites andfacilitate tissue repair by promoting angiogenesis. However, the therapeutic effect ofADSCs from patients with diabetes is impaired due to oxidative stress. Given that diabetesis a group of metabolic disorders and mitochondria are a major source of reactive oxygenspecies (ROS), it is possible that mitochondrial ROS plays an important role in theinduction of diabetic ADSC (dADSC) dysfunction. ADSCs isolated from diabetic mice weretreated with mitoTEMPO, a mitochondrial ROS scavenger, or TEMPO, a universal ROSscavenger, for three passages. The results showed that pretreatment with mitoTEMPOincreased the proliferation, multidifferentiation potential, and the migration andproangiogenic capacities of dADSCs to levels similar to those of ADSCs from control mice,whereas pretreatment with TEMPO showed only minor effects. Mechanistically, mitoTEMPOpretreatment enhanced the mitochondrial antioxidant capacity of dADSCs, and knockdown ofsuperoxide dismutase reduced the restored mitochondrial antioxidant capacity andattenuated the proangiogenic effects induced by mitoTEMPO pretreatment. In addition,mitoTEMPO pretreatment improved the survival of dADSCs in diabetic mice with critical limbischemia, showing protective effects similar to those of control ADSCs. Pretreatment ofdADSCs with mitoTEMPO decreased limb injury and improved angiogenesis in diabetic micewith critical limb ischemia. These findings suggested that short-term pretreatment ofdADSCs with a mitochondrial ROS scavenger restored their normal functions, which may be aneffective strategy for improving the therapeutic effects of ADSC-based therapies inpatients with diabetes.