Glyoxalase-1 Overexpression Reverses Defective Proangiogenic Function of Diabetic Adipose-Derived Stem Cells in Streptozotocin-Induced Diabetic Mice Model of Critical Limb Ischemia.
Adipose-derived stem cell (ADSC)-based therapy is promising for critical limb ischemia (CLI) treatment, especially in patients with diabetes. However, the therapeutic effects of diabetic ADSCs (D-ADSCs) are impaired by the diabetes, possibly through intracellular reactive oxygen species (ROS) accumulation. The objective of the present study was to detect whether overexpression of methylglyoxal-metabolizing enzyme glyoxalase-1 (GLO1), which reduces ROS in D-ADSCs, can restore their proangiogenic function in a streptozotocin-induced diabetic mice model of CLI. GLO1 overexpression in D-ADSCs (G-D-ADSCs) was achieved using the lentivirus method. G-D-ADSCs showed a significant decrease in intracellular ROS accumulation, increase in cell viability, and resistance to apoptosis under high-glucose conditions compared with D-ADSCs. G-D-ADSCs also performed better in terms of migration, differentiation, and proangiogenic capacity than D-ADSCs in a high-glucose environment. Notably, these properties were restored to the same level as that of nondiabetic ADSCs under high-glucose conditions. G-D-ADSC transplantation induced improved reperfusion and an increased limb salvage rate compared D-ADSCs in a diabetic mice model of CLI. Histological analysis revealed higher microvessel densities and more G-D-ADSC-incorporated microvessels in the G-D-ADSC group than in the D-ADSC group, which was comparable to the nondiabetic ADSC group. Higher expression of vascular endothelial growth factor A and stromal cell-derived factor-1α and lower expression of hypoxia-induced factor-1α were also detected in the ischemic muscles from the G-D-ADSC group than that of the D-ADSC group. The results of the present study have demonstrated that protection from ROS accumulation by GLO1 overexpression is effective in reversing the impaired biological function of D-ADSCs in promoting neovascularization of diabetic CLI mice model and warrants the future clinical application of D-ADSC-based therapy in diabetic patients. Stem Cells Translational Medicine 2017;6:261-271.
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Zhiyou
Z
Peng
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Xinrui
X
Yang
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Jinbao
J
Qin
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Kaichuang
K
Ye
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Xin
X
Wang
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Huihua
H
Shi
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Mier
M
Jiang
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Xiaobing
X
Liu
Department of Vascular Surgery, Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.|Vascular Center of Shanghai JiaoTong University, Shanghai, People's Republic of China.
Xinwu
X
Lu
D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D004195:Disease Models, Animal; D005121:Extremities / Q000098:blood supply*; D005947:Glucose / Q000633:toxicity; D007511:Ischemia / Q000503:physiopathology / Q000628:therapy*; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic; D017382:Reactive Oxygen Species / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000473:pathology*; D013311:Streptozocin
D016207:Cytokines; D017382:Reactive Oxygen Species; D013311:Streptozocin; D007791:Lactoylglutathione Lyase; D005947:Glucose
Adipose-derived stem cells; Angiogenesis; Critical limb ischemia; Diabetes; Glyoxalase-1