Glyoxalase-1 Overexpression Reverses Defective Proangiogenic Function of Diabetic Adipose-Derived Stem Cells in Streptozotocin-Induced Diabetic Mice Model of Critical Limb Ischemia

Stem Cells Transl Med. 2017 Jan;6(1):261-271. doi: 10.5966/sctm.2015-0380. Epub 2016 Aug 15.


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.

Keywords: Adipose-derived stem cells; Angiogenesis; Critical limb ischemia; Diabetes; Glyoxalase-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / pathology*
  • Animals
  • Apoptosis
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Survival
  • Cytokines / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diabetes Mellitus, Experimental / therapy*
  • Disease Models, Animal
  • Extremities / blood supply*
  • Glucose / toxicity
  • Ischemia / physiopathology
  • Ischemia / therapy*
  • Lactoylglutathione Lyase / metabolism*
  • Male
  • Mice
  • Neovascularization, Physiologic*
  • Reactive Oxygen Species / metabolism
  • Stem Cell Transplantation*
  • Stem Cells / pathology*
  • Streptozocin


  • Cytokines
  • Reactive Oxygen Species
  • Streptozocin
  • Lactoylglutathione Lyase
  • Glucose