Use of Modified Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Therapeutic Strategy for Obesity and Diabetes Treatment

Mesenchymal stem cells (MSCs) are multipotent cells with trans-differentiation capacity. High glucose (HG-25mM) promotes adipogenesis, accumulation of intracellular reactive oxygen species, upregulation of inflammatory genes, and decrease oxygen consumption rate (OCR) in MSCs. In this study, we investigated whether upregulation of antioxidant enzyme systems prevents those effects promoted by hyperglycemia condition (HG) in MSCs. To address this question we used GFP-tagged adenovirus constructs to upregulate superoxide dismutase (SOD1 and SOD2; mitochondrial and cytosolic, respectively) in human adipose tissue-derived MSCs. AdGFP viral construct was used as a control. After viral transduction, MSCs were exposed to HG up to 14 days or delivered intraperitoneally into diet-induced obese (DIO - 45% or 60% high fat diet) C57BL/6J mice presenting fasting blood glucose levels above 200 mg/dL. In vitro results showed that both SOD1 and SOD2 upregulation reduced intracellular superoxide anion presence and improved OCR, but SOD2 was the most efficient. In addition, the upregulation of IL-6 and TNFa was abrogated. The presence of mitochondrial complex I and II were also investigated and they both seemed to be reduced in presence of HG. However, SOD1 and SOD2 upregulation prevented that. In vivo results confirmed homing-in of eGFP labeled MSC to different inflamed fat pockets, particularly pericardial and omental fat by direct imaging. After 4 to 6 weeks, mice which received SOD2-MSCs presented a better response to glucose tolerance compared to SOD1 and GFP in both DIO models. PCR and histological analysis of fat depots as well as serum analysis are in progress to confirm reduction of local and systemic inflammation. In conclusion, adipogenesis, fat inflammation, and lower respiration observed in MSC exposed to hyperglycemia (HG) can be minimized by upregulation of superoxide dismutase, particularly mitochondrial. Besides, SOD2 upregulation improves glucose tolerance in DIO mice subjected to both 45% and 60% high fat diet. ...