Abstract 15700: Modified Human Mesenchymal Stromal Cells (MSCs) Improve Glucose Homeostasis in Diet induced Obese (DIO) Diabetic Mouse Model
Background: MSCs are undifferentiated, multipotent cells. We have previously showed that High Glucose (HG, 25mM) exposure promotes adipogenic differentiation, MSC inflammation, increased formation of ROS and decreased cellular oxygen consumption rate (OCR,using Seahorse).
Hypothesis: We hypothesized that intracellular anti-oxidant upregulation would reduce ROS and reduce cellular inflammation and possibly systemic inflammation on transplantation in hyperglycemic mouse model.
Methods: We used GFP-containing Adenoviral constructs to upregulate mitochondrial and cytosolic anti-oxidants such as SOD1, SOD2, Catalase and used Null as a control. We showed both SOD1 and SOD2 upregulation reduced intracellular ROS and improved OCR in presence of HG environment. Next, we delivered the eGFP, containing antioxidant constructs intra-peritoneally (IP) to DIO (60% and 45% high-fat diet) C57BL/6J mice. All mice had a fasting blood glucose ≥200mg/dl.
Results: We confirmed homing-in of eGFP labeled MSC to different inflamed fat pockets, such as pericardial, omental and epididymal. Mice receiving SOD2 upregulated MSCs improved glucose tolerance (GTT) wk 4 with least AUC, area under the curve, compared to SOD1 and Null (control) in both 60% and 45% DIO mice. AUC for 60% DIO mice for GFP, SOD1 and SOD2 group were: 58320, 58658 and 50745 respectively AND for 45% mice: 68423, 63608 and 41655. Catalase also showed improved GTT compared to control. AUC 57795 vs 62610 in a 60% DIO mice. Fat histology in mice receiving SOD2 and Catalase upregulated MSCs (particularly omental) showed less hyperplastic adipocyte compared to SOD1 and Null (control). We are processing other samples to demonstrate reduction of local and systemic inflammation. In summary, intracellular anti-oxidant reverses HG mediated ROS generation, OCR reduction and adipogenic differentiation in MSCs. Delivery of SOD2 and Catalase using MSCs as a gene delivery vehicle in DIO mice improved GTT. We conclude that delivery of specific antioxidant upregulated MSCs to the inflamed adipocyte depots in DIO diabetes model, may be the key to suppression of adipocyte mediated inflammation and may be a novel yet safe therapeutic tool to reduce insulin resistance and combat DIO associated prediabetes and diabetes.
Author Disclosures: C.C. Domingues: None. N. Kundu: None. N. Ahmadi: None. S. Sen: None.
- © 2016 by American Heart Association, Inc.