Modified Mesenchymal Stromal Cells Promote Multiple Metabolic Benefits in Obese Diabetic Mice

Background: Mesenchymal stromal cells (MSCs) are multipotent cells that can home-in to the sites of inflammation. Therefore, antioxidant-upregulated MSCs delivered intra-peritoneally can home-in to local inflamed fat pockets which may reduce inflammation and improve glucose tolerance in diet-induced obese and diabetic mouse model.

Methods: GFP-containing adenoviral constructs were used to upregulate antioxidants Sod2 (mitochondrial) and Catalase (cytosolic) in human adipose-derived MSCs. Modified MSCs were delivered (IP) into mice subjected to 45% and 60% high-fat diet for 8-16 weeks.

Results: Glucose tolerance was improved at week 4 in the antioxidant upregulated MSC-receiving groups with concomitant reduction in hyperplasia in omental fat. A reduction in plasma levels of TNFa, an well-known inflammatory marker, was found for all treated animal groups in comparison to control (null-MSCs). RT-PCR analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000-fold and 10-100-fold, respectively) which was confirmed by Ucp1-staining and concomitant increases in down-stream genes such as Pgc1a and Prdm16 mRNA expression. Remarkably, the treatment showed a significant reduction in liver fat content (by histology) and triglyceride content measurement.

Conclusion: Delivery of Sod2 and Catalase upregulated MSCs improved glycemic control by reducing systemic inflammation, promotes browning of white adipose tissue and reverses hepatic lipid accumulation. These results indicate that antioxidant upregulated MSCs can help to improve glucose homeostasis, adipocyte energetics and hepatic lipid metabolism. Modified MSC therapy can be a promising therapy for type 2 diabetes, obesity and fatty liver disease.