Combination Of Mitochondrial And Cytosolic Antioxidant Upregulated Msc Therapy Improves Non-Alcoholic Fatty Liver Disease (Nafld)

Introduction: Diabetes and obesity are known to cause adipose inflammation, elevated oxidative stress by reactive oxygen species (ROS) accumulation. In this report we studied the effect of human adipose derived mesenchymal stroma cells (MSCs) overexpressing antioxidants both mitochondrial (Sod2) and cytosolic (Catalase) to reduce oxidative stress and systemic inflammation in DIO mouse model. Methods: C57BL/6J male mice (4–6 weeks old) were obtained from the Jackson Lab. Obesity, glucose intolerance, and insulin resistance were induced by feeding the mice a 60% fat high-fat diet (HFD) for 12 weeks. Mouse adipose-derived MSCs and adenovirus constructs containing GFP (Null, SOD2 and Catalase), were obtained. Liver and fat tissues gene expression, liver and fat depots H& E staining and liver triglycerides (L-TG) were quantified. Results: Triglyceride assay confirmed reduced liver fat accumulation in animals that received combination -MSCs. The gene expression analysis by qPCR for liver and omental fat shows upregulation of Ucp1, Pgc1a and Prdm16 genes with concomitant increase in all antioxidant (Sod2, Sod3 and Catalase) mRNA expression. Further the systemic TNF-α levels were decreased in the mice received MSC-Sod2+catalase. Glucose tolerance showed a improvement trend with low area under curve (AUC) values for mice that received MSCs with both Sod2 and catalase upregulated compared to control null group. Discussion: The combination effect of both mitochondrial and cytosolic anti-oxidants reduced systemic inflammation and liver triglyceride levels in diet induced obesity mouse model compared to SOD2, Catalase and Null MSCs. An increase mRNA expression of genes associated with browning of white adipose tissue deposits might have contributed to improvement in NAFLD along with systemic reduction in TNF-α. Genetically modified MSC therapy can be a promising option for treating obesity and diabetes.