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Abstract
Background: Mesenchymal stromal cells (MSCs) can home-in to inflamed fat depots to deliver antioxidants locally and help reduce oxidative stress, inflammation and improve NAFLD in high-fat diet (HFD) induced obese (DIO) diabetic mice. Methods: Antioxidants Sod2 (mitochondrial), Catalase (cytosolic) or Null (control) genes were upregulated individually, or in combination in adipose-derived MSCs. Modified MSCs were examined in-vitro in presence of adipogenic media to mimic DIO milieu. Next, modified MSCs were delivered intraperitoneally (IP) in mice that received 45% or 60% HFD for 8 to16 weeks. Results: In-vitro, we noted reduced MSC lipid droplets with SOD2, Catalase and combination compared to Null. Inflammatory marker IL6 mRNA, was down-regulated in SOD2, Cat and combination MSCs vs. Null-MSCs. In-vivo, n=4, Glucose tolerance test (GTT) improved with SOD2 MSC delivery in (p=0.07) at week-4. Plasma inflammatory marker TNFa, was reduced in both SOD2 and Catalase MSC groups (p<0.05) vs. Null-MSCs group. Analysis of omental and pericardial fat showed significant up-regulation in mRNA expression of brown fat marker, Ucp1 (∼1000 and 100-fold, respectively) and PGC1A mRNA was upregulated. Increased Ucp1 was confirmed by staining. There was a reduction in liver fat content by histology and liver triglyceride assay (p<0.05). Outcome measures of SOD2+Catalase combination MSC delivery in-vivo is pending. Conclusion: Upregulation of SOD2 plus Catalase, in-vitro, reduced inflammation in adipogenic media more so than individual gene upregulation. In-vivo, delivery of Sod2 and Catalase upregulated individually in MSCs, reduced inflammation and improved GTT with concomitant increased browning of white fat and reduced liver fat. Our results indicate that antioxidant upregulated modified MSC delivery IP, to target inflamed fat depots helps reduce oxidative stress and inflammation and can be an efficient tool for treating obesity, diabetes and NAFLD. Disclosure C.C. Domingues: None. N. Kundu: None. Y. Kropotova: None. S. Sen: None. Funding Clinical and Translational Science Institute at Children's National
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