Mesenchymal Stromal Cell (MSC) Therapy Improve Nonalcoholic Fatty Liver Disease (NAFLD) in Long Term high Fat Diet (HFD) Induced Obesity (DIO) Mouse

Abstract

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> George Washington University internal Grants. <h3>Background/Synopsis</h3> Elevated oxidative stress by reactive oxygen species and mitochondrial dysfunction have been implicated in diabetes and obesity leading to insulin resistance (IR). Based on our previous studies, we investigated to see the effect of MSCs and SOD2, mitochondrial antioxidant upregulated MSCs therapy delivered intra peritoneally (IP), in DIO mouse model that has been fed 60% HFD over 52 weeks. <h3>Objective/Purpose</h3> To investigate intraperitoneal delivery of MSCs overexpressing antioxidant SOD2 can improve NAFLD in DIO mouse model. <h3>Methods</h3> C57BL/6J male mice (4 to 6weeks old) were obtained from the Jackson Lab. Mice kept in laboratory for one year on HFD. Mouse adipose-derived MSCs transduced with adenovirus constructs containing GFP with Null (termed as Null-MSCs) and Adenoviral SOD2 constructs (termed as SOD2-MSC) were obtained from Vector Biolabs, commercially. They were compared to mice that received only saline IP (control). Glucose tolerance test (GTT), liver and fat depots H& E histology were performed and liver triglycerides (L-TG) using TG kit were quantified. <h3>Results</h3> Liver triglyceride estimated levels were reduced (2-fold) in both SOD2 and Null transduced MSCs compared to control with histology demonstrating better result with SOD2 upregulated group. Next, we looked at different fat depots such as omental, subcutaneous, and liver. The gene expression studies for omental fat from mice that received Null-MSCs and SOD2-MSCs showed significant reduction in inflammatory markers (IL-6 and TNF-<b>α)</b> vs control mice. GTT showed an improvement with total area under the curve (AUC) value less compared to control mice. Moreover, the systemic inflammatory maker plasma TNF- <b>α</b> levels were lowest in mice that received SOD2-MSCs. <h3>Conclusions</h3> Our results indicates that MSC therapy improve NAFLD in aged mice fed HFD over one year (long-term HFD treatment). Antioxidant upregulated MSC therapy appears to be safe and to give even better results and helps in reducing liver fat deposits, systemic inflammation and liver triglycerides.