In Vivo MRI Tracking And Therapeutic Efficacy Of Transplanted Mesenchymal Stem Cells Labeled With Ferrimagnetic Vortex Iron Oxide Nanorings For Liver Fibrosis Repair

Liver fibrosis is a common outcome of a variety of chronic liver diseases,accompanied by impaired hepatocyte and endothelial barriers and inflammatory cell infiltration,ultimately resulting in massive collagen and extracellular matrix（ECM）deposition.Endstage liver fibrosis can develop into cirrhosis and even lead to hepatocellular carcinoma（HCC）.Currently,there is no effective treatment except liver transplantation.However,due to the shortage of donors,high cost and the significant limitations of immune-reactive liver transplantation,there is an urgent need to find new treatments.Mesenchymal stem cells（MSCs）have showed promising effects in the treatment of liver fibrosis.Long-term and noninvasive in vivo tracking of transplanted MSCs is essential for understanding the therapeutic mechanism of MSCs during the therapy of liver fibrosis.In this study,we report the development of a ferrimagnetic vortex iron oxide nanoring（FVIO）-based nanotracer for long-term visualization of transplanted human MSCs（h MSCs）by magnetic resonance imaging（MRI）.The FVIOs were prepared by hydrothermal reaction followed by hydrogen reduction.To endow the FVIOs with biocompatibility,polyethylene glycol amine（m PEG-NH₂）was covalently coupled on the surface of FVIOs,forming FVIO@PEG nanotracers with high T₂^*contrast enhancement and intracellular uptake.The h MSCs labeled with FVIO@PEG nanotracers exhibited enhanced MRI contrast than those labeled with commercial contrast agent,and could be continuously monitored by MRI in liver fibrosis mice for 28 days after transplantation,clearly clarifying the migration behavior of h MSCs in vivo.Moreover,we explored the therapeutic mechanism of the FVIO@PEG labeled h MSCs in the amelioration of liver fibrosis,including the reduction in inflammation and oxidative stress,the inhibition of hepatic fibrosis-caused histopathological damage,as well as the down-regulation of the expression of relevant cytokines.The results obtained in this work may deepen our understanding of the behavior and role of h MSCs in the treatment of liver fibrosis,which is key to the clinical application of stem cells in the therapy of liver diseases.