Korean J Transplant.  2023 Nov;37(Suppl 1):S240. 10.4285/ATW2023.F-8352.

Bone marrow-derived mesenchymal stem cells reactive oxygen species-responsively secreting hepatocyte growth factor for effective treatment of ischemia-reperfusion injury in liver transplantation

• Xu S
• Tang L
• Ling S
• Xu X

• KMID: 2551869
• DOI: http://doi.org/10.4285/ATW2023.F-8352

Abstract

Background
Ischemia-reperfusion injury (IRI) in liver transplantation is a key factor, impairing the clinical efficacy of liver transplantation. After liver reperfusion, reactive oxygen species (ROS) generated from stressed hepatocytes would aggravate liver damage. How to attenuate IRI and improve liver regeneration remains a key problem.
Methods
A ROS-responsive charge-reversal polymer B-PDEAEA has been synthesized and utilized for condensing plasmid DNA to obtain polyplexes with various N/P ratios. Inspired by the sharply increased ROS in hepatic IRI and the tendency of mesenchymal stem cells (MSCs) to migrate to injured sites, it has been put forward that construction of bone marrow-derived mesenchymal stem cells (BMSCs) ROS-responsively secreting hepatocyte growth factor (HGF-BMSCs) could realize efficient and IRI-specific HGF releasing for effective treatment of IRI in liver transplantation. Rat hepatic IRI models has been established to evaluate the efficiency of HGF-BMSCs to protect liver from IRI.
Results
The polymer B-PDEAEA showed limited cytotoxicity to both hepatocytes and stem cells. N/P ratio as 30 was identified as the optimal for gene transfection in MSCs, and the polyplexes exhibited excellent ROS responsiveness and high gene transfection efficiency. HGF-BMSCs have been constructed and could release HGF with the response to ROS. HGF-BMSCs could release over 60,000 pg HGF per 10,000 cells with low stimulation of H2O2, suggesting the ROS-responsiveness. CM-Dil was used to track stem cells and biodistribution of stem cells revealed a accumulation of stem cells in the injured liver. Furthermore, both in vitro and in vivo experiments showed HGF-BMSCs could protect hepatocytes from IRI, with deceasing of inflammation.
Conclusions
Based on stem cell therapy and nanotechnology, a novel liver transplantation IRI protection system is constructed and promising to be established and to realize targeted and efficient gene/protein therapy, thus providing a theoretical and experimental basis for translational research on the repair and regeneration of transplanted liver.