Mesenchymal Stem Cell Utilization for In Vitro Donor Liver Machine Perfusion Preservation: Current Status and Future Directions

Abstract

Liver transplantation is the only effective treatment for end-stage liver disease. Currently, the shortage of high-quality donors has led to the exploration of the use of marginal organs. However, several factors limit the in vitro long-term preservation and long-distance transport of livers, which can also lead to ischemia-reperfusion injuries, resulting in poor prognosis. Therefore, an efficient and convenient strategy to improve this situation is urgently required. Normothermic machine perfusion (NMP) is expected to improve the liver environment in vitro and provide better evaluation indices for organ repair mechanisms. Mesenchymal stem cells (MSCs) can repair damaged hepatocytes or exert their protective effects via paracrine mechanisms, such as the release of extracellular vesicles (EVs). We hypothesized that combining the regenerative ability of MSCs and the significant advantages of NMP may improve the quality and utilization rate of organs, especially marginal organs. In this study, we review different strategies for liver preservation in vitro, as well as their strengths and weaknesses. We also introduce MSCs, derived EVs, and MSCs applications in liver preservation in vitro. Finally, we discuss the current challenges and future trends of MSCs applications for in vitro liver preservation. We envision novel bioreactor designs that employ 3D cell culturing and offer the possibility to reconstruct MSCs microenvironments to promote cell growth and biofunction expression. Large-scale MSCs production can be combined with normothermic machine perfusion to enhance in vitro liver preservation, thereby promoting donor organ function to benefit recipients in need of liver transplantation.

Keywords: ischemia-reperfusion injuries; liver preservation; liver transplantation; mesenchymal stem cells; normothermic machine perfusion.

Graphical abstract

Figure 1.

A comparison of the different liver preservation methods. (A) Static cold storage (SCS); (B) normothermic machine perfusion (NMP); (C) subnormothermic machine perfusion (SNMP); (D) hypothermic machine perfusion (HMP).

Figure 2.

MSC-derived EVs and their main functions. (A) The process of EVs production from MSCs and taking impact in liver; (B) the main functions of MSC-derived EVs.

Figure 3.

The application of MSC treatment to enhance liver in vitro machine perfusion preservation. (A) Current status, the MSC culture on dish (2D) and direct added in perfusion solution or injected via portal vein which have the risk of vascular occlusion, tumorigenesis and infection; (B) future directions, MSC culture in the outer cavity of hollow fiber bioreactor (3D) and does not enter blood vessels Which have on risk of vascular occlusion, tumorigenesis and infection.