Liver disease is a major health problem that endangers human health worldwide. Currently, whole organ allograft transplantation is the gold standard for the treatment of end-stage liver disease. A shortage of suitable organs, high costs and surgical complications limit the application of liver transplantation. Mesenchymal stem cell therapy has been considered as a promising alternative approach for end-stage liver disease. Some clinical trials have confirmed the effectiveness of MSC therapy for liver disease, but its application has not been promoted and approved. There are still many issues that should be solved prior to using MSC therapy in clinical applications. The types of liver disease that are most suitable for MSC application should be determined, and the preparation and engraftment of MSCs should be standardized. These may be bottlenecks that limit the use of MSCs. We investigated 22 completed and several ongoing clinical trials to discuss these questions from a clinical perspective. We also discussed the important mechanisms by which MSCs play a therapeutic role in liver disease. Finally, we also proposed novel prospective approaches that can improve the therapeutic effect of MSCs.
With high morbidity and mortality, liver disease presents a major threat to human health. Many stimuli, such as viral hepatitis, alcohol abuse, drugs, metabolic diseases, and autoimmune attack, can trigger chronic/acute liver injury and inflammation, which result in liver failure, cirrhosis and associated hepatocellular carcinoma. Orthotopic liver transplantation is the only effective treatment for liver cirrhosis and liver failure. However, the number of suitable donor organs is very limited. Adults on the waiting list for liver transplantation suffer from a mortality rate of almost 11% . Patients are too weak to wait for suitable donor organs, so the best opportunity for treatment is missed. In addition, liver transplantation is expensive and not available for all patients. There is an urgent need to search for a more effective and feasible treatment for patients with liver cirrhosis and liver failure.
At present, cell therapy with hepatocytes, hemopoietic cells, immune cells, endothelial progenitor cells and mesenchymal stem cells has been suggested to be a promising candidate therapy for liver diseases . A large body of studies investigated their advantages and disadvantages (Table 1). Among the cell types, MSCs have been the most promising cells because of their many advantages. (1) MSCs can be isolated easily from a wide variety of tissues and can be expanded in vitro without changing their properties. (2) MSCs can be injected into patients by allogeneic transplantation because of their low immunogenicity. Therefore, we can generate reserves of MSCs that we can give to patients at any time. (3) MSCs have the properties of self-renewal and can differentiate into multiple cell types. (4) Researchers have also shown the robust immunomodulation of MSCs. (5) MSCs can also produce secretomes, including soluble factors and exosomes, which can favor regeneration and injury repair. (6) Most importantly, MSCs can migrate to injury sites where they can exert protective effects. Therefore, MSCs have been used to treat various tissue injuries and immune-related diseases in clinical trials. To date, 321 completed clinical trials using MSCs were summarized in Fig. 1 according to the website https://clinicaltrials.gov/. Among them, bone/cartilage, brain/Nero and immune-related diseases account for almost 50% of all MSC-based clinical trials. In addition, we have noticed that 16 clinical trials are related to liver-related diseases. For liver diseases, however, both tissue damage and overactivation of inflammation always go hand in hand. Therefore, from every perspective, MSCs would be the best candidate for cell therapy of liver diseases. However, there are still many issues, and any confusion should be resolved before MSC application in the clinic.