Cell therapy in end-stage liver disease: replace and remodel

Abstract

Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.

Strategies to improve the therapeutic efficacy of mesenchymal stem cell‐derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease

“…In situ analysis showed that the liver was the major organ of small-EVs(<100 nm) localization in the first hour after administration, while distribution to the lungs and spleen peaked between 2 and 12 h. Large-EVs (>200 nm) were most abundant in the lungs in the first hour, followed by a decrease in the lung and an increase in the liver between 2 and 12 h ( Wiklander et al, 2015 ; Morishita et al, 2017 ; Kang et al, 2021 ). Such an accumulation in the liver may be determined by the liver’s physiological characteristics and the immune system’s response ( Hu et al, 2023 ). The liver is characterized by large volume, high vascularity, and high metabolism, which means that EV has a higher chance of being absorbed by the liver through blood circulation ( Yang et al, 2021 ).…”

“…Therefore, prolonging the half-life of MSC-EV is also crucial for improving the rotation rate of MSC-EV. Current strategies can be largely grouped into three main categories: approaches that focus on ( Hu et al, 2023 ) modifying the surface molecules of MSC-EV to improve its liver targeting and evade capture by the immune system ( Yang et al, 2021 ), encapsulating MSC-EV in biomaterials to improve the half-life of MSC-EV, and ( Bruno et al, 2021 ) selecting appropriate delivery strategies to reduce the in vivo pathway of MSC-EV in non-target tissues.…”

“…Optimization of MSC-EV formulation technology and preparation of sustained and controlled release delivery systems can prolong the half-life of MSC-EV in vivo . The ideal delivery technology for delivering MSC-EV should have the following characteristics ( Hu et al, 2023 ): good biocompatibility ( Yang et al, 2021 ); the ability to target or stay in the specific tissue ( Bruno et al, 2021 ); sustained-release function, which means the MSC-EV can be released for a long period time after encapsulation in a stable and sustained manner.…”

“…A large number of preclinical studies have demonstrated the efficacy of MSC-EV, providing strong evidence for MSC-EV to become a new therapeutic strategy in liver disease. However, MSC-EV still needs to overcome some bottlenecks ( Hu et al, 2023 ): establishing standards for production and quality control processes ( Yang et al, 2021 ); building the clinical efficacy and adverse reaction evaluation system.…”

Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure

“…At present, MSCs are utilized to improve liver function while waiting for liver transplantation and can also be used as a potential alternative therapy to organ or hepatocyte transplantation ( 10 ). Some recent clinical trials have reported that infusion of MSCs could induce tolerance after liver transplantation to reduce immune rejection due to the low immunogenicity and immunosuppression of MSCs ( 11 – 13 ).…”