Mesenchymal stem cell therapy for liver transplantation: clinical progress and immunomodulatory properties

Abstract

Although liver transplantation (LT) is an effective strategy for end-stage liver diseases, the shortage of donor organs and the immune rejection hinder its widespread implementation in clinical practice. Mesenchymal stem cells (MSCs) transplantation offers a promising approach for patients undergoing liver transplantation due to their immune regulatory capabilities, hepatic protection properties, and multidirectional differentiation potential. In this review, we summarize the potential applications of MSCs transplantation in various LT scenarios. MSCs transplantation has demonstrated effectiveness in alleviating hepatic ischemia-reperfusion injury, enhancing the viability of liver grafts, preventing acute graft-versus-host disease, and promoting liver regeneration in split LT therapy. We also discuss the clinical progress, and explore the immunomodulatory functions of MSCs in response to both adaptive and innate immune responses. Furthermore, we emphasize the interactions between MSCs and different immune cells, including T cells, B cells, plasma cells, natural killer cells, dendritic cells, Kupffer cells, and neutrophils, to provide new insights into the immunomodulatory properties of MSCs in adoptive cell therapy.

1. Introduction

Liver transplantation (LT) is an effective life-saving procedure for multiple end-stage liver diseases, including acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma [1, 2]. Despite the rapid development of LT techniques, there are still many problems and challenges, including donor shortage, ischemia-reperfusion injury, and immune rejection [3]. Consequently, most end-stage liver disease patients exceed the transplantation criteria or die while waiting for LT allocation [4]. To overcome these obstacles, several alternative methods have been effectively used to extend the clinical application of LT. For instance, marginal LT can partly compensate for the shortage of liver donors, although the poor outcomes associated with marginal LT (e.g., primary non-function) severely limit its broad application [5].

To reduce oxidative stress and hepatocyte apoptosis in ischemia-reperfusion injuries [6, 7], several corresponding measures, including shortening ischemic time, cold preservation, and the use of antioxidants have been employed [8–10]. However, extraneous ions or residues (e.g., potassium) derived from the preservative solution (e.g., UV solution) can severely cause cardiac arrest in LT patients. Although several immunosuppressants have been effectively used to alleviate the immune rejection throughout the entire process of LT [11–13], the unmanageable dosages of immunosuppressants due to individual differences often leads to excessive use, causing additional liver damage to liver transplant recipients [14]. Therefore, novel methods or drugs are still needed to improve LT efficiency and the prognosis of liver transplant recipients.