Abstract

Liver fibrosis is an intrahepatic chronic damage repair response caused by various reasons such as alcoholic liver, fatty liver, viral hepatitis, autoimmune diseases, etc., and is closely related to the progression of liver disease. Currently, the mechanisms of liver fibrosis and its treatment are hot research topics in the field of liver disease remedy. Mesenchymal stem cells (MSCs) are a class of adult stem cells with self-renewal and multidirectional differentiation potential, which can ameliorate fibrosis through hepatic-directed differentiation, paracrine effects, and immunomodulation. However, the low inner-liver colonization rate, low survival rate, and short duration of intervention after stem cell transplantation have limited their wide clinical application. With the intensive research on liver fibrosis worldwide, it has been found that MSCs and MSCs-derived exosomes combined with drugs have shown better intervention efficiency than utilization of MSCs alone in many animal models of liver fibrosis. In this paper, we review the interventional effects and mechanisms of mesenchymal stem cells and their exosomes combined with drugs to alleviate hepatic fibrosis in vivo in animal models in recent years, which will provide new ideas to improve the efficacy of mesenchymal stem cells and their exosomes in treating hepatic fibrosis in the clinic.

Introduction

The liver is mainly composed of hepatocytes, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs) that perform a comprehensive range of hepatic functions, such as detoxification, bile acid synthesis, and participation in various metabolic processes. However, a variety of stimuli, such as alcohol, drugs, inflammation, or cholestasis, often cause damage to hepatocytes resulting in abnormal liver function and a series of pathophysiologic changes [1] . Liver fibrosis is a common intermediate pathological process of various chronic liver diseases, which is mainly manifested by diffuse excessive deposition of extracellular matrix, leading to abnormal changes in liver tissue structure and affecting the normal physiological functions of liver severely [2] . Clinically, if liver fibrosis is not effectively reversed or curbed, it will progress to irreversible cirrhosis, hepatocellular carcinoma, and other end-stage liver diseases, eventually, leading to the death of patients [3] . Therefore, finding effective therapeutic strategies to ameliorate liver fibrosis in patients is of great importance in preventing the development of end-stage liver diseases.

In the clinical setting, liver transplantation is mostly used for the treatment of end-stage liver diseases, but liver transplantation cannot be widely used due to the defects of extremely rare donors, high cost, rejection, etc [4] . Currently, mesenchymal stem cells for the treatment of liver disease have become a hot spot in the field of biomedicine. As the intermediate pathological process of end-stage liver disease, mesenchymal stem cells can effectively ameliorate hepatic fibrosis through hepatogenic differentiation, immunomodulation, paracrine effects, and other mechanisms [5] . However, it has been reported that MSCs transplanted in the body may have some disadvantages such as low inner-liver colonization and short duration of intervention, which affect their therapeutic efficacy [6] . Nowadays, an increasing number of researchers have demonstrated in animal models of liver fibrosis that the combination of MSCs with drugs can boost the therapeutic effect of MSCs in the treatment of liver fibrosis by promoting the homing of MSCs, differentiating them into functional hepatocyte-like cells, improving the microenvironment, inhibiting the activation of HSCs, and modulating the signaling pathway, and so on. In addition, MSCs-derived extracellular vesicles with the advantages of higher penetrability and lower carcinogenicity also effectively ameliorate liver fibrosis with ultimate safety. What’s more, nanoscale intracellular vesicles can also be used as carriers of natural drugs for drug delivery. This provides new ideas to solve the poor efficiency of MSCs in the treatment of liver fibrosis in the clinic.

Discussion and outlook

Liver fibrosis, as an intermediate pathological process from chronic liver disease to cirrhosis and hepatocellular carcinoma, has become a research hotspot for the treatment of liver diseases due to its reversible properties. However, there is no very effective means to treat liver fibrosis in clinical practice. MSCs, as a kind of pluripotent stem cells, have no ethical issues and wide sources compared with liver transplantation and hepatocyte transplantation, which have attracted much attention in animal experiments and clinical studies of cell transplantation for the treatment of liver fibrosis. Unfortunately, MSCs confront with the challenges such as in vivo microenvironment inadaptation and attenuation of inflammatory response ability after isolation and culture in vitro [45] , which ultimately leads to a low colonization rate and short duration of intervention after transplantation of MSCs into the liver [6] . Therefore, it has not been widely used in clinical practice.