Action mechanism of mesenchymal stem cells and their derivatives in the treatment of liver fibrosis

Abstract

BACKGROUND: Multiple chronic liver diseases that fail to heal will progress to the stage of liver fibrosis. If not treated in a timely manner, they will eventually develop into liver cancer, severely threatening the safety of patients' lives. However, there is currently no specific drug for the treatment of liver fibrosis. Recent studies have demonstrated that mesenchymal stem cell therapy has significant advantages over traditional treatment protocols, providing a new direction for the treatment of liver fibrosis. OBJECTIVE: To review the mechanisms of action of mesenchymal stem cells and their derivatives in the treatment of liver fibrosis. METHODS: The Chinese and English keywords "mesenchymal stem cells, mesenchymal stromal cells, MSCs, liver fibrosis, hepatic fibrosis, hepatocyte death, liver cell death, hepatocyte-like cells, immunomodulation, macrophage, hepatic stellate cells, clinical trials, clinical studies" were used and searched in CNKI and PubMed databases, a total of 81 eligible articles were selected for this review. RESULTS AND CONCLUSION: Through summarizing existing studies, the mechanisms by which mesenchymal stem cells and their derivatives exert anti-fibrotic effects and delay disease progression have been identified. These specific mechanisms include reducing hepatocyte death, differentiating into hepatocyte-like cells, regulating immune responses, and inhibiting hepatic stellate cell activation, confirming that mesenchymal stem cells and their derivatives can serve as a new direction for the treatment of liver fibrosis-related diseases.

1. Introduction

Liver fibrosis is a reversible excessive repair response of the liver to chronic injury, driven by a triad of pathological processes: hepatocyte damage, inflammatory response, and aberrant repair. Various chronic etiologies (such as drug injury, hepatitis viruses, alcohol) can induce necrosis and apoptosis of hepatic parenchymal cells, triggering hepatic inflammation. Subsequently, injured hepatocytes, Kupffer cells, sinusoidal endothelial cells, and lymphocytes release multiple mediators that stimulate quiescent hepatic stellate cells (HSCs) in the space of Disse, converting them into myofibroblasts that produce large amounts of extracellular matrix, leading to fibrous septa and sinusoidal capillarization, resulting in liver fibrosis [1-2]. If fibrosis progresses, it irreversibly alters liver architecture (forming pseudolobules) and function, ultimately advancing to decompensated cirrhosis, complicated by portal hypertension, hepatocellular carcinoma, and liver failure, severely threatening patient lives. Current therapeutic strategies focus on etiological control combined with anti-fibrotic agents, but most drugs are still in clinical trials, and no drug has been approved specifically for liver fibrosis [2-3].

Mesenchymal stem cells (MSCs) are adult stem cells with self-renewal capacity and multilineage differentiation potential, morphologically resembling fibroblasts, and can be isolated from various tissues such as bone marrow, umbilical cord, and adipose tissue. Studies have shown that MSCs can differentiate into hepatocyte-like cells under in vitro culture conditions, providing a theoretical basis for MSC transplantation to replenish functional hepatocytes in damaged livers. Crucially, the potent secretory function of MSCs has been confirmed as a core mechanism of their therapeutic effects; they secrete bioactive molecules and extracellular vesicles that exhibit multiple effects in liver fibrosis models, including immunomodulation, promotion of tissue repair, and inhibition of HSC activation. This multi-target intervention property makes MSCs a highly promising new strategy for liver fibrosis treatment [4]. Based on this, this article reviews the mechanisms of action and clinical application status of MSCs in the treatment of liver fibrosis in recent years, laying a foundation for further research.