The Role of Extracellular Vesicles in Liver Fibrosis: Friends or Foes?

Abstract

Liver fibrosis represents a common pathway in the progression of various chronic liver diseases towards cirrhosis and liver failure. Extracellular vesicles (EVs) are membrane-enclosed particles secreted by diverse cell types, including exosomes, microvesicles, apoptotic vesicles, and the recently identified migrasomes. These vesicles can be taken up by recipient cells, thereby modulating their function through the transport of cargo molecules. EVs facilitate intercellular communication and play a significant role in the development of liver fibrosis. Moreover, the detection of EVs in various body fluids offers sensitive diagnostic tools for assessing liver fibrosis. Additionally, EVs may serve as therapeutic targets, potential therapeutic agents, and drug delivery vehicles. This article reviews recent advances in the field of EVs concerning liver fibrosis and related diseases, with a particular focus on the potential role of the newly discovered migrasomes in intracellular crosstalk within the liver.

Keywords: exosomes; extracellular vesicles; intracellular communication; liver fibrosis; migrasomes; therapeutic strategy.

Figure 1

The classification and biogenesis of extracellular vesicles. EVs are membrane-enclosed particles secreted into the extracellular space by a variety of cells. They can be classified into four main subtypes: exosomes, microvesicles, apoptotic bodies and migrasomes. MVB, multivesicular body.

Figure 2

EVs are critical players in the progression of liver fibrosis by transferring signaling molecules between different types of liver and non-liver cells. The cartoon highlights different cells (hepatocytes, cholangiocytes, macrophages, endothelial cells, etc.) can secrete EVs enriched with a variety of molecules (mtDNA, miR-128-3p, lncRNA-H19, miR-103-3p, etc.) to regulate the activity of hepatic stellate cells and thus influence the progression of liver fibrosis. ECM, extracellular matrix; HSCs, hepatic stellate cells; KCs, Kupffer cells; lncRNA, long non-coding RNA; LSECs, liver sinusoidal endothelial cells; miR, microRNA; mtDNA, mitochondrial DNA.

Figure 3

The application of EVs (mainly exosomes and MVs) in liver fibrosis. EVs can serve as biomarkers, targets, therapeutic agents or carriers for liver fibrosis. For example, MSCs represent a source of exosomes that can induce ferroptosis in HSCs by transferring BECN1 and suppress the viability and migration of HSCs through the transfer of miR-618, thereby alleviating fibrosis in mouse liver models. Furthermore, EVs can be engineered to selectively target HSCs by modified with vitamin A, HSTP1, or miR-181-5p. ADSCs, adipose-derived mesenchymal stem cells; hESCs, human embryonic stem cells; MSCs, mesenchymal stem cells.

Figure 4

The effect of migrasomes derived from various sources. Migrasomes, a recently identified type of EV generated during cell migration, have been observed in immune cells, cancer cells, mesenchymal stromal cells, and stem cells, and they are playing a crucial role in homeostasis and diseases.

Figure 5

The probable role of migrasomes in pathophysiological processes of liver fibrosis. Immune cell-derived migrasomes may modulate the process of liver fibrosis by regulating the activation of HSCs, accumulation of extracellular matrix, angiogenesis, and immune homeostasis. In turn, migrasomes from migrating HSCs may also be involved in the occurrence and development of liver fibrosis by regulating the immune response. ECM, extracellular matrix; HSCs, hepatic stellate cells; LSECs, liver sinusoidal endothelial cells.