Extracellular vesicles: emerging roles, biomarkers and therapeutic strategies in fibrotic diseases

Abstract

Extracellular vesicles (EVs), a cluster of cell-secreted lipid bilayer nanoscale particles, universally exist in body fluids, as well as cell and tissue culture supernatants. Over the past years, increasing attention have been paid to the important role of EVs as effective intercellular communicators in fibrotic diseases. Notably, EV cargos, including proteins, lipids, nucleic acids, and metabolites, are reported to be disease-specific and can even contribute to fibrosis pathology. Thus, EVs are considered as effective biomarkers for disease diagnosis and prognosis. Emerging evidence shows that EVs derived from stem/progenitor cells have great prospects for cell-free therapy in various preclinical models of fibrotic diseases and engineered EVs can improve the targeting and effectiveness of their treatment. In this review, we will focus on the biological functions and mechanisms of EVs in the fibrotic diseases, as well as their potential as novel biomarkers and therapeutic strategies.

Keywords: Diagnosis; Extracellular vesicles; Fibrosis; Pathogenesis; Therapy.

Fig. 1

EV classification, biogenesis, and uptake. Apoptotic bodies and microvesicles are generated by directly budding from the plasma membrane, while exosomes are formed by endosomal pathway. Coasted by phospholipid bilayer, EVs are good carriers for bioactive cargos, including proteins, lipids, and nucleic acids. EVs can be internalized by receptor cells through membrane fusion, phagocytosis, micropinocytosis, clathrin-dependent endocytosis, caveolin-mediated endocytosis, or lipid raft-mediated endocytosis

Fig. 2

EV-mediated intercellular communication in liver fibrosis. In fibrotic liver, hepatocytes, HSCs, macrophages, cholangiocytes, and adipocytes communicate through vesicles carrying bioactive molecules and contribute to the disease progression

Fig. 3

EV-mediated intercellular communication in fibrotic lung diseases. During lung fibrosis, a serious of cells in bronchi, alveoli, and capillaries promote diseases development through the delivery of pathological vesicles within each other. While macrophages are capable of both activation and suppression of fibroblasts via transferring different microRNA cargos

Fig. 4

EV-mediated intercellular communication in cardiovascular fibrosis. Under pathological conditions, adipocytes secreted EVs exacerbate cardiac scarring via delivering profibrotic signals to endothelial cells and cardiomyocytes. Meanwhile fibroblasts can be activated by EVs from cardiomyocytes and immune cells through different cargos. In the blood vessels, pathological EVs released by atherosclerotic plaques spread atherogenesis to distant tissues

Fig. 5

EV-mediated intercellular communication in renal fibrosis. In fibrotic kidney, EVs establish an intricate signal transmission network within renal cells and promote their pathological changes. TECs are the key point during fibrosis process due to the capability of immune regulation and fibroblast activation

Fig. 6

Precondition and engineering strategies of EV-based fibrosis therapy. (A) Viral vectors or plasmids are often used as endogenous loading approach to express genes of interest in living cells, which can promote expression of proteins, nucleotides, or other molecules. These components in cells can then be packed into EVs(a). Exogenous cargos such as can be directly transported into EVs by electroporation, incubation, ultrasound, or extrusion(b). (B) The membrane of EVs can be modified by metabolic labeling, click chemistry, hydrophobic insertion, and ligand binding(a). Liposome mediate membrane fusion endows EVs with specific contents and ligands(b). (C) Iron oxide nanoparticles incubated with living cells can be taken and encapsulated into EVs, which are able to be guided by magnetism(a). Combination with hydrogel enables EVs local delivery(b). (D) Pretreat cells by hypoxia, cytokines, and some other chemical and physical elements change the physiological characteristic of EVs secreted by them