Extracellular vesicles: mediators of intercellular communication in tissue injury and disease

Abstract

Intercellular communication is a critical process that ensures cooperation between distinct cell types and maintains homeostasis. EVs, which were initially described as cellular debris and devoid of biological function, are now recognized as key components in cell-cell communication. EVs are known to carry multiple factors derived from their cell of origin, including cytokines and chemokines, active enzymes, metabolites, nucleic acids, and surface molecules, that can alter the behavior of recipient cells. Since the cargo of EVs reflects their parental cells, EVs from damaged and dysfunctional tissue environments offer an abundance of information toward elucidating the molecular mechanisms of various diseases and pathological conditions. In this review, we discuss the most recent findings regarding the role of EVs in the progression of cancer, metabolic disorders, and inflammatory lung diseases given the high prevalence of these conditions worldwide and the important role that intercellular communication between immune, parenchymal, and stromal cells plays in the development of these pathological states. We also consider the clinical applications of EVs, including the possibilities for their use as novel therapeutics. While intercellular communication through extracellular vesicles (EVs) is key for physiological processes and tissue homeostasis, injury and stress result in altered communication patterns in the tissue microenvironment. When left unchecked, EV-mediated interactions between stromal, immune, and parenchymal cells lead to the development of disease states Video Abstract.

Keywords: Extracellular vesicles; Immune response; Intercellular communication; Lung inflammation; Metabolic disorders; Reprogramming; Tumor microenvironment.

While intercellular communication through extracellular vesicles (EVs) is key for physiological processes and tissue homeostasis, injury and stress result in altered communication patterns in the tissue microenvironment. When left unchecked, EV-mediated interactions between stromal, immune, and parenchymal cells lead to the development of disease states

Fig. 1

Overview of EV-mediated communication in disease progression. EV secretion is a universal process among stromal, parenchymal, immune, and cancer cells. Cargo contained in EVs will reflect the state of the parent cell, and communication via EVs will occur in a selective manner with particular recipient cells in nearby and distant tissues. Ultimately, the result of EV communication will dictate persistence of tissue homeostasis or development and progression of a disease state

Fig. 2

EVs in the tumor microenvironment. Tumor cells secrete EVs that target the immune system. Monocytes that uptake tumor EVs are driven toward an M2 and tumor-associated phenotype, resulting in the secretion of immunosuppressive and tumor-supportive factors. Tumor-associated macrophages release EVs that also act on tumor cells, notably through activation of P13K-AKT and Wnt signaling, causing enhanced migration and proliferation. Additionally, tumor cells evade immune surveillance by shedding EVs that contain PD-L1, which directly inhibits the T cell-mediated immune response

Fig. 3

The role of EVs post-cancer therapy. A Chemotherapy increases intracellular levels of reactive oxygen species (ROS), which leads to higher EV secretion. EVs derived from tumors that have been exposed to chemotherapeutic drugs have been shown to contain HMG-CoA reductase (HMGCR), which acts in an autocrine/paracrine manner, resulting in a vicious cycle of cholesterol production in cancer cells. Enhanced cholesterol levels can suppress natural immunity through inhibition of NK cells. B Surgical manipulation of tumors may induce circulating tumor cell (CTC) generation while causing an inflammatory state characterized by increased neutrophils in circulation. Tumor-derived EVs in circulation interact with neutrophils to induce NETosis, which allows CTCs to reach target organs. Tumor cells and tumor-derived EVs, along with immune cells, establish a pre-metastatic niche at this site. C After tumor cells have been exposed to ionizing radiation (IR), EV secretion is enhanced with cargo contents involved in AKT signaling, cell motility, DNA damage, and cytokine responses. Under hypoxic conditions, EV secretion is further increased, and these EVs promote migration in tumor cells and angiogenesis

Fig. 4

Overview of EV-mediated communication in liver diseases. In drug-induced liver damage, EV communication between hepatocytes and macrophages induces an inflammatory and fibrotic state. Furthermore, accumulation of fat in the liver, which is often associated with obesity, leads to communication between hepatocytes and hepatic stellate cells that promotes progression of fatty liver to non-alcoholic steatohepatitis (NASH). Within adipose tissue of obese individuals, adipocytes communicate with macrophages to polarize them into an M2 phenotype and create an inflammatory environment that leads to insulin resistance

Fig. 5

EVs in inflammatory lung disease. In homeostasis, most EVs in the airway are secreted by epithelial cells lining the airways and alveolar macrophages. In inflammatory lung diseases, immune cells are recruited to the airways and contribute to EV secretion. Secreted EVs carry protein, lipid, and miRNA cargoes and can be taken up by other immune cells and epithelial cells in the local environment. These EVs and cargoes can induce pro-inflammatory or anti-inflammatory effects in target cells, depending on the cargo type and context. These EVs can also induce tissue damage and fibrosis