Vesicle-Mediated Control of Cell Function: The Role of Extracellular Matrix and Microenvironment

Abstract

Extracellular vesicles (EVs) - including exosomes, microvesicles and apoptotic bodies - have received much scientific attention last decade as mediators of a newly discovered cell-to-cell communication system, acting at short and long distances. EVs carry biologically active molecules, thus providing signals that influence a spectrum of functions in recipient cells during various physiological and pathological processes. Recent findings point to EVs as very attractive immunomodulatory therapeutic agents, vehicles for drug delivery and diagnostic and prognostic biomarkers in liquid biopsies. In addition, EVs interact with and regulate the synthesis of extracellular matrix (ECM) components, which is crucial for organ development and wound healing, as well as bone and cardiovascular calcification. EVs carrying matrix metalloproteinases (MMPs) are involved in ECM remodeling, thus modifying tumor microenvironment and contributing to premetastatic niche formation and angiogenesis. Here we review the role of EVs in control of cell function, with emphasis on their interaction with ECM and microenvironment in health and disease.

Keywords: cell function; exosomes; extracellular matrix; extracellular vesicles; microenvironment.

FIGURE 1

The role of EVs in epithelial-mesenchyme interaction during submandibular gland (A), tooth (B), and kidney (C) development. EVs diffuse through the basal membrane and participate in intercellular communication between epithelial and mesenchymal cells, carrying proteins and miRNAs that regulate key events for organogenesis, such as cell proliferation, differentiation and ECM synthesis.

FIGURE 2

The complexity of cell-to-cell interactions in tumor microenvironment mediated by EVs. During tumor progression, different cell types found in tumor microenvironment — including tumor, stromal, immune and vascular cells — interact reciprocally with each other, as well as with the ECM components, through EVs. These interactions result in immune cell activation or deactivation, which can either hamper or promote tumor growth, depending on the availability of soluble factors, which modulate the microenvironment status. In addition, tumor cell-derived EVs can spread drug resistance and invasive characteristics to other tumor cells, thus boosting tumor growth and the ability to form pre-metastatic niche.