Exosomes: Fundamental Biology and Roles in Cardiovascular Physiology

Abstract

Exosomes are nanosized membrane particles that are secreted by cells that transmit information from cell to cell. The information within exosomes prominently includes their protein and RNA payloads. Exosomal microRNAs in particular can potently and fundamentally alter the transcriptome of recipient cells. Here we summarize what is known about exosome biogenesis, content, and transmission, with a focus on cardiovascular physiology and pathophysiology. We also highlight some of the questions currently under active investigation regarding these extracellular membrane vesicles and their potential in diagnostic and therapeutic applications.

Keywords: cardiovascular disease; extracellular vesicles; intracellular communication; microRNA; regenerative medicine; stem cells.

Figure 1

Exosomes are nanosized particles with a diameter range of 30–100 nm and are secreted by all cell types. Enriched in cholesterol, ceramide, and phosphatidylserine, these lipid bilayer particles have a lipid content different from that of the parent cell. Markers ubiquitous in most exosomes include tetraspanins (CD9, CD63, and CD81); heat shock proteins; adhesion molecules; and markers of the ESCRT (endosomal sorting complexes required for transport) pathway, including LAMP1 and TSG101.

Figure 2

(a) Formation of two different multivesicular bodies (MVBs) through invagination of the plasma membrane. Exosome-associated MVBs are more enriched in cholesterol than are MVBs involved in the degradation pathway for ubiquitinated proteins. B represents the addition of ubiquitin to protein substrates; Lys denotes fusion of lysosomes. Steps 1–4 (red): Invagination of the plasma membrane to form a secretory endosome (1), followed by budding of payload into the endosomal membrane to form multivesicular endosomes (2). Maturation of the late endosome through acidification (3) triggers fusion with the plasma membrane and release of exosomes (4). Steps1 and 2(blue): Invagination of the plasma membrane to form lysosomal membrane (1), followed by fusion of ubiquitinated products for lysosomal degradation (2). Both pathways involve the ESCRT (endosomal sorting complexes required for transport) pathway for budding of molecular payload into the lumen ofa MVB as it matures to the late endosome or fuses with lysosomes for degradation. (b,c) Other extracellular vesicles and their mode of secretion include (b) microvesicles that shed from injured cells and (c) tumor cells and apoptosomes that bleb from dead and dying cells.

Figure 3

The ESCRT (endosomal sorting complexes required for transport) pathway is the mechanism by which molecular payload populates the multivesicular body (MVB). Although exosomes do not fully utilize the ESCRT machinery, here the four ESCRT complexes are shown. ESCRT 0 complex proteins (B represents a ubiquitin group bound to a protein substrate) recognize ubiquitinated protein products and concentrate them in microdomains by using clathrin molecules and recruit ESCRT I, which in turn recruits ESCRT II and triggers membrane involution. ESCRT III complexes form circular filaments and cause further invagination of the membrane and ultimately both membrane abscission and budding of the proteins into the lumen of the endosome and the elimination of ubiquitin outside the endosome.

Figure 4

Tissue injured during insult releases exosomes containing signals and factors that promote further damage in distant tissue. Such signals and factors include prohypertrophic, proinflammatory, and proapoptotic/necrotic miRs, proteins, and mRNA.