Tip:
Highlight text to annotate it
X
(1쪽) In this presenstation, I will introduce an
extracellular vesicle, exosome based on recent two review papers.
(2쪽) Intercellular communication is an essential
hallmark of multicellular organisms and can be mediated through direct cell–cell contact
or transfer of secreted molecules. In the last two decades, three mechanisms of intercellular
communication has emerged that involves intercellular transfer of extracellular vesicles. These
vesicles are generally referred to as microvesicles, ectosomes, shedding vesicles, or microparticles
among others. The term exosome was initially used for vesicles ranging from 40 to 1,000
nm that are released by a variety of cultured cells, but the subcellular origin of these
vesicles remained unclear. Intercellular communication with extracellular
vesicles originate through at least three mechanisms. First, the fusion of multivesicular
bodies (MVBs) with the plasma membrane and the release of their intraluminal vesicles
(ILVs) as exosomes. Second, Blebbing of the cellular plasma membrane (ectosomes). At last,
Breakdown of dying cells into apoptotic bodies. Extracellular vesicles, which are secreted
into the extracellular environment, contain functional mRNA, microRNA (miRNA) and DNA
molecules that can be taken up by recipient cells through mechanisms including fusion
with the plasma membrane, phagocytosis and endocytosis.
(3쪽) One of extracellular vesicles, exosome has
an elaborate structure. The first figure show that exosomes isolated from melanoma cells
were contrasted with uranyl-acetate and embedded as whole mount preparations in methylcellulose.
Their artificial cup shape appearance and heterogeneous size ranging from 30 to 100
nm. Second figure represents that exosomes from prostate epithelial cells were directly
frozen and observed by cryo–electron microscopy without chemical fixation or contrasting.
Exosomes appear round. All exosomes contain proteins involved in
membrane transport and fusion (such as RAB proteins and annexins), cytoskeletal proteins,
adhesion molecules and tetraspanins, as well as RNA (mainly miRNA). Exosome membranes are
enriched in raft lipids such as cholesterol, ceramide and sphingolipids.
(4쪽) From biogenesis to exocytosis of exosomes,
the mechanism has been discovered for details. The animatic figure shows that the release
of Multi vesiculars and exosomes. Multi vesicular endosomes bud directly from the plasma membrane,
whereas exosomes are represented by small vesicles of different sizes that are formed
agains the Intraluminal Vesicles by budding into early endosomes and MVEs and are released
by fusion of MVEs with the plasma membrane. Other MVEs fuse with lysosomes. The point
of divergence between these types of MVEs is drawn at early endosomes, but the existence
of distinct early endosomes feeding into these two pathways cannot be excluded. Red spots
symbolize clathrin associated with vesicles at the plasma membrane or bilayered clathrin
coats at endosomes. Membrane-associated and transmembrane proteins on vesicles are represented
as triangles and rectangles, respectively. Arrows represent proposed directions of protein
and lipid transport between organelles and between MVEs and the plasma membrane for exosome
secretion. And black rectangles represent TEM images of MVEs and exocytosis of exosomes.
(5쪽) Over the past years, very diverse biological
functions have been attributed to exosomes, and it is now commonly accepted that exosomes
and MVs represent important vehicles of intercellular communication in between cells locally or
at a distance. Membrane-associated and transmembrane proteins and RNAs are selectively incorporated
into the intraluminal vesicles of MVEs or into MVs budding from the plasma membrane.
MVEs fuse with the plasma membrane to release exosomes into the extracellular environment.
MVs and exosomes may dock at the plasma membrane of a target cell with three methods. First,
bound vesicles may either fuse directly with the plasma membrane, Second, or be endocytosed.
At last, endocytosed vesicles may then fuse with the delimiting membrane of an endocytic
compartment. Both pathways result in the delivery of proteins and RNA into the membrane or cytosol
of the target cell. Fusion and endocytosis are only represented for exosomal vesicles,
but plasma membrane–derived MVs may have similar fates.
(6쪽) In the early 90’s, exosome secretion by
reticulocytes was reported as a mechanism to eradicate obsolete molecules. Soon thereafter,
it was shown that dendritic cells produce exosomes with the capacity to stimulate T
cell responses. Later, the capacity of exosomes to act as antigen-presenting vesicles, to
stimulate antitumoral immune responses, or rather to induce tolerogenic effects has stimulated
the interest of immunologists to investigate their potential use in clinics.
Tumor cells as well as other cells in tumor microenvironments also secrete exosomes and
microvesicles, and there is evidence that these contribute to tumor progression by promoting
angiogenesis and tumor cell migration in metastases. Tumor-derived vesicles also bear immunosuppressive
molecules, which can inactivate T lymphocytes or natural killer cells, or promote the differentiation
of regulatory T lymphocytes or myeloid cells to suppress immune responses. And recent studies
reported the association of membrane bound morphogens to exosomes, including Wnt and
the Notch ligand DII4. Through Wnt signaling, fibroblast exosomes have recently been demonstrated
to promote breast cancer cell dynamics.
Functions of exosomes have also been reported in epithelia and in the nervous system. Exosomes
released apically or basolaterally by intestinal epithelial cells appear to be involved in
antigen presentation at inflammatory conditions, and these exosomes may confer the ability
of static epithelial cells to act at a distance. In the airways, exosomes present in the bronchoalveolar
fluid bear tolerizing molecules or, conversely, may increase proinflammatory cytokine secretion
by airway epithelial cells in asthmatic human patients.
(7쪽) Today, I briefly introduced two review paper
about exosome. Then, What will the future bring in the field
of exosome research? Today’s two reviewers and great exosome masters Graca Raposo and
Clifford V. Harding predict that. In addition to their importance to fundamental
mechanisms of intercellular communication, signaling, and regulation, exosomes and other
extracellular vesicles may have important clinical applications in the future. There
is much interest in the potential for diagnostics based on analysis of exosomes, as they may
bear the protein or RNA signatures of pathological or physiological states of their source cells.
Because exosomes may traffic from tissue sites to blood, urine, or other body fluids that
are easily accessible, they may make such signatures available for diagnostic utilization.
Furthermore, the potential for RNA-bearing exosomes to influence or regulate recipient cells suggests the possibility
of therapeutic applications for cancer, amelioration of pathological immune responses (e.g., autoimmunity),
and other applications. May the next 30 years bring yet more advances.