RNAi Therapeutic Delivery by Exosomes - RNA Interference from Biology to Therapeutics - page 186

9.3 The Origin and Biology of Membrane Vesicles

Transmission of information between cells in the body occurs through several
mechanisms. Communication can occur through (1) secreted growth factors, cytokines,
or other small molecules including nucleotides and bioactive lipids; (2) cell-to-cell
adhesions mediated by specialized adhesion molecules; and (3) tunneling nano-
tubes that interconnect cells. In addition, cells can communicate through membrane
transfer by the secretion of membrane vesicles, a mechanism that for years was
largely overlooked. Historically, when viewed under a microscope, small membrane-
bound vesicles were thought to be a result of cell damage or death. Recently, release
of these vesicles has been increasingly recognized as a novel, universally conserved
mode of intercellular communication with a role in many physiological and patho-
logical processes. Such vesicles increase the complexity of cell signaling by trans-
mitting important information via the proteins, lipids, and nucleic acids they contain,
which can alter signaling in any recipient cell [ 32, 33 ] .
Currently, this heterogeneous group of intercellular vesicle messengers is divided
into subgroups based on their biogenesis, biophysical properties, and functions,
although they share some common characteristics of an internal microenvironment
protected from the extracellular milieu by a lipid bilayer and retain the same mem-
brane topology as the cell of origin. A precise definition and nomenclature of the
diverse group of membrane vesicles is lacking as current understanding is limited
by the lack of supporting technologies necessary for their accurate isolation and
characterization. This review will use the term membrane vesicles to refer collec-
tively to these membrane-derived particles with a role in intercellular communica-
tion. Depending on the location of cell origin, membrane vesicles can be divided
into three broad categories (Fig. 9.1 ).

9.3.1 Microvesicles

Microvesicles (MVs) are a group of membrane vesicles secreted by budding or shed-
ding from the plasma membrane of most cell types. They usually have a diameter
between 100 and 1,000 nm [ 33 ]. In the literature, they are also referred to as
microparticles, ectosomes, shedding vesicles, and exovesicles depending on the cell
type they originate from. Their release can be stimulated by calcium, upon ligand
binding and activation, or stress either physical, e.g., shear stress, or chemical, e.g.,
hypoxia [ 34, 35 ]. Calcium can modify the asymmetric phospholipid distribution of
the plasma membrane into cholesterol-rich microdomains by inhibiting translocase
and activating scramblase causing phosphatidylserine to translocate from the inner
facing membrane to be exposed on the outer at sites of MV shedding [ 36 ] . Small
cytoplasmic protrusions bud from the plasma membrane due to curvature-mediated
lateral redistribution of membrane components at these microdomains; a calcium
influx activates calpain which alters the cytoskeletal structure causing the protrusions