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Shedding light on the cell biology of extracellular
vesicles.
Guillaume van Niel, Gisela d’Angelo, Graca Raposo
To cite this version:
Guillaume van Niel, Gisela d’Angelo, Graca Raposo. Shedding light on the cell biology of extracellular
vesicles.. Nature Reviews Molecular Cell Biology, Nature Publishing Group, 2018, 19 (4), pp.213-228.
�10.1038/nrm.2017.125�. �hal-02359760�
1
Shedding light on the cell biology of extracellular vesicles 1
2
Guillaume van Niel
1
, Gisela D’Angelo
2
and Graça Raposo
2
3
4
1. France Center of Psychiatry and Neurosciences, INSERM U895, Paris 5
75014, France 6
7
2. Institut Curie, PSL Research University, CNRS UMR144, Structure and 8
Membrane Compartments, Paris F-75005 9
10
Correspondence should be addressed to: G.R graca.raposo@curie.fr 11
12
13
Abstract : 14
15
Extracellular vesicles are a heterogeneous group of cell-derived membranous 16
structures that comprises exosomes and microvesicles, which originate from 17
the endosomal system or are shed from the plasma membrane, respectively. 18
They are present in biological fluids and are involved in multiple physiological 19
and pathological processes. Extracellular vesicles are now considered as an 20
additional mechanism for intercellular communication allowing cells to 21
exchange proteins, lipids and the genetic material. Knowledge of the cellular 22
processes that govern extracellular vesicle biology is essential to shed light on 23
physiological and pathological functions of these vesicles as well as on clinical 24
applications involving their use and/or analysis. Yet, many unknowns still 25
remain in this expanding field related to their origin, biogenesis, secretion, 26
targeting and fate. 27
28
29
30
31
32
33
[H1] Introduction 34
2
35
Apart from the release of secretory vesicles by specialized cells, which carry, 36
for example, hormones or neurotransmitters, all cells are capable of secreting 37
different types of membrane vesicles, known as extracellular vesicles, and 38
this process is conserved throughout evolution from bacteria to humans and 39
plants
1
2,3
. Secretion of extracellular vesicles has been initially described as 40
means of eliminating obsolete compounds
4
from the cell. However, now we 41
know that extracellular vesicles are more than waste carriers, and the main 42
interest in the field is now focused on their capacity to exchange components 43
between cells — varying from nucleic acids to lipids and proteins — and to act 44
as signalling vehicles in normal cell homeostatic processes or as a 45
consequence of pathological developments
5,6,7
. 46
47
Even though one generic term — extracellular vesicles – is currently in use to 48
refer to all these secreted membrane vesicles, they are in fact highly 49
heterogeneous (Fig. 1), which has largely hampered characterization and 50
manipulation of their properties and functions. Insights into the biogenesis of 51
secreted vesicles was provided by transmission and immuno-electron 52
microscopy, and by biochemical means
8-10
. Based on the current knowledge 53
of their biogenesis, extracellular vesicles can be broadly divided into two main 54
categories: exosomes and microvesicles (Fig 1a). 55
56
The term exosome (which should not be confused with the exosome complex, 57
which is involved in RNA degradation
11
) was initially used to name vesicles of 58
an unknown origin released from a variety of cultured cells and carrying 5’-59
nucleotidase activity
12
. Subsequently, the term exosomes was adopted to 60
refer to membrane vesicles (30-100 nm in diameter) released by reticulocytes 61
[G] during differentiation
4
. In essence, exosomes are intraluminal vesicles 62
(ILVs) formed by the inward budding of endosomal membrane during 63
maturation of multivesicular endosomes (MVEs) — which are intermediates 64
within the endosomal system — and secreted upon fusion of MVEs with the 65
cell surface
13,14
(Fig 1a-c). In the mid 1990’s exosomes were reported to be 66
secreted by B lymphocytes
15
and dendritic cells
16
with potential functions 67
related to immune regulation, and considered for use as vehicles in anti-68
3
tumoral immune responses. Exosome secretion is now largely extended to 69
many different cell types and their implications in intercellular communication 70
in normal and pathological states are now well documented
5
. 71
72
Microvesicles, formerly called “platelet dust”, were described as subcellular 73
material originating from platelets in normal plasma and serum
17
. Later, 74
ectocytosis, a process allowing the release of plasma membrane vesicles, 75
was described in stimulated neutrophils
18
. Although microvesicles were mainly 76
studied for their role in blood coagulation
19,20
, more recently they were 77
reported to have a role in cell–cell communication in different cell types, 78
including cancer cells
21
where they are generally called oncosomes. 79
Microvesicles range in size from 50-1000 nm in diameter, but can be even 80
larger (up to 10µm) in the case of oncosomes. They are generated by the 81
outward budding and fission of the plasma membrane and the subsequent 82
release of vesicles into the extracellular space
22
(Fig 1a-c). 83
84
There is now evidence that each cell type tunes extracellular vesicle 85
biogenesis depending on its physiological state, and to release extracellular 86
vesicles with particular lipid, protein and nucleic acid compositions
5
(Fig. 1d). 87
Because most published reports of extracellular vesicles have focused on 88
their potential functions rather their origins, it is still unclear which sub-species 89
of vesicles is responsible for any given effect. The current available protocols 90
to recover extracellular vesicles from cell culture supernatants or liquid 91
biopsies result in a heterogeneous population of vesicles of unknown origin
23
. 92
Moreover, the diversity of isolated extracellular vesicle populations is further 93
expanded by the inclusion of additional structures into the pool of extracellular 94
vesicles, such as the apoptotic bodies, migrasomes, which transport 95
multivesicular cytoplasmic contents during cell migration
24
or arrestin domain-96
containing protein 1-mediated microvesicles (ARMMS)
25
, which are largely 97
uniform, ~50 nm in diameter, microvesicles that have been shown to bud 98
directly from the plasma membrane in a manner resembling the budding of 99
viruses and dependent on arrestin domain-containing protein 1 (ARRDC1) 100
and on endosomal sorting complex required for transport (ESCRT) proteins 101
(similarly to a sub-population of exosomes; see also below). 102
4
103
104
The overlapping range of size, similar morphology and variable composition 105
challenge current attempts to devise a more precise nomenclature of 106
extracellular vesicles
26
27
. Nevertheless, novel isolation and characterization 107
methods are being developed to allow a more thorough description of 108
respective functions of the different types of extracellular vesicles and to 109
establish a suitable classification and terminology. Moreover, to validate 110
respective roles of exosomes and microvesicles, efforts are being made to 111
uncover mechanisms underlying the targeting of the different cargoes that 112
these vesicles transport to the site of extracellular vesicle biogenesis, the 113
generation and secretion of vesicles, and their fate in target cells. Here, we 114
review current knowledge and delineate unknown aspects of the essential 115
cellular processes that govern the biology of mammalian extracellular 116
vesicles, including their potential physiological roles, as well as their relevance 117
to disease and to clinical applications. 118
119
120
[H1] Biogenesis of extracellular vesicles 121
122
Exosomes and microvesicles have different modes of biogenesis (but both 123
involve membrane trafficking processes): exosomes are generated within the 124
endosomal system as ILVs and secreted during fusion of MVEs with the cell 125
surface, whereas microvesicles originate by an outward budding at the 126
plasma membrane
10
. This nomenclature is still questionable as extracellular 127
vesicle biogenesis pathways may differ according to the producing cell type. 128
For example, T cells generate primarily extracellular vesicles from the cell 129
surface with characteristics of exosomes, likely exploiting at the plasma 130
membrane molecular components and mechanisms that are usually 131
associated with the endosomal biogenesis of ILVs
28
. This peculiar biogenesis 132
of exosomes from the plasma membrane might be specific to T cells, which 133
also use the endosomal machinery for HIV budding at the plasma 134
membrane
29
. 135
136