Introduction
Exosomes | Microvesicles | Apoptotic bodies | References | |
---|---|---|---|---|
Size | 30–100 nm | 100–1,000 nm | 1–5 μm | [3] |
Origin | Intraluminal vesicles within multivesicular bodies | Plasma membrane and cellular content | Plasma membrane, cellular fragments | [4] |
Mechanism of formation | Fusion of multivesicular bodies with the plasma membrane | Outward blebbing of the plasma membrane | Cell shrinkage and programmed cell death | |
Release | Constitutive and/or cellular activation | Constitutive and/or cellular activation | Apoptosis | [4] |
Time of release | Ten minutes or more | Few seconds | – | |
Pathways | ESCRT-dependent Tetraspanin-dependent Ceramide-dependent Stimuli-dependent | Ca2+-dependent Stimuli- and cell-dependent | Apoptosis-related | [3] |
Lipid membrane composition | Enriched in cholesterol and ceramide, expose phosphatidylserine, contain lipid rafts | Expose phosphatidylserine, enriched in cholesterol and diacylglycerol, contain lipid rafts | – | |
Content | Proteins, mRNA, miRNA, lipids | Proteins, mRNA, miRNA, lipids | Cell organelles, proteins, nuclear fractions, DNA, coding and noncoding RNA, lipids | [3] |
Extracellular vesicle biogenesis and release
Clearance and uptake of extracellular vesicles
Detection
Method | Detection limit | Quantitative | Qualitative | Advantages | Limitations | Applicable to | Reference |
---|---|---|---|---|---|---|---|
Flow cytometry | 300 nm | Yes | Yes | Easily available, single particle counting, offers multi-antibody labeling of vesicles | Requires skilled staff, swarm detection, limitations in sizing of microvesicles, can miss small vesicles | Exosomesa, microvesicles and apoptotic bodies | [53] |
Nanoparticle tracking analysis | 50 nm | Yesb
| Yes | Short sample preparation, high resolution, and size determination of vesicles | Limited use of fluorescence, photo-bleachingc, can miss larger vesicles | Exosomes and microvesicles | [54] |
Dynamic light scattering | 5 nm | No | No | Size determination of vesicles and good reproducibility | Does not measure morphology or composition of vesicles | Exosomes, microvesicles, and apoptotic bodies | [55] |
Resistive pulse sensing | 70 nm | Yes | No | Is semi-quantitative and enables single vesicle detection | Does not measure morphology or composition of vesicles, risk of pore clogging | Exosomes, microvesicles, and apoptotic bodies | [56] |
Transmission electron microscopy | ~1 nm | No | Yes | Multiple antibody labeling, high resolution, and structural analysis | Labor-intensive, requires extensive sample preparation and skilled staff, morphological changes of vesicles during sample preparation | Exosomes, microvesicles, and apoptotic bodies | [57] |
Atomic force microscopy | <1 nm | No | No | Relative size distribution of the vesicles, structural analysis, and high resolution | Extensive sample preparation, morphological changes of vesicles during sample preparation | Exosomes, microvesicles, and apoptotic bodies | |
Immunoblot | N/A | No | Yes | Vesicle content detection | Requires larger quantities. Does not distinguish between exosomes, microvesicles or soluble antigens | Exosomes, microvesicles, and apoptotic bodies | [60] |
ELISA | N/A | No | Yes | Vesicle content detection and quantification | Can only measure captured vesicles, and requires larger quantities. Does not distinguish between exosomes, microvesicles or soluble antigens | Exosomes, microvesicles, and apoptotic bodies | [61] |
Proteomics | N/A | No | Yes | Quantifiable proteomic analysis of vesicle content | Does not distinguish between exosomes, microvesicles or soluble antigens. Time-consuming | Exosomes, microvesicles, and apoptotic bodies | [62] |
Flow cytometry
Transmission electron microscopy
Nanoparticle tracking analysis
Extracellular vesicles in physiological and pathological processes
Intercellular communication
Extracellular vesicles in cell signaling
Transfer of receptors
Transfer of proteins and lipids
Transfer of mRNA and microRNA
Protection against stress and cell death
Coagulation and thrombosis
Angiogenesis
Immune modulation
Malignancies
Inflammation
Anti-microbial effects
Extracellular vesicles as biomarkers and promoters of kidney disease
Renal disease | Presence in bodily fluid or tissue | Type of extracellular vesicle | Cell of origin | Importance | References | ||
---|---|---|---|---|---|---|---|
Biomarker | Association with pathophysiology or beneficial effect | ||||||
AKI/sepsis | Blood | EVa or MV | P, E, L | +b
| |||
ns | May induce proteinuria and renal failure | ||||||
P, E | Induce vessel reactivity | [138] | |||||
E | Proadhesive (PECAM-1, endoglin-positive) in association with DIC | [139] | |||||
E | Levels of EVs correlate inversely with survival | ||||||
N | Antimicrobial properties | ||||||
Bone marrow, blood, and tissue | Ex and MV | MSCsc and renal progenitor cells | EVs have regenerative properties during AKI | ||||
Urine | Ex or EV | ns | +d
| ||||
CKD or ESRF | Blood | EV | P, L, RBC, E | + | |||
P, E | Pro-thrombotic | ||||||
E | Correlate with vascular dysfunction | ||||||
E | Predict cardiovascular disease | [158] | |||||
Urine | Ex | +e
| |||||
TMA | STEC-HUS | Blood | MV | P | C3 and C9f
| Pro-thrombotic (TF- and PS-positive) | |
RBC | Partake in hemolysis | [23] | |||||
P, N, M | Transfer Shiga toxin to the kidneys | [22] | |||||
aHUS | Blood | MV | P | Pro-thrombotic (TF- and PS-positive) | [161] | ||
TTP | Blood | MV | P | Associated with calpain activity | [162] | ||
E | C3 and C9f
| Pro-coagulant and proadhesive (VWF, CD62E, ICAM-1, PECAM-1, endoglin-positive) | |||||
Vasculitis | Blood | MV | P, N, E | +g
| |||
N | PS-, TF-, selectin-, integrin-, PR3- and MPO-positive | ||||||
N or ns | Pro-thrombotic | ||||||
N | Bind C1qf
| [168] | |||||
N | Activate endothelial cells and monocytes | [167] | |||||
Blood and kidney | N | Transfer the kinin B1 receptor to endothelial cells inducing inflammation | [71] | ||||
Blood | E | Induce neutrophil chemotaxis | [127] | ||||
IgA nephropathy | Urine | MV and Ex | RBC | +h
| |||
Nephrotic syndrome | Blood | EV | RBC, E, P | Pro-thrombotic (PS-positive) | [175] | ||
MV | E, M | May contribute to albuminuriai
| |||||
Urine | MV and Ex | Pod | +j
| ||||
Urinary tract infection/urosepsis | Blood | MV | ns | Pro-thrombotic (TF-positive) | [181] | ||
Urine | Ex | Antimicrobial properties | [131] | ||||
Tubulopathies | Bartter syndrome | Urine | Ex | + | |||
Gitelman syndrome | Urine | Ex | + | [184] | |||
Diabetes insipidus | Urine | EV | ns | Aquaporin-2 and its response to vasopressin differ in NDI vs CDI | [185] | ||
ADPKD | Urine | Ex | +k
| [186] | |||
Inverse correlation of the polycystin-1 or polycystin-2/transmembrane 2 ratios with kidney volume | [187] | ||||||
Exosomes interacted with primary cilia of renal epithelial cells | [188] | ||||||
Hypertension | Blood | EV | P, E | +l
| [189] | ||
MV | E | Indicate vascular injury | [190] | ||||
EV | E | Elevated in patients with microalbuminuria | [191] | ||||
Urine | EV | ns | + | [182] | |||
Pod | +m
| [192] | |||||
Renal transplantation | Blood | MV | P, L, RBC | +n
| TF activity decreases after transplantation | [193] | |
Ex | Antigen-presenting vesicles activate anti-donor T cells | [194] | |||||
Ex | E | Transfer of CMV antigens | [195] | ||||
MV | P, E | Treatment with ATG and calcineurin inhibitors induces the release of complement-coated MVs | |||||
Urine | MV | CD133+ nephron-derived | + | Delayed graft function and vascular injury | [198] | ||
Ex | +o
| [199] | |||||
Ex | + | NGAL marker of delayed graft function | |||||
Ex | + | Decreased aquaporin 1 indicative of ischemia–reperfusion injury | [202] | ||||
Kidney | MV | P | + | Platelets and platelet-derived MVs at sites of endothelial damage | [203] | ||
SLE | Blood | EV | E or ns | +p
| Contribute to immune complex deposition and complement activation | ||
MV | P | Prothrombotic | [206] | ||||
Urine | Ex | miRNA 29 correlated inversely with renal fibrosis | [207] | ||||
APS | Blood | MV | E | Pro-thrombotic | |||
Atherosclerosis | Blood | MV | E, P, L | Pro-thrombotic and proinflammatory | [210] | ||
Diabetes mellitus | Blood | EV | A, I, M | + | Beta cell metabolism, inflammation | [211] | |
MV | P, E, L | Pro-thrombotic, proinflammatory, correlated with arterial stiffness | |||||
Urine | Ex | Urinary exosomal regucalcin decreased in diabetic nephropathy | [216] | ||||
Ex | + | mRNA and protein markers of diabetic nephropathy |