Proteomic Research of Extracellular Vesicles in Clinical Biofluid
Abstract
:1. Introduction
2. The Features of EVs
3. An Overview of the EV Biology in Disease Context
3.1. Cancer Progression
3.2. Immune Response Modulation
3.3. Neurodegenerative Disease
3.4. Viral Infection
4. Methods of EV Isolation
4.1. Conventional Approaches for the Isolation of EVs
4.2. Advanced Approaches for the Isolation of EVs
4.2.1. Asymmetric Flow Field Flow Fraction, AF4
4.2.2. Microfluidic-Based Technologies
4.2.3. Dichotomic SEC
4.2.4. Ultrafast-Isolation System, EXODUS
4.2.5. EV Enrichment Device, EVrich
4.2.6. Commercial Exosome Isolation Kits
4.2.7. Others
5. -Omics Approaches to Study EV in Clinical Biofluid
The Role of -Omics Methods in Clinical Applications of EVs
Source | Biomarker | Isolation Method/Identification Method | Screening Method/Verification Method | Disease | Ref. |
---|---|---|---|---|---|
Serum | COPB2↑ | Filter column/WB, SEM | LC-MS/MS/WB, ELISA | COVID-19 | [140] |
Plasma and serum | HSP90A↑, STIP1↑, TAGLN-2↑ | Ultrafiltration, differential centrifugation, density gradient centrifugation/TEM, NTA, WB, LVSEM | LC-MS/MS/WB | Adenomyosis | [141] |
Plasma | PKG1↑, RALGAPA2↑, TJP2↑ | Ultracentrifugation/WB | LC-MS/MS/PRM | Breast Cancer | [142] |
Plasma | TSPAN1↑ | Differential centrifugation, ExoQuick®/TEM, NTA, WB | LC-MS/MS/WB, ELISA | Colon Cancer | [143] |
Serum | GCLM↓, KEL↑, APOF↑, CFB↓, PDE5A↓, ATIC↓ | Size-exclusion chromatography/TEM, WB | LC-MS/MS/NA | Colon Cancer | [43] |
Blood | ORM1 | NA/NA | Large-scale targeted proteomics analysis/NA | Colon Cancer | [144] |
Serum | Stratifin↑ | Size-exclusion chromatography, exoEasy kit/TEM, NTA, WB | LC-MS/MS (TMT)/ELISA | Colon Cancer | [45] |
Serum | Annexin A3↑, A4↑, and A11↑ | Differential ultracentrifugation, density gradient centrifugation/NA | LC-MS/MS (SRM)/NA | Colon Cancer | [145] |
Serum | TRIM3↓ | ExoQuick®/WB, TEM, NTA, | LC-MS/MS/ELISA, WB | Gastric Cancer | [146] |
Plasma | TGFβ1↑ | Extracellular vesicles enrichment kit/TEM, NTA, WB | LC-MS/MS(TMT)/ELISA | Head and Neck Squamous Cell Carcinoma | [147] |
Serum | AMPN↑, PIGR↑, VNN↑ | Filtration, ultracentrifugation/TEM, NTA, WB | LC-MS/MS/WB | Liver Cancer | [148] |
Plasma | SRGN↑, TPM3↑, THBS1↑, HUWE1↑ | Density gradient flotation/TEM, NTA, WB | LC-MS/MS/WB | Lung Cancer | [149] |
Serum | CD5L↑ | Precipitation and magnetic-based immunoaffinity/TEM, NTA, WB, DLS | MALDI-TOF-MS/WB | Lung Cancer | [150] |
Serum | CD91↑ | MSIA monolith tips/NA | LC-MS/MS/ELISA | Lung Cancer | [151] |
Serum | α-synuclein↑, Clusterin↑ | Immunoaffinity/SEM, NTA, WB | LC-MS/MS/electrochemiluminescence | Parkinson’s Disease | [152] |
Serum | Syntenin-1↑ | Ultracentrifugation/NTA, EM, WB | LC-MS/MS/WB | Parkinson’s Disease | [153] |
Plasma | IgG↑, IgM↑, C1q↑ | Immunoaffinity/flow cytometry | LC-MS/MS/NA | Systemic Lupus Erythematosus | [154] |
Plasma | G3BP↑, TGFβ1↓ | Centrifugation/NA | LC-MS/MS/NA | Systemic Lupus Erythematosus | [155] |
Urine | Hsp 90↑, syndecan-1↑, MARCKS↑, ZO-2↑ | Gradient density ultracentrifugation, differential ultracentrifugation/TEM, NTA, WB | LC-MS/MS(TMT/SRM/MRM)/immunohistochemical | Bladder Cancer | [156] |
Urine | EHD4↑, EPS8L1↑, EPS8L2↑, GBP3↑, GsGTPa↑, GTPase Nras↑, MUC4↑, RAI3↑, Resistin↑ | Ultracentrifugation/WB | LC-MS/MS/WB | Bladder Cancer | [157] |
Urine | APOA1↑, TTR↑, PIGR↑, HPX↑, AZGP1↑, CP↑ | Differential ultracentrifugation/protein concentration | LC-MS/MS (DDA)/WB | Chronic Active Antibody-Mediated Rejection | [158] |
Urine | Calbindin↑, SNAP23↑ | Ultracentrifugation/NTA, TEM, WB | LC-MS/MS/WB | Parkinson’s Disease | [159] |
Urine | AGP1↑ | Differential ultracentrifugation/TEM, NTA, WB | LC-MS/MS/WB | Primary Aldosteronism | [160] |
Urine | AQP1↓, CAIX↑, CD10↓, CD147↓, CP↑, DKK4↑, DPEP1↓, MMP9↑, PODXL↑, Syntenin-1↓ | Differential centrifugation, density gradient ultracentrifugation, ultrafiltration/TEM, WB, NTA | LC-MS/MS/WB | Renal Cancer | [161] |
Saliva | BASP1↑, NUCB2↑, PSMA7↑, PSMB7↑, TKT↑, TLN1↑, WDR1↑ | Centrifugation, exosome isolation kit/EM, WB | LC-MS/MS/WB | Inflammatory Bowel Disease/Ulcerative Colitis/Crohn’s Disease | [162] |
Tear and Saliva | STOM↑, ANXA4↑, ANXA1↑ | Size-exclusion chromatography/NTA, flow cytometry | LC-MS/MS/NA | Primary Sjögren’s Syndrome | [163] |
Source | Type | Biomarker | Isolation Method/Identification Method | Screening Method/Verification Method | Disease | Ref. |
---|---|---|---|---|---|---|
Serum | circular RNAs | Chr10q11↑, Chr1p11↑, Chr7q11↑ | exoRNeasy Midi kit, ultracentrifugation/TEM, NTA, WB | RNA Seq/RT-qPCR | Gastric Cancer | [164] |
Plasma | circRNAs↑ | Differential centrifugation/cryo-EM, NTA | RNA-Seq/NA | Multiple Sclerosis | [165] | |
Serum | long non-coding RNAs | HULC↑ | Ultracentrifugation/- | Microarray/RT-qPCR | Pancreatic Cancer | [166] |
Serum | LINC00853↑ | ExoQuick/TEM, NTA, WB | RNA Seq/RT-qPCR | Hepatocellular Carcinoma | [167] | |
Plasma | RP3-399L15.2↓, CH507-513H4.6↓ | exoRNeasy/TEM, NTA, WB | RNA Seq/RT-qPCR | Endometriosis | [168] | |
Plasma | exLR | NFKBIA↑, NDUFB10↑, SLC7A7↑, ARPC5↑, SEPTIN9↑, etc. | Ultracentrifugation/TEM, NTA, WB | RNA Seq/RT-qPCR | Lung Cancer | [169] |
Plasma | microRNAs | hsa-miR-106b-3p↑, hsa-miR-125a-5p↑, hsa-miR-3615↑, et al. | Ultracentrifugation/TEM, NTA, WB | RNA Seq/RT-qPCR | Lung Cancer | [170] |
Plasma | hsa-miR-186-5p↑, hsa-miR-200c-3p↑, hsa-miR-429↑, etc. | SEC/TEM, NTA, WB | RNA Seq/RT-qPCR | Gastric Cancer | [171] | |
Plasma | long RNAs | hsa-miR-483-5p↑ | Total Exosome Isolation Kit, differential ultracentrifugation/TEM, DLS, flowcytometry | Microarray/RT-qPCR | Adrenocortical Tumors | [172] |
Plasma | microRNAs | microRNA-29a↑ | Differential centrifugation, density gradient centrifugation/TEM, NTA, WB | RNA Seq/ddPCR | Chronic Methamphetamine Use Disorder | [173] |
Serum | MicroRNA-431-5p↑ | Differential centrifugation/TEM, NTA, WB | Microarray/RT-qPCR | Diabetic Retinopathy | [174] | |
Plasma | microRNA-491-5p↑ | ExoQuick/TEM, NTA, WB | NanoString miRNAs analysis/RT-qPCR | Head and Neck Squamous Cell Carcinoma | [175] | |
Plasma | miR-101↓ | Differential centrifugation/TEM, NTA, WB | RNA Seq/RT-qPCR | Osteosarcoma | [176] | |
Plasma | miR-101-3p↓, miR-150-5p↑ | Precipitation/TEM, NTA, WB, ExoView | RNA Seq/RT-qPCR | Lung Cancer | [177] | |
Plasma | miR-103a-3p↑, miR-30e-3p↓ | Ultracentrifugation/TEM, NTA, flow cytometry | OpenArray/RT-qPCR | Malignant Pleural Mesothelioma | [178] | |
Serum | miR-122-5p↑, miR-2110↑, miR-483-5p↑; miR-370-3p↓, miR-409-3p↓, etc. | miRCURY/NA | RNA-Seq/RT-qPCR- | Atherosclerosis | [179] | |
Serum | miR-1246↑ | SEC/TEM, NTA | Microarray/RT-qPCR | Gallbladder Cancer | [180] | |
Plasma | miR-127-3p↓, miR-155-5p↓, miR-21-5p↓, miR-24-3p↓, let-7a-5p↓ | SEC/NA | RNA Seq/RT-qPCR | Classical Hodgkin Lymphoma | [181] | |
Plasma | miR-134-5p↓, miR-205-5p↑, miR-409-3p↓ | SEC/TEM, NTA, WB | RNA Seq/RT-qPCR | Nasopharyngeal Carcinoma | [182] | |
Plasma | miR-181a↑, miR-1908↑, miR-21↑, miR-486↑, miR-223↑ | ExoQuick, exoRNeasy/NA | RNA Seq/NA | Ovarian Cancer | [183] | |
Serum | miR-181a-5p↑ | Total exosome isolation kit/TEM, NTA, WB | Microarray/RT-qPCR | Prostate Cancer | [184] | |
Serum | miR-21-5p’(3′ addition C)↑, miR-23a-3p↑, tRF-Lys↑ | Total exosome isolation kit/TEM, NTA, WB | RNA Seq/NA | Breast Cancer | [185] | |
Serum | miR-223↑, let-7e-5p↑, miR-486-3p↑, etc. | ExoQuick/TEM, NTA, flowcytometry | RNA Seq/RT-qPCR | Acute Rejection | [186] | |
Plasma | miR-22-3p↑, miR-99a-5p↑, miR-151a-5p↑, miR-320b↑, miR-320d↑, etc. | ExoQuick, Exo-Spin/TEM, NTA, tunable resistive pulse sensing, WB | RNA Seq/RT-qPCR | Chronic Obstructive Pulmonary Disease | [187] | |
Serum | miR-342-3p↑, miR-1254↓ | ExoChip/SEM, NTA, WB | NanoString miRNAs Analysis/NA | Sporadic Amyotrophic Lateral Sclerosis | [100] | |
Plasma | miR-92b-3p↑, miR-374a-5p↑, miR-106b-3p↑ | miRCURY/NTA, TEM, WB | RNA Seq/RT-qPCR | Chronic Obstructive Pulmonary Disease | [188] | |
Plasma | miRNA-152-3p↑, miRNA-1277-5p↑ | SEC/NTA, TEM, WB | RNA Seq/RT-qPCR | Lung Cancer | [189] | |
Serum | miRNA-21↑ | ExoQuick/NTA, WB | miRNA array/RT-qPCR | Chronic Lung Disease | [190] | |
Plasma | miRNAs, miR-500a-3p↑, miR-501-3p↑, miR-502-3p↑ | 3D medicine isolation reagent, polyethylene glycol-based method/NTA, SEM, WB | RNA Seq/NA | Pulmonary Ground-Glass Nodules | [191] | |
Plasma | Let-7b-5p↑, miR-184↓, circulating miR-22-3p↓ | SEC/NTA, EM, WB | RNA Seq/RT-qPCR | Lung Cancer | [192] | |
Plasma | let-7e↑ | Norgen plasma, serum exosome purification mini kit/WB | RNA Seq/RT-qPCR | Alzheimer’s Disease | [193] | |
Plasma | let-7i-5p↑ | ExoQuick/TEM, NanoFCM, WB | RNA Seq/RT-qPCR | Asthma | [194] | |
Serum | piRNAs | DQ593039↑ | Total exosome isolation reagent, exoEasy kit/TEM, NTA, WB | RNA Seq/RT-qPCR | Pulmonary Hypertension | [195] |
CSF | microRNAs | miR-21↑ | miRCURY/TEM, NanoFCM, WB | RNA Seq/ddPCR | Leptomeningeal Metastasis | [196] |
Urine | microRNAs | hsa-miR-193b-3p↓, hsa-miR-8485↓ | miRCURY/ExoView | miRNA Seq/NA | Acute Exercise-Induced Fatigue | [197] |
Neurosurgical aspirate fluids | microRNAs | miR-486-3p↑ | Ultracentrifugation/TEM, NTA, WB | RNA Seq/NA | Glioblastoma | [198] |
TDV | microRNAs | miR-203a-3p↑ | Ultracentrifugation/TEM, NTA, WB | RNA Seq/RT-qPCR | Lung Cancer | [199] |
6. The Identification of EVs
7. The Proteomic Profile Workflow of EVs in Clinical Investigation
8. Challenges for Proteomics of EVs in Clinical Investigation
9. Recent Progress and Future Directions in EV Proteomics
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
References
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Feature | Exosome | Microvesicle | Apoptotic Body |
---|---|---|---|
Size (nm) | 40–150 | 150–1000 | 1000–5000 |
Density (g/mL) | 1.13–1.19 | 1.25–1.30 | 1.16–1.28 |
Origin | Living cell | Living cell | Dying cell |
Process | Releasing ILVs during plasma membrane fusion of MVBs | Budding from the plasma membrane directly | Blebbing from the plasma membrane during cell apoptosis |
Contents | Nucleic acid, protein, lipid, etc. | Nucleic acid, protein, lipid, etc. | Fragments of the cellular components |
Markers [28] | CD63, TSG101, Alix, HSP70, etc. | Integrins, selections, CD40 | Histones, TSP, C3b |
Clinical application | Diagnosis, therapy [1,29] | Diagnosis, therapy [27,30] | Emerging [31] |
Biomarker and therapeutic research ^ | High [32] | Medium [15] | Low [31,33] |
Method | Yield | Purity | Time | Workload | Price | Practice |
---|---|---|---|---|---|---|
Conventional approaches | ||||||
Differential ultracentrifugation | High | Medium | Long | >100 mL | Low | Easy |
Ultrafiltration | High | Low | Medium | >100 mL | Medium | Easy |
Tangential flow filtration | High | Medium | Medium | >100 mL | Medium | Medium |
Size-exclusion chromatography | Low | Medium | Short | Up to a few mL | Medium | Easy |
Density gradient ultracentrifugation | Low | High | Long | Up to 1 mL | Medium | Medium |
Precipitation | High | Low | Medium | >100 µL | Low | Easy |
Affinity | Low | High | Long | Up to 1 mL | High | Medium |
Advanced approaches | ||||||
AF4 | Low | High | Medium | 100 µL | / # | Medium |
Microfluidic-based technologies | Low | High | - * | >10 µL | High | Medium |
Dichotomic SEC | Medium | High | Short | 20 mL | Medium | Easy |
EXODUS | High | High | Short | >100 mL | Medium | Easy |
EVrich | - * | High | - * | / # | / # | Easy |
Commercial EV isolation kits | High | High | Various | Various | High | Easy |
Commercial Exosomes Isolation Kits | Separation Principle | Company | Cat. No. |
---|---|---|---|
Capturem | Affinity, lectin | Takara | 635741 |
EasySep | Affinity, antibody | Stem Cell | 100-0812 |
exoEasy | Affinity, membrane-based | Qiagen | 76064 |
ExoPure | Precipitation | Abcam | ab287883 |
ExoQuick | Precipitation | System Biosciences | EXOQ20A-1 |
Exo-spin | Size-exclusion chromatography | Cell Guidance Systems | EX05 |
ExoSure | Size-exclusion chromatography | Gene Copoeia | EP001 |
Hieff | Precipitation | YEASEN | 41201ES25 |
MagCapture | Affinity, phosphatidylserine | FUJIFILM Wako | 290-84103 |
miRCURY | Precipitation | Qiagen | 76603 |
PureExo | Precipitation | 101Bio | P101 |
Total Exosome Isolation Reagent | Precipitation | Invitrogen | 4478359 |
Omics | Subject | Current Challenges |
---|---|---|
Genomics | DNA [116] | The DNA of EVs is still difficult to preserve and isolate [117]. |
Epigenomics | DNA [118] | The interpretation of the data from dynamic and specific tissue [119]. |
Transcriptomics | RNA | A relatively robust method has been studied in high throughput even at a single EV level [120]. Now, analysis is the bottleneck. |
Proteomics | Protein | Comprehensive, reproducible, and accurate data depends on the purity of EVs [121]; sensitivity and throughput. |
Metabolomics/Lipidomics/Glycomics | Metabolite [122]/Lipid [123]/Glycan [124] | The sensitivity, reproducibility, robustness, speed, and accuracy; the investigation of EV subpopulation; comprehensive analysis. |
Challenges | Future Directions |
---|---|
1. The heterogeneity of EVs. | Applying integrated module approaches at a single EV level. |
2. The purity of EVs. | Selecting the most appropriate approach for each specific research scenario and sample type. |
3. The identification methods of EVs. | Considering reproducible and accurate approaches. |
4. The proteome coverage of EVs by LC/ESI-MS/MS and DDA/DIA. | Alternative data analysis strategies according to set parameters with robust bioinformatic tools. |
5. The PTM-proteome of EVs. | High capture efficiency of enrichment strategy. |
6. Tradeoffs between throughput and depth of LC-MS/MS. | Robust, automated, and high-throughput workflow. |
7. Systems biology overview of the EVs function. | Advanced computational and biological algorithms. |
8. Final biological effects validation in EVs. | A routine research workflow between labs and collaborative efforts from many different fields. |
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Fan, S.; Poetsch, A. Proteomic Research of Extracellular Vesicles in Clinical Biofluid. Proteomes 2023, 11, 18. https://doi.org/10.3390/proteomes11020018
Fan S, Poetsch A. Proteomic Research of Extracellular Vesicles in Clinical Biofluid. Proteomes. 2023; 11(2):18. https://doi.org/10.3390/proteomes11020018
Chicago/Turabian StyleFan, Shipan, and Ansgar Poetsch. 2023. "Proteomic Research of Extracellular Vesicles in Clinical Biofluid" Proteomes 11, no. 2: 18. https://doi.org/10.3390/proteomes11020018