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Biomolecules
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Extracellular Vesicles as Biomarkers of Diseases
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Extracellular Vesicles as Biomarkers of Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biomarkers".

Deadline for manuscript submissions: 15 January 2025 | Viewed by 11370

Special Issue Editors

Dr. Mebarek Saida

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Guest Editor
University Lyon, Université. Claude Bernard Lyon 1, CNRS UMR 5246, ICBMS, F-69622 Lyon, France
Interests: lipid signaling and signal transduction; prostate cancer; bone metastasis; vascular calcification; atherosclerosis; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals
Dr. Leyre Brizuela

E-Mail Website
Guest Editor
University Lyon, Université. Claude Bernard Lyon 1, CNRS UMR 5246, ICBMS, F-69622 Lyon, France
Interests: lipid signaling and signal transduction; prostate cancer; bone metastasis; vascular calcification; atherosclerosis; extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This issue aims at summarizing the most recent literature on extracellular vesicles (EVs) as disease biomarkers, as well as candidates for cell-free therapeutic approaches.

EVs (a terminology that encompasses microparticles, exosomes, and apoptotic bodies among others) are active players of cell-to-cell communication and convey fundamental information between cells. These microstructures contain proteins, lipids, and genetic information able to modify the phenotype and function of the target cells. EVs carry specific markers of the cell of origin, which could reveal the state of the cell and could be used to diagnose diseases. Indeed, EVs have attracted considerable interest in the metabolic diseases such as obesity or diabetes, in cardiovascular diseases field as reservoirs of molecules produced during arterial remodelling, in the pathogenesis of neuro-degenerative diseases such as Parkinson and Alzheimer’s diseases, but also in the cancer domain. In this Special Issue, we would like to receive experimental and clinical articles or reviews about how EVs can be identified as biomarkers of diseases.

Dr. Mebarek Saida
Dr. Leyre Brizuela
Guest Editors

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Keywords

  • extracellular vesicles
  • metabolic syndrome
  • cancer
  • cardiovascular diseases
  • neurodegenerative diseases
  • biomarkers

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Published Papers (7 papers)

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Research

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9 pages, 1627 KiB  
Communication
Untargeted Metabolomic Profiling of Extracellular Vesicles Isolated from Human Seminal Plasma
by Manesh Kumar Panner Selvam, Partha K. Chandra, Zahra Bakhtiary, David W. Busija and Suresh C. Sikka
Biomolecules 2024, 14(10), 1211; https://doi.org/10.3390/biom14101211 - 26 Sep 2024
Viewed by 666
Abstract
Seminal extracellular vesicles (SemEVs) are repositories of biomolecules, including metabolites involved in the regulation of sperm function. The correlation between the metabolite profile of SemEVs and semen parameters, along with their role in regulating sperm function, is an unexplored area. This preliminary study [...] Read more.
Seminal extracellular vesicles (SemEVs) are repositories of biomolecules, including metabolites involved in the regulation of sperm function. The correlation between the metabolite profile of SemEVs and semen parameters, along with their role in regulating sperm function, is an unexplored area. This preliminary study evaluated the metabolomic content of SemEVs. Semen samples were obtained from 18 healthy men, and SemEVs were extracted from seminal plasma using the size exclusion chromatography qEV Gen 2–35 nm column coupled with an automatic fraction collector. The physical characterization of SemEVs was carried out with the ZetaView PMX-430-Z QUATT laser system. EV protein markers were detected using Western blot. In addition, these SemEVs were used for metabolomic profiling and functional bioinformatic analysis. The mean concentration of isolated SemEVs was 1.7 ± 1.1 × 1011/mL of seminal plasma, whereas SemEVs size and zeta potential were 129.5 ± 5.5 nm and −40.03 ± 3.99 mV, respectively. Western blot analysis confirmed the presence of EV specific markers such as CD81, ALIX, and TSG101. A total of 107 metabolites were identified using this untargeted metabolomic approach in SemEVs. Bioinformatics analysis further revealed that metabolites associated with tyrosine metabolism were highly enriched in these SemEVs. Ingenuity Pathway Analysis (IPA) also indicated that these metabolites present in SemEVs were involved in the regulation of the free radical scavenging pathway. Furthermore, our metabolomic results suggest that these SemEV-associated metabolites may play a pivotal role in the maintenance of seminal plasma redox homeostasis. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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14 pages, 2405 KiB  
Article
Urinary Extracellular Vesicles for Non-Invasive Quantification of Principal Cell Damage in Kidney Transplant Recipients
by Per Svenningsen, Rima Maslauskiene, Yaseelan Palarasah, Inga A. Bumblyte and Martin Tepel
Biomolecules 2024, 14(9), 1124; https://doi.org/10.3390/biom14091124 - 5 Sep 2024
Viewed by 732
Abstract
The objective of the present study was to compare principal cell-specific aquaporin-2 (AQP2) abundances in urinary extracellular vesicles (uEVs) on the first postoperative day in deceased-donor kidney transplant recipients without and with acute kidney injury. We measured uEV markers (CD9 and CD63) and [...] Read more.
The objective of the present study was to compare principal cell-specific aquaporin-2 (AQP2) abundances in urinary extracellular vesicles (uEVs) on the first postoperative day in deceased-donor kidney transplant recipients without and with acute kidney injury. We measured uEV markers (CD9 and CD63) and the abundances of proximal tubular sodium-glucose transporter 2, distal tubular sodium/chloride cotransporter, and principal cell-specific aquaporin-2 using Western blotting of urine. uEV-AQP2 levels were normalized to living donor controls. The validation cohort consisted of 82 deceased-donor kidney transplant recipients who had a median age of 50 years (IQR 43 to 57 years). A total of 32% of recipients had acute kidney injury. The median uEV-AQP2 was significantly higher in recipients with acute kidney injury compared to immediate allograft function (2.05; IQR 0.87 to 2.83; vs. 0.81; IQR 0.44 to 1.78; p < 0.01). The Youden index indicated a uEV-AQP2 threshold of 2.00. Stratifying uEV-AQP2 into quartiles showed that recipients with higher uEV-AQP2 levels had higher rates of acute kidney injury (Cochran–Armitage, p = 0.001). The discovery cohort showed elevated CD9, CD63, and uEV-AQP2 levels in urine from recipients with acute kidney injury compared to immediate allograft function. We were able to quantify the damage of principal cells after kidney transplant to predict acute kidney injury using uEV-AQP2. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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14 pages, 8343 KiB  
Article
EGFR Mutation and TKI Treatment Promote Secretion of Small Extracellular Vesicle PD-L1 and Contribute to Immunosuppression in NSCLC
by Hai-Ming Liu, Zi-Li Yu, Hou-Fu Xia, Lin-Zhou Zhang, Qiu-Yun Fu, Yi Wang, Hong-Yun Gong and Gang Chen
Biomolecules 2024, 14(7), 820; https://doi.org/10.3390/biom14070820 - 9 Jul 2024
Viewed by 1196
Abstract
In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment [...] Read more.
In Asian populations with non-small-cell lung cancer (NSCLC), EGFR mutations are highly prevalent, occurring in roughly half of these patients. Studies have revealed that individuals with EGFR mutation typically fare worse with immunotherapy. In patients who received EGFR tyrosine kinase inhibitor (TKI) treatment followed by anti-PD-1 therapy, poor results were observed. The underlying mechanism remains unclear. We used high-resolution flow cytometry and ELISA to detect the circulating level of small extracellular vesicle (sEV) PD-L1 in NSCLC individuals with EGFR mutations before and after receiving TKIs. The secretion amount of sEV PD-L1 of lung cancer cell lines with EGFR mutations under TKI treatment or not were detected using high-resolution flow cytometry and Western blotting. The results revealed that patients harboring EGFR mutations exhibit increased levels of sEV PD-L1 in circulation, which inversely correlated with the presence of CD8+ T cells in tumor tissues. Furthermore, tumor cells carrying EGFR mutations secrete a higher quantity of PD-L1-positive sEVs. TKI treatment appeared to amplify the levels of PD-L1-positive sEVs in the bloodstream. Mutation-induced and TKI-induced sEVs substantially impaired the functionality of CD8+ T cells. Importantly, our findings indicated that EGFR mutations and TKI therapies promote secretion of PD-L1-positive sEVs via distinct molecular mechanisms, namely the HRS and ALIX pathways, respectively. In conclusion, the increased secretion of PD-L1-positive sEVs, prompted by genetic alterations and TKI administration, may contribute to the limited efficacy of immunotherapy observed in EGFR-mutant patients and patients who have received TKI treatment. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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14 pages, 1609 KiB  
Article
Circulating Small Extracellular Vesicles Reflect the Severity of Myocardial Damage in STEMI Patients
by Marta Zarà, Andrea Baggiano, Patrizia Amadio, Jeness Campodonico, Sebastiano Gili, Andrea Annoni, Gianluca De Dona, Maria Ludovica Carerj, Francesco Cilia, Alberto Formenti, Laura Fusini, Cristina Banfi, Paola Gripari, Calogero Claudio Tedesco, Maria Elisabetta Mancini, Mattia Chiesa, Riccardo Maragna, Francesca Marchetti, Marco Penso, Luigi Tassetti, Alessandra Volpe, Alice Bonomi, Giancarlo Marenzi, Gianluca Pontone and Silvia Stella Barbieriadd Show full author list remove Hide full author list
Biomolecules 2023, 13(10), 1470; https://doi.org/10.3390/biom13101470 - 29 Sep 2023
Cited by 3 | Viewed by 1569
Abstract
Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease. The ability of sEVs to reflect myocardial damage assessed by Cardiac Magnetic Resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) is unknown. [...] Read more.
Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease. The ability of sEVs to reflect myocardial damage assessed by Cardiac Magnetic Resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) is unknown. To fill this gap, plasma sEVs were isolated from 42 STEMI patients treated by primary percutaneous coronary intervention (pPCI) and evaluated by CMR between days 3 and 6. Nanoparticle tracking analysis showed that sEVs were greater in patients with anterior STEMI (p = 0.0001), with the culprit lesion located in LAD (p = 0.045), and in those who underwent late revascularization (p = 0.038). A smaller sEV size was observed in patients with a low myocardial salvage index (MSI, p = 0.014). Patients with microvascular obstruction (MVO) had smaller sEVs (p < 0.002) and lower expression of the platelet marker CD41–CD61 (p = 0.039). sEV size and CD41–CD61 expression were independent predictors of MVO/MSI (OR [95% CI]: 0.93 [0.87–0.98] and 0.04 [0–0.61], respectively). In conclusion, we provide evidence that the CD41–CD61 expression in sEVs reflects the CMR-assessed ischemic damage after STEMI. This finding paves the way for the development of a new strategy for the timely identification of high-risk patients and their treatment optimization. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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Review

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19 pages, 1359 KiB  
Review
Exosomes: Key Factors in Ovarian Cancer Peritoneal Metastasis and Drug Resistance
by Ming Shao, Yunran Gao, Xiling Xu, David Wai Chan and Juan Du
Biomolecules 2024, 14(9), 1099; https://doi.org/10.3390/biom14091099 - 2 Sep 2024
Viewed by 1225
Abstract
Ovarian cancer remains a leading cause of death among gynecological cancers, largely due to its propensity for peritoneal metastasis and the development of drug resistance. This review concentrates on the molecular underpinnings of these two critical challenges. We delve into the role of [...] Read more.
Ovarian cancer remains a leading cause of death among gynecological cancers, largely due to its propensity for peritoneal metastasis and the development of drug resistance. This review concentrates on the molecular underpinnings of these two critical challenges. We delve into the role of exosomes, the nano-sized vesicles integral to cellular communication, in orchestrating the complex interactions within the tumor microenvironment that facilitate metastatic spread and thwart therapeutic efforts. Specifically, we explore how exosomes drive peritoneal metastasis by promoting epithelial–mesenchymal transition in peritoneal mesothelial cells, altering the extracellular matrix, and supporting angiogenesis, which collectively enable the dissemination of cancer cells across the peritoneal cavity. Furthermore, we dissect the mechanisms by which exosomes contribute to the emergence of drug resistance, including the sequestration and expulsion of chemotherapeutic agents, the horizontal transfer of drug resistance genes, and the modulation of critical DNA repair and apoptotic pathways. By shedding light on these exosome-mediated processes, we underscore the potential of exosomal pathways as novel therapeutic targets, offering hope for more effective interventions against ovarian cancer’s relentless progression. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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14 pages, 2141 KiB  
Review
Emerging Roles of Extracelluar Vesicles Derived from Bacteria, Mammalian or Plant Cells in the Pathogenesis and Clinical Application of Neurodegenerative Diseases
by Yihong Li, Chenglong Zhou, Huina Liu, Ting Cai and Huadong Fan
Biomolecules 2024, 14(3), 312; https://doi.org/10.3390/biom14030312 - 6 Mar 2024
Cited by 1 | Viewed by 2329
Abstract
A growing number of studies have indicated that extracellular vesicles (EVs), such as exosomes, are involved in the development of neurodegenerative diseases. Components of EVs with biological effects like proteins, nucleic acids, or other molecules can be delivered to recipient cells to mediate [...] Read more.
A growing number of studies have indicated that extracellular vesicles (EVs), such as exosomes, are involved in the development of neurodegenerative diseases. Components of EVs with biological effects like proteins, nucleic acids, or other molecules can be delivered to recipient cells to mediate physio-/pathological processes. For instance, some aggregate-prone proteins, such as β-amyloid and α-synuclein, had been found to propagate through exosomes. Therefore, either an increase of detrimental molecules or a decrease of beneficial molecules enwrapped in EVs may fully or partly indicate disease progression. Numerous studies have demonstrated that dysbiosis of the gut microbiota and neurodegeneration are tightly correlated, well-known as the “gut–brain axis”. Accumulating evidence has revealed that the gut bacteria-derived EVs play a pivotal role in mediating microbe–host interactions and affect the function of the “gut–brain axis”, which subsequently contributes to the pathogenesis of neurodegenerative diseases. In this review, we first briefly discuss the role of EVs from mammalian cells and microbes in mediating the progression of neurodegenerative diseases, and then propose a novel strategy that employs EVs of plants (plant cell-derived exosome-like nanoparticles) for treating neurodegeneration. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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20 pages, 2745 KiB  
Review
Do Media Extracellular Vesicles and Extracellular Vesicles Bound to the Extracellular Matrix Represent Distinct Types of Vesicles?
by Saida Mebarek, Rene Buchet, Slawomir Pikula, Agnieszka Strzelecka-Kiliszek, Leyre Brizuela, Giada Corti, Federica Collacchi, Genevieve Anghieri, Andrea Magrini, Pietro Ciancaglini, Jose Luis Millan, Owen Davies and Massimo Bottini
Biomolecules 2024, 14(1), 42; https://doi.org/10.3390/biom14010042 - 28 Dec 2023
Cited by 2 | Viewed by 2544
Abstract
Mineralization-competent cells, including hypertrophic chondrocytes, mature osteoblasts, and osteogenic-differentiated smooth muscle cells secrete media extracellular vesicles (media vesicles) and extracellular vesicles bound to the extracellular matrix (matrix vesicles). Media vesicles are purified directly from the extracellular medium. On the other hand, matrix vesicles [...] Read more.
Mineralization-competent cells, including hypertrophic chondrocytes, mature osteoblasts, and osteogenic-differentiated smooth muscle cells secrete media extracellular vesicles (media vesicles) and extracellular vesicles bound to the extracellular matrix (matrix vesicles). Media vesicles are purified directly from the extracellular medium. On the other hand, matrix vesicles are purified after discarding the extracellular medium and subjecting the cells embedded in the extracellular matrix or bone or cartilage tissues to an enzymatic treatment. Several pieces of experimental evidence indicated that matrix vesicles and media vesicles isolated from the same types of mineralizing cells have distinct lipid and protein composition as well as functions. These findings support the view that matrix vesicles and media vesicles released by mineralizing cells have different functions in mineralized tissues due to their location, which is anchored to the extracellular matrix versus free-floating. Full article
(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers of Diseases)
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