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Extracellular Vesicles: From Biomarkers to Therapeutic Tools
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Extracellular Vesicles: From Biomarkers to Therapeutic Tools

A topical collection in Biology (ISSN 2079-7737). This collection belongs to the section "Cell Biology".

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Editors

Dr. Simona Bernardi

E-Mail Website
Collection Editor
Department Clinical and Experimental Sciences, University of Brescia, Viale Europa 11 (Brescia) Chair di Hematology, Unit of Bone Marrow Transplantation, ASST-Spedali Civili of Brescia, Brescia, Italy
Interests: acute myeloid leukemia (AML); chronic myeloid leukemia (CML); familiarity and genetic predisposition in hematologic malignancies; next generation sequencing (NGS); digital PCR (dPCR); exosomes and extracellular vesicles; liquid biopsy; zebrafish model; mesenchymal and hematopoietic stem cells (MSCs and HSCs); regenerative medicine; circulating endothelial cells (CEC)
Dr. Carolina Balbi

E-Mail Website
Collection Editor
Cellular & molecular Cardiology Laboratory, Cardiocentro Ticino, Associated Institute of University of Zurich, Lugano, Switzerland
Interests: myocardial infarction (MI); drug cardiotoxicity; amniotic fluid stem cells (AFS); mesenchymal stem cells (MSC); cardiac progenitor cells (CPC); regenerative medicine; paracrine therapy; exosome and extracellular vesicles; biomarkers

Topical Collection Information

Dear Colleagues,

Intercellular communication is an essential hallmark of multicellular organisms and can be mediated through direct cell–cell contact or transfer of secreted molecules. In the last two decades, a third mechanism for intercellular communication has emerged that involves intercellular transfer of extracellular vesicles (EVs).

EVs are membranous vesicles of 30–5000 nm in size. Based on their dimension and biogenesis, EVs can be divided into different categories, such as microvesicles, apoptotic bodies, ectosomes, and exosomes. It has already been demonstrated that changing in protein, expressed on surfaces or content in these vesicles, may reflect the status of producing cells. For this reason, EVs, and exosomes in particular, are considered ideal biomarkers in several types of disease from cancer diagnosis to heart rejection. Furthermore, extracellular vesicles can be carriers of cytoprotective or cytotoxic factors and used as a therapeutic tool applied from regenerative medicine to target cancer therapy.

This Topical Collection focuses on recent findings pertaining to EV in different areas from biomarkers to therapeutic application. We warmly welcome experts to submit previously unpublished original scientific research with novel findings and reviews with a comprehensive overview of EVs.

Dr. Simona Bernardi
Dr. Carolina Balbi
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • extracellular vesicles
  • exosomes
  • biomarkers
  • drug carrier
  • solid and hematologic malignancies
  • extracellular vesicle engineering
  • extracellular vesicle isolation
  • extracellular vesicle characterization
  • regenerative medicine
  • liquid biopsy
  • cell–cell communication

Published Papers (12 papers)

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2021

Jump to: 2020

15 pages, 669 KiB  
Review
Diagnostic Impact of Radiological Findings and Extracellular Vesicles: Are We Close to Radiovesicolomics?
by Francesco Lorenzo Serafini, Paola Lanuti, Andrea Delli Pizzi, Luca Procaccini, Michela Villani, Alessio Lino Taraschi, Luca Pascucci, Erica Mincuzzi, Jacopo Izzi, Piero Chiacchiaretta, Davide Buca, Giulia Catitti, Giuseppina Bologna, Pasquale Simeone, Damiana Pieragostino and Massimo Caulo
Biology 2021, 10(12), 1265; https://doi.org/10.3390/biology10121265 - 03 Dec 2021
Cited by 3 | Viewed by 2184
Abstract
Currently, several pathologies have corresponding and specific diagnostic and therapeutic branches of interest focused on early and correct detection, as well as the best therapeutic approach. Radiology never ceases to develop newer technologies in order to give patients a clear, safe, early, and [...] Read more.
Currently, several pathologies have corresponding and specific diagnostic and therapeutic branches of interest focused on early and correct detection, as well as the best therapeutic approach. Radiology never ceases to develop newer technologies in order to give patients a clear, safe, early, and precise diagnosis; furthermore, in the last few years diagnostic imaging panoramas have been extended to the field of artificial intelligence (AI) and machine learning. On the other hand, clinical and laboratory tests, like flow cytometry and the techniques found in the “omics” sciences, aim to detect microscopic elements, like extracellular vesicles, with the highest specificity and sensibility for disease detection. If these scientific branches started to cooperate, playing a conjugated role in pathology diagnosis, what could be the results? Our review seeks to give a quick overview of recent state of the art research which investigates correlations between extracellular vesicles and the known radiological features useful for diagnosis. Full article
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18 pages, 1149 KiB  
Review
Extracellular Vesicles in Regeneration and Rehabilitation Recovery after Stroke
by Alice Gualerzi, Silvia Picciolini, Francesca Rodà and Marzia Bedoni
Biology 2021, 10(9), 843; https://doi.org/10.3390/biology10090843 - 30 Aug 2021
Cited by 7 | Viewed by 3376
Abstract
Patients that survive after a stroke event may present disabilities that can persist for a long time or permanently after it. If stroke prevention fails, the prompt and combinatorial intervention with pharmacological and rehabilitation therapy is pivotal for the optimal recovery of patients [...] Read more.
Patients that survive after a stroke event may present disabilities that can persist for a long time or permanently after it. If stroke prevention fails, the prompt and combinatorial intervention with pharmacological and rehabilitation therapy is pivotal for the optimal recovery of patients and the reduction of disabilities. In the present review, we summarize some key features of the complex events that occur in the brain during and after the stroke event, with a special focus on extracellular vesicles (EVs) and their role as both carriers of biomarkers and potential therapeutics. EVs have already demonstrated their ability to be used for diagnostic purposes for multiple brain disorders and could represent valuable tools to track the regenerative and inflammatory processes occurring in the injured brain after stroke. Last, but not least, the use of artificial or stem cell-derived EVs were proved to be effective in stimulating brain remodeling and ameliorating recovery after stroke. Still, effective biomarkers of recovery are needed to design robust trials for the validation of innovative therapeutic strategies, such as regenerative rehabilitation approaches. Full article
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14 pages, 834 KiB  
Review
Interplay between Hypoxia and Extracellular Vesicles in Cancer and Inflammation
by Marta Venturella, Mattia Criscuoli, Fabio Carraro, Antonella Naldini and Davide Zocco
Biology 2021, 10(7), 606; https://doi.org/10.3390/biology10070606 - 30 Jun 2021
Cited by 11 | Viewed by 3090
Abstract
Hypoxia is a severe stress condition often observed in cancer and chronically inflamed cells and tissues. Extracellular vesicles play pivotal roles in these pathological processes and carry biomolecules that can be detected in many biofluids and may be exploited for diagnostic purposes. Several [...] Read more.
Hypoxia is a severe stress condition often observed in cancer and chronically inflamed cells and tissues. Extracellular vesicles play pivotal roles in these pathological processes and carry biomolecules that can be detected in many biofluids and may be exploited for diagnostic purposes. Several studies report the effects of hypoxia on extracellular vesicles’ release, molecular content, and biological functions in disease. This review summarizes the most recent findings in this field, highlighting the areas that warrant further investigation. Full article
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16 pages, 1692 KiB  
Review
Bone Regeneration Improves with Mesenchymal Stem Cell Derived Extracellular Vesicles (EVs) Combined with Scaffolds: A Systematic Review
by Federica Re, Elena Gabusi, Cristina Manferdini, Domenico Russo and Gina Lisignoli
Biology 2021, 10(7), 579; https://doi.org/10.3390/biology10070579 - 24 Jun 2021
Cited by 13 | Viewed by 3634
Abstract
Scaffolds associated with mesenchymal stem cell (MSC) derivatives, such as extracellular vesicles (EVs), represent interesting carriers for bone regeneration. This systematic review aims to analyze in vitro and in vivo studies that report the effects of EVs combined with scaffolds in bone regeneration. [...] Read more.
Scaffolds associated with mesenchymal stem cell (MSC) derivatives, such as extracellular vesicles (EVs), represent interesting carriers for bone regeneration. This systematic review aims to analyze in vitro and in vivo studies that report the effects of EVs combined with scaffolds in bone regeneration. A methodical review of the literature was performed from PubMed and Embase from 2012 to 2020. Sixteen papers were analyzed; of these, one study was in vitro, eleven were in vivo, and four were both in vitro and in vivo studies. This analysis shows a growing interest in this upcoming field, with overall positive results. In vitro results were demonstrated as both an effect on bone mineralization and proangiogenic ability. The interesting in vitro outcomes were confirmed in vivo. Particularly, these studies showed positive effects on bone regeneration and mineralization, activation of the pathway for bone regeneration, induction of vascularization, and modulation of inflammation. However, several aspects remain to be elucidated, such as the concentration of EVs to use in clinic for bone-related applications and the definition of the real advantages. Full article
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16 pages, 13298 KiB  
Review
Extracellular Vesicles as Promising Carriers in Drug Delivery: Considerations from a Cell Biologist’s Perspective
by Giona Pedrioli, Ester Piovesana, Elena Vacchi and Carolina Balbi
Biology 2021, 10(5), 376; https://doi.org/10.3390/biology10050376 - 27 Apr 2021
Cited by 20 | Viewed by 4877
Abstract
The use of extracellular vesicles as cell-free therapy is a promising approach currently investigated in several disease models. The intrinsic capacity of extracellular vesicles to encapsulate macromolecules within their lipid bilayer membrane-bound lumen is a characteristic exploited in drug delivery to transport active [...] Read more.
The use of extracellular vesicles as cell-free therapy is a promising approach currently investigated in several disease models. The intrinsic capacity of extracellular vesicles to encapsulate macromolecules within their lipid bilayer membrane-bound lumen is a characteristic exploited in drug delivery to transport active pharmaceutical ingredients. Besides their role as biological nanocarriers, extracellular vesicles have a specific tropism towards target cells, which is a key aspect in precision medicine. However, the little knowledge of the mechanisms governing the release of a cargo macromolecule in recipient cells and the Good Manufacturing Practice (GMP) grade scale-up manufacturing of extracellular vesicles are currently slowing their application as drug delivery nanocarriers. In this review, we summarize, from a cell biologist’s perspective, the main evidence supporting the role of extracellular vesicles as promising carriers in drug delivery, and we report five key considerations that merit further investigation before translating Extracellular Vesicles (EVs) to clinical applications. Full article
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14 pages, 666 KiB  
Review
Extracellular Vesicles as Biomarkers and Therapeutic Tools: From Pre-Clinical to Clinical Applications
by Maria Chiara Ciferri, Rodolfo Quarto and Roberta Tasso
Biology 2021, 10(5), 359; https://doi.org/10.3390/biology10050359 - 23 Apr 2021
Cited by 74 | Viewed by 5687
Abstract
Extracellular vesicles (EVs) are ubiquitous masters of intercellular communication, being detectable in tissues, circulation, and body fluids. Their complex cargo reflects the (patho)physiologic status of the cells from which they originate. Due to these properties, the potential of EVs, and in particular exosomes, [...] Read more.
Extracellular vesicles (EVs) are ubiquitous masters of intercellular communication, being detectable in tissues, circulation, and body fluids. Their complex cargo reflects the (patho)physiologic status of the cells from which they originate. Due to these properties, the potential of EVs, and in particular exosomes, to serve as biomarkers or therapeutics has grown exponentially over the past decade. On one side, numerous studies have demonstrated that EV-associated nucleic acids and proteins are implicated in cancer progression, as well as neurodegenerative, infectious, and autoimmune disorders. On the other, the therapeutic use of EVs secreted by various cell types, and in particular stem/progenitor cells, present significant advantages in comparison to the corresponding parental cells, such as the less complex production and storage conditions. In this review, we examine some of the major pre-clinical studies dealing with EVs and exosomes, that led to the development of numerous completed clinical trials. Full article
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31 pages, 5874 KiB  
Review
Mesenchymal Stem Cell-Derived Extracellular Vesicles: Regenerative Potential and Challenges
by Shivkanya Fuloria, Vetriselvan Subramaniyan, Rajiv Dahiya, Sunita Dahiya, Kalvatala Sudhakar, Usha Kumari, Kathiresan Sathasivam, Dhanalekshmi Unnikrishnan Meenakshi, Yuan Seng Wu, Mahendran Sekar, Rishabha Malviya, Amit Singh and Neeraj Kumar Fuloria
Biology 2021, 10(3), 172; https://doi.org/10.3390/biology10030172 - 25 Feb 2021
Cited by 31 | Viewed by 5157
Abstract
Evidence suggests that stem cells exert regenerative potential via the release of extracellular vesicles. Mesenchymal stem cell extracellular vesicles (MSCEVs) offer therapeutic benefits for various pathophysiological ailments by restoring tissues. Facts suggest that MSCEV action can be potentiated by modifying the mesenchymal stem [...] Read more.
Evidence suggests that stem cells exert regenerative potential via the release of extracellular vesicles. Mesenchymal stem cell extracellular vesicles (MSCEVs) offer therapeutic benefits for various pathophysiological ailments by restoring tissues. Facts suggest that MSCEV action can be potentiated by modifying the mesenchymal stem cells culturing methodology and bioengineering EVs. Limited clinical trials of MSCEVs have questioned their superiority, culturing quality, production scale-up and isolation, and administration format. Translation of preclinically successful MSCEVs into a clinical platform requires paying attention to several critical matters, such as the production technique, quantification/characterization, pharmacokinetics/targeting/transfer to the target site, and the safety profile. Keeping these issues as a priority, the present review was designed to highlight the challenges in translating preclinical MSCEV research into clinical platforms and provide evidence for the regenerative potential of MSCEVs in various conditions of the liver, kidney, heart, nervous system, bone, muscle, cartilage, and other organs/tissues. Full article
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Graphical abstract

32 pages, 6846 KiB  
Article
Cytochalasin B-Induced Membrane Vesicles from Human Mesenchymal Stem Cells Overexpressing IL2 Are Able to Stimulate CD8+ T-Killers to Kill Human Triple Negative Breast Cancer Cells
by Daria S. Chulpanova, Zarema E. Gilazieva, Sevindzh K. Kletukhina, Aleksandr M. Aimaletdinov, Ekaterina E. Garanina, Victoria James, Albert A. Rizvanov and Valeriya V. Solovyeva
Biology 2021, 10(2), 141; https://doi.org/10.3390/biology10020141 - 10 Feb 2021
Cited by 25 | Viewed by 3823
Abstract
Interleukin 2 (IL2) was one of the first cytokines used for cancer treatment due to its ability to stimulate anti-cancer immunity. However, recombinant IL2-based therapy is associated with high systemic toxicity and activation of regulatory T-cells, which are associated with the pro-tumor immune [...] Read more.
Interleukin 2 (IL2) was one of the first cytokines used for cancer treatment due to its ability to stimulate anti-cancer immunity. However, recombinant IL2-based therapy is associated with high systemic toxicity and activation of regulatory T-cells, which are associated with the pro-tumor immune response. One of the current trends for the delivery of anticancer agents is the use of extracellular vesicles (EVs), which can carry and transfer biologically active cargos into cells. The use of EVs can increase the efficacy of IL2-based anti-tumor therapy whilst reducing systemic toxicity. In this study, human adipose tissue-derived mesenchymal stem cells (hADSCs) were transduced with lentivirus encoding IL2 (hADSCs-IL2). Membrane vesicles were isolated from hADSCs-IL2 using cytochalasin B (CIMVs-IL2). The effect of hADSCs-IL2 and CIMVs-IL2 on the activation and proliferation of human peripheral blood mononuclear cells (PBMCs) as well as the cytotoxicity of activated PBMCs against human triple negative cancer MDA-MB-231 and MDA-MB-436 cells were evaluated. The effect of CIMVs-IL2 on murine PBMCs was also evaluated in vivo. CIMVs-IL2 failed to suppress the proliferation of human PBMCs as opposed to hADSCs-IL2. However, CIMVs-IL2 were able to activate human CD8+ T-killers, which in turn, killed MDA-MB-231 cells more effectively than hADSCs-IL2-activated CD8+ T-killers. This immunomodulating effect of CIMVs-IL2 appears specific to human CD8+ T-killer cells, as the same effect was not observed on murine CD8+ T-cells. In conclusion, the use of CIMVs-IL2 has the potential to provide a more effective anti-cancer therapy. This compelling evidence supports further studies to evaluate CIMVs-IL2 effectiveness, using cancer mouse models with a reconstituted human immune system. Full article
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24 pages, 1212 KiB  
Review
Exosomes and Extracellular Vesicles in Myeloid Neoplasia: The Multiple and Complex Roles Played by These “Magic Bullets”
by Simona Bernardi and Mirko Farina
Biology 2021, 10(2), 105; https://doi.org/10.3390/biology10020105 - 02 Feb 2021
Cited by 15 | Viewed by 3280
Abstract
Extracellular vesicles (exosomes, in particular) are essential in multicellular organisms because they mediate cell-to-cell communication via the transfer of secreted molecules. They are able to shuttle different cargo, from nucleic acids to proteins. The role of exosomes has been widely investigated in solid [...] Read more.
Extracellular vesicles (exosomes, in particular) are essential in multicellular organisms because they mediate cell-to-cell communication via the transfer of secreted molecules. They are able to shuttle different cargo, from nucleic acids to proteins. The role of exosomes has been widely investigated in solid tumors, which gave us surprising results about their potential involvement in pathogenesis and created an opening for liquid biopsies. Less is known about exosomes in oncohematology, particularly concerning the malignancies deriving from myeloid lineage. In this review, we aim to present an overview of immunomodulation and the microenvironment alteration mediated by exosomes released by malicious myeloid cells. Afterwards, we review the studies reporting the use of exosomes as disease biomarkers and their influence in response to treatment, together with the recent experiences that have focused on the use of exosomes as therapeutic tools. The further development of new technologies and the increased knowledge of biological (exosomes) and clinical (myeloid neoplasia) aspects are expected to change the future approaches to these malignancies. Full article
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13 pages, 1373 KiB  
Article
Plasma Concentrations of Extracellular Vesicles Are Decreased in Patients with Post-Infarct Cardiac Remodelling
by Aleksandra Gąsecka, Kinga Pluta, Katarzyna Solarska, Bartłomiej Rydz, Ceren Eyileten, Marek Postula, Edwin van der Pol, Rienk Nieuwland, Monika Budnik, Janusz Kochanowski, Miłosz J. Jaguszewski, Łukasz Szarpak, Tomasz Mazurek, Agnieszka Kapłon-Cieślicka, Grzegorz Opolski and Krzysztof J. Filipiak
Biology 2021, 10(2), 97; https://doi.org/10.3390/biology10020097 - 30 Jan 2021
Cited by 8 | Viewed by 2614
Abstract
Background, the mechanisms underlying left ventricular remodelling (LVR) after acute myocardial infarction (AMI) remain obscure. In the course of AMI, blood cells and endothelial cells release extracellular vesicles (EVs). We hypothesized that changes in EV concentrations after AMI may underlie LVR. Methods, plasma [...] Read more.
Background, the mechanisms underlying left ventricular remodelling (LVR) after acute myocardial infarction (AMI) remain obscure. In the course of AMI, blood cells and endothelial cells release extracellular vesicles (EVs). We hypothesized that changes in EV concentrations after AMI may underlie LVR. Methods, plasma concentrations of EVs from endothelial cells (CD146+), erythrocytes (CD235a+), leukocytes (CD45+), platelets (CD61+), activated platelets (P-selectin+), and EVs exposing phosphatidylserine after AMI were determined by flow cytometry in 55 patients with the first AMI. LVR was defined as an increase in left ventricular end-diastolic volume by 20% at 6 months after AMI, compared to baseline. Results, baseline concentrations of EVs from endothelial cells, erythrocytes and platelets were lower in patients who developed LVR (p ≤ 0.02 for all). Concentrations of EVs from endothelial cells and erythrocytes were independent LVR predictors (OR 8.2, CI 1.3–54.2 and OR 17.8, CI 2.3–138.6, respectively) in multivariate analysis. Combining the three EV subtypes allowed to predict LVR with 83% sensitivity and 87% specificity. Conclusions, decreased plasma concentrations of EVs from endothelial cells, erythrocytes and platelets predict LVR after AMI. Since EV release EVs contributes to cellular homeostasis by waste removal, decreased concentrations of EVs may indicate dysfunctional cardiac homeostasis after AMI, thus promoting LVR. Full article
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17 pages, 2130 KiB  
Communication
Does KRAS Play a Role in the Regulation of Colon Cancer Cells-Derived Exosomes?
by Shu-Kee Eng, Ilma Ruzni Imtiaz, Bey-Hing Goh, Long Chiau Ming, Ya-Chee Lim and Wai-Leng Lee
Biology 2021, 10(1), 58; https://doi.org/10.3390/biology10010058 - 14 Jan 2021
Cited by 4 | Viewed by 3196
Abstract
Exosomes are cell-derived nanovesicles, and lately, cancer-derived exosomes have been reported to carry KRAS protein, which contributes to the malignancy of many cancers. In this study, farnesylthiosalicylic acid (FTS) was used to inhibit the activities of mutated KRAS in colon cancer SW480 cells [...] Read more.
Exosomes are cell-derived nanovesicles, and lately, cancer-derived exosomes have been reported to carry KRAS protein, which contributes to the malignancy of many cancers. In this study, farnesylthiosalicylic acid (FTS) was used to inhibit the activities of mutated KRAS in colon cancer SW480 cells to discover the potential link between KRAS activities and cancer-derived exosomes. We observed that FTS inhibits KRAS activity in SW480 cells, but promotes their exosome production. When the exosomal proteins of SW480 cells were profiled, a total of 435 proteins were identified with 16 of them showing significant changes (greater than or equal to two-fold) in response to FTS treatment. Protein network analysis suggests KRAS inhibition may trigger stress in the cells. In addition, a high level of acetyl-coA synthetase family member 4 protein which plays an important role in colon cancer survival was identified in the exosomes secreted by FTS-treated SW480 cells. The uptake of these exosomes suppresses the growth of some cell types, but in general exosomes from FTS-treated cells enhance the recipient cell survival when compared to that of untreated cells. Together our findings suggest that FTS may trigger stress in SW480 cells, and induce more exosomes secretion as the survival messenger to mitigate the impact of KRAS inhibition in colon cancer cells. Full article
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2020

Jump to: 2021

6 pages, 221 KiB  
Editorial
Extracellular Vesicles: From Biomarkers to Therapeutic Tools
by Simona Bernardi and Carolina Balbi
Biology 2020, 9(9), 258; https://doi.org/10.3390/biology9090258 - 31 Aug 2020
Cited by 42 | Viewed by 3819
Abstract
Intercellular communication is an essential hallmark of multicellular organisms and can be mediated through direct cell–cell contact or transfer of secreted molecules. In the last two decades, a third mechanism for intercellular communication has emerged that involves intercellular transfer of extracellular vesicles (EVs). [...] Read more.
Intercellular communication is an essential hallmark of multicellular organisms and can be mediated through direct cell–cell contact or transfer of secreted molecules. In the last two decades, a third mechanism for intercellular communication has emerged that involves intercellular transfer of extracellular vesicles (EVs). EVs are membranous vesicles of 30–5000 nm in size. Based on their dimension and biogenesis, EVs can be divided into different categories, such as microvesicles, apoptotic bodies, ectosomes, and exosomes. It has already been demonstrated that protein changes, expressed on the surfaces or in the content of these vesicles, may reflect the status of producing cells. For this reason, EVs, and exosomes in particular, are considered ideal biomarkers in several types of disease—from cancer diagnosis to heart rejection. This aspect opens different opportunities in EVs clinical application, considering the importance given to liquid biopsy in the recent years. Furthermore, extracellular vesicles can be natural or engineered carriers of cytoprotective or cytotoxic factors and applied, as a therapeutic tool, from regenerative medicine to target cancer therapy. This is of pivotal importance in the so called “era of the 4P medicine”. This Editorial focuses on recent findings pertaining to EVs in different medical areas, from biomarkers to therapeutic applications. Full article
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