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Roles and Function of Extracellular Vesicles in Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 28679

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Dr. Won Jong Rhee

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Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
Interests: exosome; cell engineering; liquid biopsy; disease diagnosis; biologics development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Extracellular vesicles (EVs) are small nano-sized particles that are constantly produced and secreted by cells. Since EVs originate from cells, they contain cellular components such as proteins, lipids, carbohydrates, DNAs, and RNAs. They play key roles in cell-to-cell communication through transferring those encapsulated components. As central mediators of intercellular communication, EVs play important roles in the pathogenesis of various diseases, such as cancer progression and metastasis. In this context, understanding the roles and function of EVs in our bodies is essential for the practical applications of EVs in therapy and diagnosis.

The Special Issue of the International Journal of Molecular Sciences, “Roles and Function of Extracellular Vesicles in Disease”, will focus on (1) biogenesis or biochemical properties of EVs, (2) functions of EVs, (3) engineering EVs for therapeutic development, (4) development of novel EV sources, and (5) EV-based applications in therapy and diagnosis. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Dr. Won Jong Rhee
Guest Editor

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Keywords

extracellular vesicle
exosome
disease
roles and function

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Published Papers (10 papers)

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Research

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13 pages, 1664 KiB

Open AccessArticle

Coculture with Neural Stem Cells May Shift the Transcription Profile of Glioblastoma Multiforme towards Cancer-Specific Stemness

by Manjusha Vaidya, Sandeep Sreerama, Maxine Gonzalez-Vega, Jonhoi Smith, Melvin Field and Kiminobu Sugaya

Int. J. Mol. Sci. 2023, 24(4), 3242; https://doi.org/10.3390/ijms24043242 - 7 Feb 2023

Cited by 6 | Viewed by 2490

Abstract

Glioblastoma multiforme (GBM) possesses a small but significant population of cancer stem cells (CSCs) thought to play a role in its invasiveness, recurrence, and metastasis. The CSCs display transcriptional profiles for multipotency, self-renewal, tumorigenesis, and therapy resistance. There are two possible theories regarding the origin of CSCs in the context of neural stem cells (NSCs); i.e., NSCs modify cancer cells by conferring them with cancer-specific stemness, or NSCs themselves are transformed into CSCs due to the tumor environment created by cancer cells. To test the theories and to investigate the transcriptional regulation of the genes involved in CSC formation, we cocultured NSC and GBM cell lines together. Where genes related to cancer stemness, drug efflux, and DNA modification were upregulated in GBM, they were downregulated in NSCs upon coculture. These results indicate that cancer cells shift the transcriptional profile towards stemness and drug resistance in the presence of NSCs. Concurrently, GBM triggers NSCs differentiation. Because the cell lines were separated by a membrane (0.4 µm pore size) to prevent direct contact between GBM and NSCs, cell-secreted signaling molecules and extracellular vesicles (EVs) are likely involved in reciprocal communication between NSCs and GBM, causing transcription modification. Understanding the mechanism of CSC creation will aid in the identification of precise molecular targets within the CSCs to exterminate them, which, in turn, will increase the efficacy of chemo-radiation treatment. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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12 pages, 2164 KiB

Open AccessArticle

Comparative Analysis of Normoxia- and Hypoxia-Modified Extracellular Vesicle Therapy in Function, Perfusion, and Collateralization in Chronically Ischemic Myocardium

by Sharif A. Sabe, Cynthia M. Xu, Brittany A. Potz, Akshay Malhotra, Mohamed Sabra, Dwight D. Harris, Mark Broadwin, M. Ruhul Abid and Frank W. Sellke

Int. J. Mol. Sci. 2023, 24(3), 2076; https://doi.org/10.3390/ijms24032076 - 20 Jan 2023

Cited by 9 | Viewed by 1647

Abstract

We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, n = 10) or hypoxia-modified EVs (HYP, n = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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12 pages, 2119 KiB

Open AccessArticle

Proteomic Assessment of Hypoxia-Pre-Conditioned Human Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Demonstrates Promise in the Treatment of Cardiovascular Disease

by Cynthia M. Xu, Catherine Karbasiafshar, Rayane Brinck Teixeira, Nagib Ahsan, Giana Blume Corssac, Frank W. Sellke and M. Ruhul Abid

Int. J. Mol. Sci. 2023, 24(2), 1674; https://doi.org/10.3390/ijms24021674 - 14 Jan 2023

Cited by 10 | Viewed by 2082

Abstract

Human bone marrow mesenchymal stem cell derived-extracellular vesicles (HBMSC-EV) are known for their regenerative and anti-inflammatory effects in animal models of myocardial ischemia. However, it is not known whether the efficacy of the EVs can be modulated by pre-conditioning of HBMSC by exposing them to either starvation or hypoxia prior to EV collection. HBMSC-EVs were isolated following normoxia starvation (NS), normoxia non-starvation (NNS), hypoxia starvation (HS), or hypoxia non-starvation (HNS) pre-conditioning. The HBMSC-EVs were characterized by nanoparticle tracking analysis, electron microscopy, Western blot, and proteomic analysis. Comparative proteomic profiling revealed that starvation pre-conditioning led to a smaller variety of proteins expressed, with the associated lesser effect of normoxia versus hypoxia pre-conditioning. In the absence of starvation, normoxia and hypoxia pre-conditioning led to disparate HBMSC-EV proteomic profiles. HNS HBMSC-EV was found to have the greatest variety of proteins overall, with 74 unique proteins, the greatest number of redox proteins, and pathway analysis suggestive of improved angiogenic properties. Future HBMSC-EV studies in the treatment of cardiovascular disease may achieve the most therapeutic benefits from hypoxia non-starved pre-conditioned HBMSC. This study was limited by the lack of functional and animal models of cardiovascular disease and transcriptomic studies. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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15 pages, 3050 KiB

Open AccessArticle

The Upregulation of Regenerative Activity for Extracellular Vesicles with Melatonin Modulation in Chemically Defined Media

by Jun Yong Kim, Won-Kyu Rhim, Jiwon Woo, Seung-Gyu Cha, Chun Gwon Park and Dong Keun Han

Int. J. Mol. Sci. 2022, 23(23), 15089; https://doi.org/10.3390/ijms232315089 - 1 Dec 2022

Cited by 8 | Viewed by 1918

Abstract

Extracellular vesicles (EVs) derived from human mesenchymal stem cells (hMSCs) have been widely known to have therapeutic effects by representing characteristics of the origin cells as an alternative for cell-based therapeutics. Major limitations of EVs for clinical applications include low production yields, unknown effects from serum impurities, and relatively low bioactivities against dose. In this study, we proposed a cell modulation method with melatonin for human umbilical cord MSCs (hUCMSCs) cultured in serum-free chemically defined media (CDM) to eliminate the effects of serum-derived impurities and promote regeneration-related activities. miRNAs highly associated with regeneration were selected and the expression levels of them were comparatively analyzed among various types of EVs depending on culture conditions. The EVs derived from melatonin-stimulated hUCMSCs in CDM (CDM mEVs) showed the highest expression levels of regeneration-related miRNAs, and 7 times more hsa-let-7b-5p, 5.6 times more hsa-miR-23a-3p, and 5.7 times more hsa-miR-100-5p than others, respectively. In addition, the upregulation of various functionalities, such as wound healing, angiogenesis, anti-inflammation, ROS scavenging, and anti-apoptosis, were proven using in vitro assays by simulating the characteristics of EVs with bioinformatics analysis. The present results suggest that the highly regenerative properties of hUCMSC-derived EVs were accomplished with melatonin stimulation in CDM and provided the potential for clinical uses of EVs. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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22 pages, 5680 KiB

Open AccessArticle

Morphological and Mechanical Characterization of Extracellular Vesicles and Parent Human Synoviocytes under Physiological and Inflammatory Conditions

by Samira Filali, Nesrine Darragi-Raies, Layth Ben-Trad, Agnès Piednoir, Saw-See Hong, Fabrice Pirot, Ahmed Landoulsi, Agnès Girard-Egrot, Thierry Granjon, Ofelia Maniti, Pierre Miossec and Ana-Maria Trunfio-Sfarghiu

Int. J. Mol. Sci. 2022, 23(21), 13201; https://doi.org/10.3390/ijms232113201 - 30 Oct 2022

Cited by 3 | Viewed by 2374

Abstract

The morphology of fibroblast-like synoviocytes (FLS) issued from the synovial fluid (SF) of patients suffering from osteoarthritis (OA), rheumatoid arthritis (RA), or from healthy subjects (H), as well as the ultrastructure and mechanical properties of the FLS-secreted extracellular vesicles (EV), were analyzed by confocal microscopy, transmission electron microscopy, atomic force microscopy, and tribological tests. EV released under healthy conditions were constituted of several lipid bilayers surrounding a viscous inner core. This “gel-in” vesicular structure ensured high mechanical resistance of single vesicles and good tribological properties of the lubricant. RA, and to a lesser extent OA, synovial vesicles had altered morphology, corresponding to a “gel-out” situation with vesicles surrounded by a viscous gel, poor mechanical resistance, and poor lubricating qualities. When subjected to inflammatory conditions, healthy cells developed phenotypes similar to that of RA samples, which reinforces the importance of inflammatory processes in the loss of lubricating properties of SF. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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17 pages, 1857 KiB

Open AccessArticle

Synovial Extracellular Vesicles: Structure and Role in Synovial Fluid Tribological Performances

by Layth Ben-Trad, Constantin Ionut Matei, Mirela Maria Sava, Samira Filali, Marie-Eve Duclos, Yves Berthier, Michel Guichardant, Nathalie Bernoud-Hubac, Ofelia Maniti, Ahmed Landoulsi, Marie-Genevieve Blanchin, Pierre Miossec, Thierry Granjon and Ana-Maria Trunfio-Sfarghiu

Int. J. Mol. Sci. 2022, 23(19), 11998; https://doi.org/10.3390/ijms231911998 - 9 Oct 2022

Cited by 12 | Viewed by 2947

Abstract

The quality of the lubricant between cartilaginous joint surfaces impacts the joint’s mechanistic properties. In this study, we define the biochemical, ultrastructural, and tribological signatures of synovial fluids (SF) from patients with degenerative (osteoarthritis-OA) or inflammatory (rheumatoid arthritis-RA) joint pathologies in comparison with SF from healthy subjects. Phospholipid (PL) concentration in SF increased in pathological contexts, but the proportion PL relative to the overall lipids decreased. Subtle changes in PL chain composition were attributed to the inflammatory state. Transmission electron microscopy showed the occurrence of large multilamellar synovial extracellular vesicles (EV) filled with glycoprotein gel in healthy subjects. Synovial extracellular vesicle structure was altered in SF from OA and RA patients. RA samples systematically showed lower viscosity than healthy samples under a hydrodynamic lubricating regimen whereas OA samples showed higher viscosity. In turn, under a boundary regimen, cartilage surfaces in both pathological situations showed high wear and friction coefficients. Thus, we found a difference in the biochemical, tribological, and ultrastructural properties of synovial fluid in healthy people and patients with osteoarthritis and arthritis of the joints, and that large, multilamellar vesicles are essential for good boundary lubrication by ensuring a ball-bearing effect and limiting the destruction of lipid layers at the cartilage surface. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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11 pages, 1739 KiB

Open AccessArticle

Isolation and Characterization of Urinary Extracellular Vesicles from Healthy Donors and Patients with Castration-Resistant Prostate Cancer

by Haneul Lee, Su Jin Kang, Jimin Lee, Kyong Hwa Park and Won Jong Rhee

Int. J. Mol. Sci. 2022, 23(13), 7134; https://doi.org/10.3390/ijms23137134 - 27 Jun 2022

Cited by 12 | Viewed by 3058

Abstract

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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15 pages, 2914 KiB

Open AccessArticle

The Role of Telocytes and Telocyte-Derived Exosomes in the Development of Thoracic Aortic Aneurysm

by Thomas Aschacher, Olivia Aschacher, Katy Schmidt, Florian K. Enzmann, Eva Eichmair, Bernhard Winkler, Zsuzsanna Arnold, Felix Nagel, Bruno K. Podesser, Andreas Mitterbauer, Barbara Messner, Martin Grabenwöger, Günther Laufer, Marek P. Ehrlich and Michael Bergmann

Int. J. Mol. Sci. 2022, 23(9), 4730; https://doi.org/10.3390/ijms23094730 - 25 Apr 2022

Cited by 12 | Viewed by 3214

Abstract

A hallmark of thoracic aortic aneurysms (TAA) is the degenerative remodeling of aortic wall, which leads to progressive aortic dilatation and resulting in an increased risk for aortic dissection or rupture. Telocytes (TCs), a distinct type of interstitial cells described in many tissues and organs, were recently observed in the aortic wall, and studies showed the potential regulation of smooth muscle cell (SMC) homeostasis by TC-released shed vesicles. The purpose of the present work was to study the functions of TCs in medial degeneration of TAA. During aneurysmal formation an increase of aortic TCs was identified in human surgical specimens of TAA-patients, compared to healthy thoracic aortic (HTA)-tissue. We found the presence of epithelial progenitor cells in the adventitial layer, which showed increased infiltration in TAA samples. For functional analysis, HTA- and TAA-telocytes were isolated, characterized, and compared by their protein levels, mRNA- and miRNA-expression profiles. We detected TC and TC-released exosomes near SMCs. TAA-TC-exosomes showed a significant increase of the SMC-related dedifferentiation markers KLF-4-, VEGF-A-, and PDGF-A-protein levels, as well as miRNA-expression levels of miR-146a, miR-221 and miR-222. SMCs treated with TAA-TC-exosomes developed a dedifferentiation-phenotype. In conclusion, the study shows for the first time that TCs are involved in development of TAA and could play a crucial role in SMC phenotype switching by release of extracellular vesicles. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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Review

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20 pages, 1850 KiB

Open AccessReview

Extracellular Vesicles from Mesenchymal Stem Cells: Towards Novel Therapeutic Strategies for Neurodegenerative Diseases

by Ermanna Turano, Ilaria Scambi, Federica Virla, Bruno Bonetti and Raffaella Mariotti

Int. J. Mol. Sci. 2023, 24(3), 2917; https://doi.org/10.3390/ijms24032917 - 2 Feb 2023

Cited by 19 | Viewed by 3192

Abstract

Neurodegenerative diseases are fatal disorders of the central nervous system (CNS) which currently lack effective treatments. The application of mesenchymal stem cells (MSCs) represents a new promising approach for treating these incurable disorders. Growing evidence suggest that the therapeutic effects of MSCs are due to the secretion of neurotrophic molecules through extracellular vesicles. The extracellular vesicles produced by MSCs (MSC-EVs) have valuable innate properties deriving from parental cells and could be exploited as cell-free treatments for many neurological diseases. In particular, thanks to their small size, they are able to overcome biological barriers and reach lesion sites inside the CNS. They have a considerable pharmacokinetic and safety profile, avoiding the critical issues related to the fate of cells following transplantation. This review discusses the therapeutic potential of MSC-EVs in the treatment of neurodegenerative diseases, focusing on the strategies to further enhance their beneficial effects such as tracking methods, bioengineering applications, with particular attention to intranasal delivery as a feasible strategy to deliver MSC-EVs directly to the CNS in an effective and minimally invasive way. Current progresses and limiting issues to the extent of the use of MSC-EVs treatment for human neurodegenerative diseases will be also revised. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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15 pages, 15266 KiB

Open AccessReview

Roles and Applications of Red Blood Cell-Derived Extracellular Vesicles in Health and Diseases

by Lan Yang, Shiqi Huang, Zhirong Zhang, Zhenmi Liu and Ling Zhang

Int. J. Mol. Sci. 2022, 23(11), 5927; https://doi.org/10.3390/ijms23115927 - 25 May 2022

Cited by 13 | Viewed by 4763

Abstract

Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood–brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation. Full article

(This article belongs to the Special Issue Roles and Function of Extracellular Vesicles in Diseases)

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