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New Challenges and Opportunities: Extracellular Vesicles in Biological and Biochemical Processes

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

Deadline for manuscript submissions: closed (12 March 2024) | Viewed by 12143

Special Issue Editors


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Guest Editor
Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
Interests: extracellular vesicles; tumor microenvironment; angiogenesis; platelet derivatives; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biomedicine, Neurosciences and Advanced Diagnostic (BiND), Human Anatomy Section, University of Palermo, 90127 Palermo, Italy
Interests: extracellular vesicles; exosomes; miRNA; liquid biopsy; cancerogenesis; anatomy; molecular chaperones; heat shock proteins; extracellular chaperones
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell-to-cell communication is mediated by the release of a plethora of soluble molecules of varying nature and functions. However, extracellular vesicles (EVs) have been recognized as essential mediators of this intercellular crosstalk for many years now, being involved in all key biological processes in humans, such as cell differentiation, tissue homeostasis, and organ remodeling.

EVs are membrane-enclosed structures, containing a complex cargo composed of proteins, lipids, and nucleic acids, which can be fully functional once transferred to target cells, and when released by normal and tumor cells, they act as critical modulators in both physiological and pathological conditions.

This Special Issue, “New Challenges and Opportunities: Extracellular Vesicles in Biological and Biochemical Processes”, will comprise a selection of research papers and reviews, focusing on the novel biochemical and molecular aspects of biological processes mediated by EVs. Contributions are welcome on EVs molecular characterization and cell signaling pathways involved in EVs-mediated physiological and pathological processes, as well as their impact on possible clinical implications.

Dr. Ilaria Giusti
Dr. Celeste Caruso Bavisotto
Guest Editors

Manuscript Submission Information

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Keywords

  • extracellular vesicles
  • exosomes
  • intercellular crosstalk
  • liquid biopsy
  • carcinogenesis
  • cell differentiation
  • tissue homeostasis
  • organ remodeling
  • biomedicine
  • advanced diagnostics

Published Papers (7 papers)

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Research

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14 pages, 2468 KiB  
Article
Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells
by Ji Hye Im, Kyue-Yim Lee, Yoona Seo, Jiho Rhim, Yun-Sik Dho, Byong Chul Yoo, Jong Bae Park, Sang Hoon Shin, Heon Yoo, Jong Heon Kim and Ho-Shin Gwak
Int. J. Mol. Sci. 2024, 25(6), 3124; https://doi.org/10.3390/ijms25063124 - 08 Mar 2024
Viewed by 527
Abstract
Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued [...] Read more.
Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM. Full article
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20 pages, 11308 KiB  
Article
Consistency between Primary Uterine Corpus Malignancies and Their Corresponding Patient-Derived Xenograft Models
by Shoko Ueda, Tomohito Tanaka, Kensuke Hirosuna, Shunsuke Miyamoto, Hikaru Murakami, Ruri Nishie, Hiromitsu Tsuchihashi, Akihiko Toji, Natsuko Morita, Sousuke Hashida, Atsushi Daimon, Shinichi Terada, Hiroshi Maruoka, Yuhei Kogata, Kohei Taniguchi, Kazumasa Komura and Masahide Ohmichi
Int. J. Mol. Sci. 2024, 25(3), 1486; https://doi.org/10.3390/ijms25031486 - 25 Jan 2024
Viewed by 672
Abstract
Patient-derived xenograft (PDX) models retain the characteristics of tumors and are useful tools for personalized therapy and translational research. In this study, we aimed to establish PDX models for uterine corpus malignancies (UC-PDX) and analyze their similarities. Tissue fragments obtained from 92 patients [...] Read more.
Patient-derived xenograft (PDX) models retain the characteristics of tumors and are useful tools for personalized therapy and translational research. In this study, we aimed to establish PDX models for uterine corpus malignancies (UC-PDX) and analyze their similarities. Tissue fragments obtained from 92 patients with uterine corpus malignancies were transplanted subcutaneously into immunodeficient mice. Histological and immunohistochemical analyses were performed to compare tumors of patients with PDX tumors. DNA and RNA sequencing were performed to validate the genetic profile. Furthermore, the RNA in extracellular vesicles (EVs) extracted from primary and PDX tumors was analyzed. Among the 92 cases, 52 UC-PDX models were established, with a success rate of 56.5%. The success rate depended on tumor histology and staging. The pathological and immunohistochemical features of primary and PDX tumors were similar. DNA sequencing revealed similarities in gene mutations between the primary and PDX tumors. RNA sequencing showed similarities in gene expressions between primary and PDX tumors. Furthermore, the RNA profiles of the EVs obtained from primary and PDX tumors were similar. As UC-PDX retained the pathological and immunohistochemical features and gene profiles of primary tumors, they may provide a platform for developing personalized medicine and translational research. Full article
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20 pages, 1172 KiB  
Article
Secretory Proteomic Responses of Endometrial Epithelial Cells to Trophoblast-Derived Extracellular Vesicles
by Subhashini Muhandiram, Keerthie Dissanayake, Toomos Orro, Kasun Godakumara, Suranga Kodithuwakku and Alireza Fazeli
Int. J. Mol. Sci. 2023, 24(15), 11924; https://doi.org/10.3390/ijms241511924 - 25 Jul 2023
Viewed by 1965
Abstract
Synchronized crosstalk between the embryo and endometrium during the periconception period is integral to pregnancy establishment. Increasing evidence suggests that the exchange of extracellular vesicles (EVs) of both embryonic and endometrial origin is a critical component of embryo–maternal communication during peri-implantation. Here, we [...] Read more.
Synchronized crosstalk between the embryo and endometrium during the periconception period is integral to pregnancy establishment. Increasing evidence suggests that the exchange of extracellular vesicles (EVs) of both embryonic and endometrial origin is a critical component of embryo–maternal communication during peri-implantation. Here, we investigated whether embryonic signals in the form of EVs can modulate the endometrial epithelial cell secretome. Receptive endometrial analog RL95-2 cells were supplemented with trophoblast analog JAr cell-derived EVs, and the secretory protein changes occurring in the RL95-2 cells were analyzed using mass spectrometry. EVs of non-trophoblastic origin (HEK 293 cells) were used as the control EV source to supplement endometrial cells. Trophoblast cell-derived EVs enriched endometrial epithelial cell secretions with proteins that support embryo development, attachment, or implantation, whereas control EVs were unable to induce the same effect. The present study suggests that embryonic signals in the form of EVs may prime receptive endometrial epithelial cells to enrich their secretory proteome with critical proteomic molecules with functional importance for periconception milieu formation. Full article
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28 pages, 4723 KiB  
Article
Molecular Markers in Maternal Blood Exosomes Allow Early Detection of Fetal Alcohol Spectrum Disorders
by Nune Darbinian, Armine Darbinyan, John Sinard, Gabriel Tatevosian, Nana Merabova, Faith D’Amico, Tarek Khader, Ahsun Bajwa, Diana Martirosyan, Alina K. Gawlinski, Richa Pursnani, Huaqing Zhao, Shohreh Amini, Mary Morrison, Laura Goetzl and Michael E. Selzer
Int. J. Mol. Sci. 2023, 24(1), 135; https://doi.org/10.3390/ijms24010135 - 21 Dec 2022
Cited by 8 | Viewed by 2584
Abstract
Prenatal alcohol exposure can cause developmental abnormalities (fetal alcohol spectrum disorders; FASD), including small eyes, face and brain, and neurobehavioral deficits. These cannot be detected early in pregnancy with available imaging techniques. Early diagnosis could facilitate development of therapeutic interventions. Banked human fetal [...] Read more.
Prenatal alcohol exposure can cause developmental abnormalities (fetal alcohol spectrum disorders; FASD), including small eyes, face and brain, and neurobehavioral deficits. These cannot be detected early in pregnancy with available imaging techniques. Early diagnosis could facilitate development of therapeutic interventions. Banked human fetal brains and eyes at 9–22 weeks’ gestation were paired with maternal blood samples, analyzed for morphometry, protein, and RNA expression, and apoptotic signaling. Alcohol (EtOH)-exposed (maternal self-report) fetuses were compared with unexposed controls matched for fetal age, sex, and maternal race. Fetal brain-derived exosomes (FB-E) were isolated from maternal blood and analyzed for protein, RNA, and apoptotic markers. EtOH use by mothers, assessed by self-report, was associated with reduced fetal eye diameter, brain size, and markers of synaptogenesis. Brain caspase-3 activity was increased. The reduction in eye and brain sizes were highly correlated with amount of EtOH intake and caspase-3 activity. Levels of several biomarkers in FB-E, most strikingly myelin basic protein (MBP; r > 0.9), correlated highly with morphological abnormalities. Reduction in FB-E MBP levels was highly correlated with EtOH exposure (p < 1.0 × 10−10). Although the morphological features of FAS appear long before they can be detected by live imaging, FB-E in the mother’s blood may contain markers, particularly MBP, that predict FASD. Full article
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Review

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15 pages, 1119 KiB  
Review
Exosome–Autophagy Crosstalk in Enveloped Virus Infection
by Yuqi Wang, Linzhu Ren, Haocheng Bai, Qing Jin and Liying Zhang
Int. J. Mol. Sci. 2023, 24(13), 10618; https://doi.org/10.3390/ijms241310618 - 25 Jun 2023
Cited by 1 | Viewed by 1721
Abstract
Exosomes, which are extracellular vesicles (EVs) predominantly present in bodily fluids, participate in various physiological processes. Autophagy, an intracellular degradation mechanism, eliminates proteins and damaged organelles by forming double-membrane autophagosomes. These autophagosomes subsequently merge with lysosomes for target degradation. The interaction between autophagy [...] Read more.
Exosomes, which are extracellular vesicles (EVs) predominantly present in bodily fluids, participate in various physiological processes. Autophagy, an intracellular degradation mechanism, eliminates proteins and damaged organelles by forming double-membrane autophagosomes. These autophagosomes subsequently merge with lysosomes for target degradation. The interaction between autophagy and endosomal/exosomal pathways can occur at different stages, exerting significant influences on normal physiology and human diseases. The interplay between exosomes and the autophagy pathway is intricate. Exosomes exhibit a cytoprotective role by inducing intracellular autophagy, while autophagy modulates the biogenesis and degradation of exosomes. Research indicates that exosomes and autophagy contribute to the infection process of numerous enveloped viruses. Enveloped viruses, comprising viral nucleic acid, proteins, or virions, can be encapsulated within exosomes and transferred between cells via exosomal transport. Consequently, exosomes play a crucial role in the infection of certain viral diseases. This review presents recent findings on the interplay between exosomes and autophagy, as well as their implications in the infection of enveloped viruses, thereby offering valuable insights into the pathogenesis and vaccine research of enveloped virus infection. Full article
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24 pages, 1052 KiB  
Review
Metastatic Dissemination: Role of Tumor-Derived Extracellular Vesicles and Their Use as Clinical Biomarkers
by Ilaria Giusti, Giuseppina Poppa, Giulia Di Fazio, Sandra D’Ascenzo and Vincenza Dolo
Int. J. Mol. Sci. 2023, 24(11), 9590; https://doi.org/10.3390/ijms24119590 - 31 May 2023
Cited by 2 | Viewed by 1049
Abstract
Cancer is a major cause of mortality in humans; often, rather than the primary tumor, it is the presence of metastases that are the cause of death. Extracellular vesicles (EVs) are small structures released by both normal and cancer cells; regarding the latter, [...] Read more.
Cancer is a major cause of mortality in humans; often, rather than the primary tumor, it is the presence of metastases that are the cause of death. Extracellular vesicles (EVs) are small structures released by both normal and cancer cells; regarding the latter, they have been demonstrated to modulate almost all cancer-related processes, such as invasion, angiogenesis induction, drug resistance, and immune evasion. In the last years, it has become clear how EVs are widely involved in metastatic dissemination as well as in pre-metastatic niche (PMN) formation. Indeed, in order to achieve a successful metastatic process, i.e., penetration by cancer cells into distant tissues, the shaping of a favorable environment into those distant tissue, i.e., PMN formation, is mandatory. This process consists of an alteration that takes place in a distant organ and paves the way for the engraftment and growth of circulating tumor cells derived from the tumor primary site. This review focuses on the role of EVs in pre-metastatic niche formation and metastatic dissemination, also reporting the last studies suggesting the EVs role as biomarkers of metastatic diseases, possibly in a liquid biopsy approach. Full article
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25 pages, 794 KiB  
Review
Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles?
by Pavel Burko, Giuseppa D’Amico, Ilia Miltykh, Federica Scalia, Everly Conway de Macario, Alberto J. L. Macario, Giuseppe Giglia, Francesco Cappello and Celeste Caruso Bavisotto
Int. J. Mol. Sci. 2023, 24(5), 4883; https://doi.org/10.3390/ijms24054883 - 02 Mar 2023
Cited by 5 | Viewed by 2665
Abstract
Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly [...] Read more.
Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly review the mechanisms underpinning radioresistance and discuss research to stop it and install anti-tumor defenses. Factors that participate in radioresistance are varied and include stem cells, tumor heterogeneity, tumor microenvironment, hypoxia, metabolic reprogramming, the chaperone system, non-coding RNAs, DNA repair, and extracellular vesicles (EVs). We direct our attention toward EVs because they are emerging as promising candidates as diagnostic and prognostication tools and as the basis for developing nanodevices for delivering anti-cancer agents directly into the tumor mass. EVs are relatively easy to obtain and manipulate to endow them with the desired anti-cancer properties and to administer them using minimally invasive procedures. Thus, isolating EVs from a GBM patient, supplying them with the necessary anti-cancer agent and the capability of recognizing a specified tissue-cell target, and reinjecting them into the original donor appears, at this time, as a reachable objective of personalized medicine. Full article
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