Extracellular vesicles (EVs) represent a new paradigm, both in cell biology and medicine; specifically, the idea that functional content itself may be delivered directly to cells. EVs are cell-derived membranous structures that work as intercellular communicators exerting their function by transporting their cargo that includes nucleic acids, proteins and lipids. EVs play an essential role in normal physiology, but also in pathological communication, for instance, in cancer, EVs are thought to deliver oncogenic molecules (such as proteins, peptides, RNAs…) to neighboring cells, enhancing propagation of neoplastic cells. Not surprisingly, EV research has become common-place in every field of biomedicine, being explored as diagnostics and therapeutics.
This Collection gathers original Articles that investigate the application of extracellular vesicles on diagnostics and therapeutics, and that report advances in the knowledge of EV biology and the methodological tools for their study.
Extracellular vesicles in disease
The Articles gathered in this Collection have unveiled a number of ways in which EVs may serve in disease identification, for instance: the EV-associated miRNA of pleural fluids and lavages provide an untapped source of biomarkers for lung cancer diagnosis1; chemoresistance in colorectal cancer may be predicted through the evaluation of exosomal circRNA2, or exosomal miRNAs may serve for the identification and prognosis of metastatic colorectal cancer3; and a decrease in the Gelsolin content of plasma-EVs acts as a biomarker for dementia with Lewy Bodies, distinguishing these patients from those with Alzheimer’s Disease4.
Other Articles included in the Collection have explored the use of EVs in therapeutics. For the treatment of immune-related diseases, the application of an inflammatory stimulus is shown to improve the anti-inflammatory and/or immunosuppressive potential of EVs secreted by adipose mesenchymal stem cells5. Cytoprotection of stressed cardiomyocytes through the use of EVs derived from mesenchymal stromal cells6, and the prevention of glucocorticoid-induced osteoporosis – through the suppression of osteoblasts’ ferroptic pathway – by EVs extracted from bone marrow-derived endothelial progenitor7, were also demonstrated. As well as applying naturally occurring EVs, one of the published original Articles has demonstrated engineered EVs as a feasible therapeutic tool. Do et al. have developed a chimeric protein by fusing human lysosomal β-glucocerebrosidase (GBA) to an exosome-anchoring protein; this chimeric protein was successfully secreted into EVs, and delivered to recipient cells, providing a potential strategy for the treatment of lysosomal storage diseases8.
Extracellular vesicles’ biology and endogenous function
The Collection also advances our knowledge of EVs biology and function. For example, two articles have studied the lipidome and glycans of EVs, highlighting the lipidome profile as a possible marker to discriminate exosomes from microvesicles9, and identifying glycans as key players in the tuning of EV uptake through charge-based effects, direct glycan recognition or both10. Other roles of EVs have also been explored, such as oviductal EVs modulating sperm function and fertilization11, or EVs from aged astrocytes inhibiting the maturation of oligodendrocyte progenitor cells into oligodendrocytes12. In addition, the involvement of EVs in the formation of the pre-metastatic niche13, or the neuroprotective role of EVs containing Cystatin C14, were also investigated.
Tools and methods for studying Extracellular Vesicles
Given EVs size and heterogeneity, their isolation, detection and characterization still remains a challenge, although much effort is being made to improve methodological tools for EV study. A new aqueous two-phase system-based isolation protocol for EVs isolation at high efficiency and purity was reported15. A further Article reported a new EV immunolabeling method that can be incorporated into existing NTA protocols to provide particle concentration, size distribution, and surface phenotype of EV samples16. In addition, a luminescence-based assay for EV uptake assays – clearly discriminating between EV uptake, and EV binding to the target cell – has been developed17. Finally, an inducible CD9-GFP mouse was generated, providing a tool that enables EV labelling in a cell-type specific manner, while simultaneously allowing in vivo experimentation18.
Many thanks to all the contributors (authors and reviewers) to this Collection.
Roman-Canal, B. et al. EV-associated miRNAs from pleural lavage as potential diagnostic biomarkers in lung cancer. Sci. Rep 9, 1–9 (2019).
Hon, K. W., Ab-Mutalib, N. S., Abdullah, N. M. A., Jamal, R. & Abu, N. Extracellular Vesicle-derived circular RNAs confers chemoresistance in Colorectal cancer. Sci. Rep 9, 1–13 (2019).
de Miguel Pérez, D. et al. Extracellular vesicle-miRNAs as liquid biopsy biomarkers for disease identification and prognosis in metastatic colorectal cancer patients. Sci. Rep. 10, 1–13 (2020).
Gámez-Valero, A., Campdelacreu, J., Reñé, R., Beyer, K. & Borràs, F. E. Comprehensive proteomic profiling of plasma-derived Extracellular Vesicles from dementia with Lewy Bodies patients. Sci. Rep 9, 1–13 (2019).
An, J. H., Li, Q., Bhang, D. H., Song, W. J. & Youn, H. Y. TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis. Sci. Rep 10, 1–14 (2020).
Kore, R. A. et al. Molecular events in MSC exosome mediated cytoprotection in cardiomyocytes. Sci. Rep 9, 1–12 (2019).
Lu, J., Yang, J., Zheng, Y., Chen, X. & Fang, S. Extracellular vesicles from endothelial progenitor cells prevent steroid-induced osteoporosis by suppressing the ferroptotic pathway in mouse osteoblasts based on bioinformatics evidence. Sci. Rep 9, 1–18 (2019).
Do, M. A., Levy, D., Brown, A., Marriott, G. & Lu, B. Targeted delivery of lysosomal enzymes to the endocytic compartment in human cells using engineered extracellular vesicles. Sci. Rep 9, 1–11 (2019).
Singhto, N., Vinaiphat, A. & Thongboonkerd, V. Discrimination of urinary exosomes from microvesicles by lipidomics using thin layer liquid chromatography (TLC) coupled with MALDI-TOF mass spectrometry. Sci. Rep 9, 1–11 (2019).
Williams, C. et al. Assessing the role of surface glycans of extracellular vesicles on cellular uptake. Sci. Rep 9, 1–14 (2019).
Ferraz, M., de, A. M. M., Carothers, A., Dahal, R., Noonan, M. J. & Songsasen, N. Oviductal extracellular vesicles interact with the spermatozoon’s head and mid-piece and improves its motility and fertilizing ability in the domestic cat. Sci. Rep 9, 1–12 (2019).
Willis, C. M. et al. Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with. Age. Sci. Rep. 10, 1–14 (2020).
Tubita, V. et al. Effect of immunosuppression in miRNAs from extracellular vesicles of colorectal cancer and their influence on the pre-metastatic niche. Sci. Rep 9, 1–11 (2019).
Pérez-González, R. et al. Neuroprotection mediated by cystatin C-loaded extracellular vesicles. Sci. Rep 9, 11104 (2019).
Kırbaş, O. K. et al. Optimized Isolation of Extracellular Vesicles From Various Organic Sources Using Aqueous Two-Phase System. Sci. Rep 9, 1–11 (2019).
Thane, K. E., Davis, A. M. & Hoffman, A. M. Improved methods for fluorescent labeling and detection of single extracellular vesicles using nanoparticle tracking analysis. Sci. Rep 9, 1–13 (2019).
Toribio, V. et al. Development of a quantitative method to measure EV uptake. Sci. Rep 9, 1–14 (2019).
Neckles, V. N. et al. A transgenic inducible GFP extracellular-vesicle reporter (TIGER) mouse illuminates neonatal cortical astrocytes as a source of immunomodulatory extracellular vesicles. Sci. Rep 9, 1–11 (2019).
This work was supported by the Instituto de Salud Carlos III, Ministerio de Economía y Competividad, co-funded by the ESF European Social Fund (MS16/00124).
The authors declare no competing interests.
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Ramis, J.M. Extracellular Vesicles in Cell Biology and Medicine. Sci Rep 10, 8667 (2020). https://doi.org/10.1038/s41598-020-65826-z
Archivum Immunologiae et Therapiae Experimentalis (2021)