Isolation and characterization of extracellular vesicles and future directions in diagnosis and therapy

Sousa, Karina Pires de; Rossi, Izadora Volpato; Abdullahi, Mahamed; Ramirez, Marcel I.; Stratton, Dan; Inal, Jameel M.

doi:10.1002/wnan.1835

Cited by 97 publications

(63 citation statements)

References 259 publications

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“…Accordingly, the literature reports that EVs from adipose stem cells ameliorate the disease course in SOD1 G93A mice [ 75 ]. EVs have been demonstrated to play a key role in pathological processes since their cargo can contribute to the spread or modulation of a disease, but indeed they can be also exploited as a therapeutic strategy to overcome neurodegeneration associated with CNS pathologies, and this has been demonstrated with particular emphasis on Alzheimer’s disease and Parkinson’s disease, other than amyotrophic lateral sclerosis [ 76 , 77 ]. In particular, EVs secreted by MSCs have aroused considerable interest as a potential cell-free therapy [ 78 , 79 ].…”

Section: Discussionmentioning

confidence: 99%

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

Provenzano

Nyberg

Giunti

et al. 2022

Cells

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes’ neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration in SOD1G93A ALS mice, but the mechanisms are still unclear. We postulated that the effects could be mediated by extracellular vesicles (EVs) secreted by MSCs. We investigated, by immunohistochemical, molecular, and in vitro functional analyses, the activity of MSC-derived EVs on the pathological phenotype and neurotoxicity of astrocytes isolated from the spinal cord of symptomatic SOD1G93A mice and human astrocytes (iAstrocytes) differentiated from inducible neural progenitor cells (iNPCs) of ALS patients. In vitro EV exposure rescued mouse and human ALS astrocytes’ neurotoxicity towards MNs. EVs significantly dampened the pathological phenotype and neuroinflammation in SOD1G93A astrocytes. In iAstrocytes, exposure to EVs increased the antioxidant factor Nrf2 and reduced reactive oxygen species. We previously found nine miRNAs upregulated in MSC-derived EVs. Here, the transfection of SOD1G93A astrocytes with single miRNA mimics reduced astrocytes’ activation and the expression of neuroinflammatory factors. Moreover, miR-466q and miR-467f mimics downregulate Mapk11, while miR-466m-5p and miR-466i-3p mimics promote the nuclear translocation of Nrf2. In iAstrocytes, transfection with miR-29b-3p mimic upregulated NQO1 antioxidant activity and reduced neurotoxicity towards MNs. MSC-derived EVs modulate astrocytes’ reactive phenotype and neurotoxicity through anti-inflammatory and antioxidant-shuttled miRNAs, thus representing a therapeutic strategy in ALS.

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Section: Discussionmentioning

confidence: 99%

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

Provenzano

Nyberg

Giunti

et al. 2022

Cells

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“…EVs are membrane-bound intercellular communicative vesicles [ 21 ]. Carrying receptor proteins, cytokines, miRNA, mRNA, bioactive lipids and various metabolites, they are released from a wide range of cells and found in all body fluids and interstitial spaces [ 22 ]. Classified according to their mechanism of biogenesis, EVs comprise exosomes, microvesicles (or microparticles/ectosomes, MVs) and apoptotic bodies (ApoBs).…”

Section: Calpeptin-mediated Inhibition Of Extracellular Vesicle/sars-...mentioning

confidence: 99%

Therapeutic use of calpeptin in COVID-19 infection

2022

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This perspective considers the benefits of the potential future use of the cell permeant calpain inhibitor, calpeptin, as a drug to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recent work has reported calpeptin’s capacity to inhibit entry of the virus into cells. Elsewhere, several drugs, including calpeptin, were found to be able to inhibit extracellular vesicle (EV) biogenesis. Unsurprisingly, because of similarities between viral and EV release mechanisms, calpeptin has also been shown to inhibit viral egress. This approach, identifying calpeptin, through large-scale screening studies as a candidate drug to treat COVID-19, however, has not considered the longer term likely benefits of calpain inhibition, post-COVID-19. This perspective will reflect on the capacity of calpeptin for treating long COVID by inhibiting the overproduction of neutrophil extracellular traps potentially damaging lung cells and promoting clotting, together with limiting associated chronic inflammation, tissue damage and pulmonary fibrosis. It will also reflect on the tolerated and detrimental in vivo side-effects of calpain inhibition from various preclinical studies.

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“…Interestingly, the composition of EVs also varies depending on the producing cells, thus suggesting the possibility to use EVs, collected from different biological fluids, as diagnostic biomarkers [ 271 , 272 , 273 , 274 , 275 ].…”

Section: Role Of Rbps In Rna Sorting To Extracellular Vesiclesmentioning

confidence: 99%

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

Schiera

Schirò

Liegro

2022

IJMS

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A central aspect of nervous system development and function is the post-transcriptional regulation of mRNA fate, which implies time- and site-dependent translation, in response to cues originating from cell-to-cell crosstalk. Such events are fundamental for the establishment of brain cell asymmetry, as well as of long-lasting modifications of synapses (long-term potentiation: LTP), responsible for learning, memory, and higher cognitive functions. Post-transcriptional regulation is in turn dependent on RNA-binding proteins that, by recognizing and binding brief RNA sequences, base modifications, or secondary/tertiary structures, are able to control maturation, localization, stability, and translation of the transcripts. Notably, most RBPs contain intrinsically disordered regions (IDRs) that are thought to be involved in the formation of membrane-less structures, probably due to liquid–liquid phase separation (LLPS). Such structures are evidenced as a variety of granules that contain proteins and different classes of RNAs. The other side of the peculiar properties of IDRs is, however, that, under altered cellular conditions, they are also prone to form aggregates, as observed in neurodegeneration. Interestingly, RBPs, as part of both normal and aggregated complexes, are also able to enter extracellular vesicles (EVs), and in doing so, they can also reach cells other than those that produced them.

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Isolation and characterization of extracellular vesicles and future directions in diagnosis and therapy

Cited by 97 publications

References 259 publications

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

Therapeutic use of calpeptin in COVID-19 infection

RNA-Binding Proteins as Epigenetic Regulators of Brain Functions and Their Involvement in Neurodegeneration

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