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MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles

Osorio-Querejeta, Iñaki, Carregal-Romero, Susana, Ayerdi-Izquierdo, Ana, Mäger, Imre, Nash, Leslie A., Wood, Matthew, Egimendia, Ander, Betanzos, M., Alberro, Ainhoa, Iparraguirre, Leire, Moles, Laura, Llarena, Irantzu, Möller, Marco, Goñi-de-Cerio, Felipe, Bijelic, Goran, Ramos-Cabrer, Pedro, Muñoz-Culla, Maider, Otaegui, David·2020·Pharmaceutics
DOI 10.3390/pharmaceutics12020186PMC PMC7076664
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Abstract

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood–brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients.

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Figures

Figure 1 Schematic representation of liposomes, polymeric nanoparticles and extracellular vesicles. Carriers with their main components and the type of miR219a-5p they were loaded with. Liposomes and polymeric nanoparticles were loaded with synthetic microRNA. In contrast, extracellular vesicles (EVs) contained biologically produced microRNA. Polymeric nanoparticles and liposomes were also loaded with a dye (coumarin and DiOC18, respectively) to perform up-take studies.
Figure 1 Schematic representation of liposomes, polymeric nanoparticles and extracellular vesicles. Carriers with their main components and the type of miR219a-5p they were loaded with. Liposomes and polymeric nanoparticles were loaded with synthetic microRNA. In contrast, extracellular vesicles (EVs) contained biologically produced microRNA. Polymeric nanoparticles and liposomes were also loaded with a dye (coumarin and DiOC18, respectively) to perform up-take studies.CC BY · PubMed Central
Figure 2 Vehicles characterization: (A) Nanoparticle Tracking Analysis (NTA) of liposomes, polymeric nanoparticles and extracellular vesicles. (B) Transmission electron cryomicroscopy images of the three vehicles showing correlation in size with NTA. (C) Levels of miR-219a-5p in liposomes (219-Lp), nanoparticles (219-Np) and Extracellular vesicles (219-EVs). Liposomes are the most enriched vehicles followed by nanoparticles and finally EVs.
Figure 2 Vehicles characterization: (A) Nanoparticle Tracking Analysis (NTA) of liposomes, polymeric nanoparticles and extracellular vesicles. (B) Transmission electron cryomicroscopy images of the three vehicles showing correlation in size with NTA. (C) Levels of miR-219a-5p in liposomes (219-Lp), nanoparticles (219-Np) and Extracellular vesicles (219-EVs). Liposomes are the most enriched vehicles followed by nanoparticles and finally EVs.CC BY · PubMed Central
Figure 3 Up-take and differentiation levels of oligodendrocyte precursor cells (OPCs) after vehicles administration. (A) Uptake studies of liposomes, polymeric nanoparticles and extracellular vesicles. Liposomes containing 3,3′-Dioctadecyloxacarbocyanine perchlorate dissolved in chloroform (1mg/mL) (DOiC)18 (green) and mimic-Red (red), nanoparticles containing Coumarin (green) and mimic-Red (red) and EVs labelled with CM-DiL (red) are shown. Dapi (blue) was used to stain nucleus. Individual cells are imaged by confocal fluorescence microscopy of representative samples. (B) Percentage of OPCs that are able to take up each vehicle. Liposomes are the most efficient vehicle followed by polymeric nanoparticles and finally EVs. (C) Expression levels (expressed as de logarithm 2 of the fold change; Log2FC) of myelin related genes in OPC cultures treated with each vehicle compared to the same empty vehicle. EVs are the only vehicle able to induce OPC differentiation. Note the lack of PDGFRa and NG2 data in liposomes due to technical problems.
Figure 3 Up-take and differentiation levels of oligodendrocyte precursor cells (OPCs) after vehicles administration. (A) Uptake studies of liposomes, polymeric nanoparticles and extracellular vesicles. Liposomes containing 3,3′-Dioctadecyloxacarbocyanine perchlorate dissolved in chloroform (1mg/mL) (DOiC)18 (green) and mimic-Red (red), nanoparticles containing Coumarin (green) and mimic-Red (red) and EVs labelled with CM-DiL (red) are shown. Dapi (blue) was used to stain nucleus. Individual cells are imaged by confocal fluorescence microscopy of representative samples. (B) Percentage of OPCs that are able to take up each vehicle. Liposomes are the most efficient vehicle followed by polymeric nanoparticles and finally EVs. (C) Expression levels (expressed as de logarithm 2 of the fold change; Log2FC) of myelin related genes in OPC cultures treated with each vehicle compared to the same empty vehicle. EVs are the only vehicle able to induce OPC differentiation. Note the lack of PDGFRa and NG2 data in liposomes due to technical problems.CC BY · PubMed Central
Figure 4 Transendothelial migration of liposomes and exosomes: Permeability of endothelial monolayer for liposomes and extracellular vesicles. Polymeric nanoparticles were not able to cross the blood–brain barrier (BBB) and are not, therefore, shown in the figure. EVs showed the highest levels of permeability, indicating that could be a proper candidate for microRNA delivery to the central nervous system (CNS). (*) p < 0.005 with respect to Liposomes values.
Figure 4 Transendothelial migration of liposomes and exosomes: Permeability of endothelial monolayer for liposomes and extracellular vesicles. Polymeric nanoparticles were not able to cross the blood–brain barrier (BBB) and are not, therefore, shown in the figure. EVs showed the highest levels of permeability, indicating that could be a proper candidate for microRNA delivery to the central nervous system (CNS). (*) p < 0.005 with respect to Liposomes values.CC BY · PubMed Central
Figure 5 Intranasal administration of miR-219a-5p enriched exosomes promotes myelin regeneration. (A) Clinical evaluation of animals treated with non-enriched extracellular vesicles (Ne-EVs) and with miR-219a-5p enriched extracellular vesicles (219-EVs) (100 μg of EVs per dose; animals received two doses at days 2 and 8 after disease induction). 219-EVs treated animals showed a significant decrease in the clinical evaluation after the disease peak (n = 4). (B) MRI of spinal cord of a Ne-EVs treated animal and a 219-EVs treated mouse showing the fractional anisotropy (FA). (C) FA values of a section of the spinal cord of previous animals showing a decrease in FA values when treatment was Ne-EVs, indicating that remyelination is occurring. (D) No significant differences between both groups in pro-inflammatory cytokines were found, indicating that the effect induced by EVs was not related to an anti-inflammatory process.
Figure 5 Intranasal administration of miR-219a-5p enriched exosomes promotes myelin regeneration. (A) Clinical evaluation of animals treated with non-enriched extracellular vesicles (Ne-EVs) and with miR-219a-5p enriched extracellular vesicles (219-EVs) (100 μg of EVs per dose; animals received two doses at days 2 and 8 after disease induction). 219-EVs treated animals showed a significant decrease in the clinical evaluation after the disease peak (n = 4). (B) MRI of spinal cord of a Ne-EVs treated animal and a 219-EVs treated mouse showing the fractional anisotropy (FA). (C) FA values of a section of the spinal cord of previous animals showing a decrease in FA values when treatment was Ne-EVs, indicating that remyelination is occurring. (D) No significant differences between both groups in pro-inflammatory cytokines were found, indicating that the effect induced by EVs was not related to an anti-inflammatory process.CC BY · PubMed Central

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Authors
Osorio-Querejeta, I., Carregal-Romero, S., Ayerdi-Izquierdo, A., Mäger, I., Nash, L. A., Wood, M., Egimendia, A., Betanzos, M., Alberro, A., Iparraguirre, L., Moles, L., Llarena, I., Möller, M., Goñi-de-Cerio, F., Bijelic, G., Ramos-Cabrer, P., Muñoz-Culla, M., & Otaegui, D.
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2020-02-21
Volume
12
Issue
2
Pages
186
ISSN
1999-4923
DOI
10.3390/pharmaceutics12020186
PMC
PMC7076664
Cited by
85
References
4
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Instituto de Salud Carlos III (PI17/00189 and DTS15/00069)
  • Gipuzkoa Regional Council (DFG 15/006)
  • European Regional Development Fund (PI17/00189 and DTS15/00069)
  • Eusko Jaurlaritza (RIS3/DTS/2018222025)
  • Spanish Estate Reserach Agency (SAF2017-87670-R)

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