Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation

Abstract Mesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). O...

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Autores principales: Debora Giunti, Chiara Marini, Benedetta Parodi, Cesare Usai, Marco Milanese, Giambattista Bonanno, Nicole Kerlero de Rosbo, Antonio Uccelli
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Publicado: Nature Portfolio 2021
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Acceso en línea:https://doaj.org/article/40e21f5e398c46c497545b4acec1a82e
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spelling oai:doaj.org-article:40e21f5e398c46c497545b4acec1a82e2021-12-02T10:49:16ZRole of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation10.1038/s41598-021-81039-42045-2322https://doaj.org/article/40e21f5e398c46c497545b4acec1a82e2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81039-4https://doaj.org/toc/2045-2322Abstract Mesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One mode of action through which MSCs exert their immunomodulatory effects is release of extracellular vesicles that carry proteins, mRNAs, and microRNAs (miRNAs), which, once transferred, modify the function of target cells. We identified nine miRNAs significantly dysregulated in IFN-γ-primed MSCs, but present at different levels in their derived small extracellular vesicles (s-EV). We show that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression. Further analysis of the mode of action of miR-467f and miR-466q indicated that they dampen the pro-inflammatory phenotype of microglia by modulating p38 MAPK signaling pathway via inhibition of expression of their target genes, Map3k8 and Mk2. Finally, we demonstrated that in vivo administration of s-EV leads to decreased expression of neuroinflammation markers in the spinal cord of EAE-affected mice, albeit without affecting disease course. Overall, our data suggest that MSC-derived exosomes could affect neuroinflammation possibly through specific immunomodulatory miRNAs acting on microglia.Debora GiuntiChiara MariniBenedetta ParodiCesare UsaiMarco MilaneseGiambattista BonannoNicole Kerlero de RosboAntonio UccelliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Debora Giunti
Chiara Marini
Benedetta Parodi
Cesare Usai
Marco Milanese
Giambattista Bonanno
Nicole Kerlero de Rosbo
Antonio Uccelli
Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
description Abstract Mesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One mode of action through which MSCs exert their immunomodulatory effects is release of extracellular vesicles that carry proteins, mRNAs, and microRNAs (miRNAs), which, once transferred, modify the function of target cells. We identified nine miRNAs significantly dysregulated in IFN-γ-primed MSCs, but present at different levels in their derived small extracellular vesicles (s-EV). We show that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression. Further analysis of the mode of action of miR-467f and miR-466q indicated that they dampen the pro-inflammatory phenotype of microglia by modulating p38 MAPK signaling pathway via inhibition of expression of their target genes, Map3k8 and Mk2. Finally, we demonstrated that in vivo administration of s-EV leads to decreased expression of neuroinflammation markers in the spinal cord of EAE-affected mice, albeit without affecting disease course. Overall, our data suggest that MSC-derived exosomes could affect neuroinflammation possibly through specific immunomodulatory miRNAs acting on microglia.
format article
author Debora Giunti
Chiara Marini
Benedetta Parodi
Cesare Usai
Marco Milanese
Giambattista Bonanno
Nicole Kerlero de Rosbo
Antonio Uccelli
author_facet Debora Giunti
Chiara Marini
Benedetta Parodi
Cesare Usai
Marco Milanese
Giambattista Bonanno
Nicole Kerlero de Rosbo
Antonio Uccelli
author_sort Debora Giunti
title Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
title_short Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
title_full Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
title_fullStr Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
title_full_unstemmed Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
title_sort role of mirnas shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/40e21f5e398c46c497545b4acec1a82e
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