2. Academic Validation
  3. 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

  • Cells. 2022 Dec 4;11(23):3923. doi: 10.3390/cells11233923.
Francesca Provenzano 1,  Sophie Nyberg 2,  Debora Giunti 3 4,  Carola Torazza 1,  Benedetta Parodi 3,  Tiziana Bonifacino 1 5,  Cesare Usai 6,  Nicole Kerlero de Rosbo 4 7,  Marco Milanese 1 4,  Antonio Uccelli 3 4,  Pamela J Shaw 2,  Laura Ferraiuolo 2,  Giambattista Bonanno 1 4
Affiliations

Affiliations

  • 1 Department of Pharmacy (DIFAR), University of Genoa, Viale Cembrano 4, 16148 Genova, Italy.
  • 2 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
  • 3 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Paolo Daneo, 316132 Genoa, Italy.
  • 4 IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
  • 5 Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 56122 Pisa, Italy.
  • 6 Institute of Biophysics, National Research Council (CNR), Via De Marini 6, 16149 Genoa, Italy.
  • 7 TomaLab, Institute of Nanotechnology, National Research Council (CNR), Piazzale Aldo Moro 5, 0018 Rome, Italy.
PMID: 36497181 DOI: 10.3390/cells11233923
Abstract

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.

Keywords

adult mice spinal cord astrocytes; amyotrophic lateral sclerosis; cell therapy; extracellular vesicles; iNPCs-derived human astrocytes; mesenchymal stem cells.

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