{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T11:43:48Z","timestamp":1771328628059,"version":"3.50.1"},"reference-count":132,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-NEU\/31395\/2017"],"award-info":[{"award-number":["PTDC\/MED-NEU\/31395\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Santa Casa Scientific Research Program on ALS, by Santa Casa da Miseric\u00f3rdia de Lisboa (SCML)","award":["ELA-2015-002"],"award-info":[{"award-number":["ELA-2015-002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four sporadic (sALS) and three mSOD1-ALS patients were transdifferentiated into induced astrocytes (iAstrocytes). ALS iAstrocytes were neurotoxic toward HB9-GFP mouse motor neurons (MNs) and exhibited subtype stratification through GFAP, CX43, Ki-67, miR-155 and miR-146a expression levels. Up- (two cases) and down-regulated (three cases) miR-146a values in iAstrocytes were recapitulated in their secretome, either free or as cargo in small extracellular vesicles (sEVs). We previously showed that the neuroprotective phenotype of depleted miR-146 mSOD1 cortical astrocytes was reverted by its mimic. Thus, we tested such modulation in the most miR-146a-depleted patient-iAstrocytes (one sALS and one mSOD1-ALS). The miR-146a mimic in ALS iAstrocytes counteracted their reactive\/inflammatory profile and restored miR-146a levels in sEVs. A reduction in lysosomal activity and enhanced synaptic\/axonal transport-related genes in NSC-34 MNs occurred after co-culture with miR-146a-modulated iAstrocytes. In summary, the regulation of miR-146a in depleted ALS astrocytes may be key in reestablishing their normal function and in restoring MN lysosomal\/synaptic dynamic plasticity in disease sub-groups.<\/jats:p>","DOI":"10.3390\/cells11071186","type":"journal-article","created":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T21:22:39Z","timestamp":1648848159000},"page":"1186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Neurotoxic Astrocytes Directly Converted from Sporadic and Familial ALS Patient Fibroblasts Reveal Signature Diversities and miR-146a Theragnostic Potential in Specific Subtypes"],"prefix":"10.3390","volume":"11","author":[{"given":"C\u00e1tia","family":"Gomes","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}]},{"given":"Catarina","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Shibi","family":"Likhite","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}]},{"given":"Cassandra N.","family":"Dennys","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8503-8459","authenticated-orcid":false,"given":"Stephen J.","family":"Kolb","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43214, USA"}]},{"given":"Pamela J.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3418-3269","authenticated-orcid":false,"given":"Ana R.","family":"Vaz","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]},{"given":"Brian K.","family":"Kaspar","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"}]},{"given":"Kathrin","family":"Meyer","sequence":"additional","affiliation":[{"name":"The Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"},{"name":"Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3024-9777","authenticated-orcid":false,"given":"Dora","family":"Brites","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"},{"name":"Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"566858","DOI":"10.3389\/fnins.2020.566858","article-title":"Amyotrophic Lateral Sclerosis: A Neurodegenerative Motor Neuron Disease with Ocular Involvement","volume":"14","author":"Rojas","year":"2020","journal-title":"Front. 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