期刊
CELLS
卷 11, 期 7, 页码 -出版社
MDPI
DOI: 10.3390/cells11071186
关键词
amyotrophic lateral sclerosis (ALS); astrocyte-mediated neurotoxicity; fibroblast-transdifferentiated astrocytes; inflammatory-associated miRNAs; miR-146a modulation; patient phenotype subtypes; small extracellular vesicles (sEVs); mutant SOD1 (mSOD1); sporadic ALS (sALS)
类别
资金
- Research Grant of the Santa Casa Scientific Research Program on ALS
- Santa Casa da Misericordia de Lisboa (SCML), Portugal [ELA-2015-002]
- Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/MED-NEU/31395/2017, UID/DTP/04138/2019, UIDB/UIDP/04138/2020]
- Programa Operacional Regional de Lisboa
- Programa Operacional Competitividade e Internacionalizacao [LISBOA-01-0145-FEDER-031395]
- FCT [SFRH/BD/102718/2014]
- SCML
- Muscular Dystrophy Association (MDA)
- Swiss National Science Foundation
- NIHR Sheffield Biomedical Research Centre [JS-BRC-1215-20017]
- Motor Neurone Disease Association [AMBRoSIA 972-797]
- Julie Bonasera Fund for ALS and Neuromuscular Diseases at the Ohio State University Wexner Medical Center
- Fundação para a Ciência e a Tecnologia [SFRH/BD/102718/2014] Funding Source: FCT
Transdifferentiation of fibroblasts from ALS patients into astrocytes can help study the pathophysiology of the disease. Modulating miR-146a can restore neuroprotective phenotype and improve neuronal function in ALS patients.
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.
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