Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition.
Stem Cell Reports
; 16(9): 2213-2227, 2021 09 14.
Article
em En
| MEDLINE
| ID: mdl-33891869
ABSTRACT
Neuromuscular junctions (NMJs) ensure communication between motor neurons (MNs) and muscle; however, in MN disorders, such as amyotrophic lateral sclerosis (ALS), NMJs degenerate resulting in muscle atrophy. The aim of this study was to establish a versatile and reproducible in vitro model of a human motor unit to investigate the effects of ALS-causing mutations. Therefore, we generated a co-culture of human induced pluripotent stem cell (iPSC)-derived MNs and human primary mesoangioblast-derived myotubes in microfluidic devices. A chemotactic and volumetric gradient facilitated the growth of MN neurites through microgrooves resulting in the interaction with myotubes and the formation of NMJs. We observed that ALS-causing FUS mutations resulted in reduced neurite outgrowth as well as an impaired neurite regrowth upon axotomy. NMJ numbers were likewise reduced in the FUS-ALS model. Interestingly, the selective HDAC6 inhibitor, Tubastatin A, improved the neurite outgrowth, regrowth, and NMJ morphology, prompting HDAC6 inhibition as a potential therapeutic strategy for ALS.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína FUS de Ligação a RNA
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Inibidores de Histona Desacetilases
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Dispositivos Lab-On-A-Chip
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Desacetilase 6 de Histona
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Mutação
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Junção Neuromuscular
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Revista:
Stem Cell Reports
Ano de publicação:
2021
Tipo de documento:
Article