Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition
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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.
Originalsprog | Engelsk |
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Tidsskrift | Stem Cell Reports |
Vol/bind | 16 |
Udgave nummer | 9 |
Sider (fra-til) | 2213-2227 |
Antal sider | 15 |
ISSN | 2213-6711 |
DOI | |
Status | Udgivet - 2021 |
Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
The authors thank Sebastian Munck and Nikky Corthout from LiMoNe, Research Group Molecular Neurobiology (VIB-KU Leuven) for discussions concerning Ca 2+ live-cell imaging. This research was supported by the Fulbright Commission to Belgium and Luxembourg, the VIB, the KU Leuven (C1 and “Opening the Future” Fund), the “Fund for Scientific Research Flanders” (FWO-Vlaanderen), the Agency for Innovation by Science and Technology (IWT; SBO-iPSCAF), the Belgian Government (Interuniversity Attraction Poles Program P7/16 initiated by the Belgian Federal Science Policy Office ), the Thierry Latran Foundation , the “Association Belge contre les Maladies neuro-Musculaires” (ABMM), Target ALS, and the ALS Liga België (A Cure for ALS). T.V., E.R., and J.B. are supported by strategic basic research PhD fellowships awarded by FWO-Vlaanderen.
Publisher Copyright:
© 2021 The Authors
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