Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition.
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Authors
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Stoklund Dittlau, Katarina1
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Krasnow, Emily N1
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Fumagalli, Laura1
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Vandoorne, Tijs1
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Baatsen, Pieter2
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Kerstens, Axelle2
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Giacomazzi, Giorgia3
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Pavie, Benjamin2
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Rossaert, Elisabeth1
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Beckers, Jimmy1
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Sampaolesi, Maurilio3
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Van Damme, Philip4
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Van Den Bosch, Ludo5
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1
KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium.
,
(Belgium)
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2
VIB, Center for Brain & Disease Research, Research Group Molecular Neurobiology, Leuven, Belgium; KU Leuven - University of Leuven, VIB Bio Imaging Core, Leuven, Belgium.
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(Belgium)
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3
KU Leuven - University of Leuven, Department of Development and Regeneration, Stem Cell and Developmental Biology, Leuven, Belgium.
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(Belgium)
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4
KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
,
(Belgium)
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5
KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium. Electronic address: [email protected]
,
(Belgium)
- Type
- Published Article
- Journal
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Stem Cell Reports
- Publisher
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Elsevier
- Publication Date
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Sep 14, 2021
- Volume
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16
- Issue
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9
- Pages
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2213–2227
- Identifiers
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DOI: 10.1016/j.stemcr.2021.03.029
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PMID: 33891869
- Source
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Medline
- Keywords
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- Language
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English
- License
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Unknown
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. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
This record was last updated on 01/14/2022 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at
https://www.ncbi.nlm.nih.gov/pubmed/33891869
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