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Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition.

Authors
  • Stoklund Dittlau, Katarina1
  • Krasnow, Emily N1
  • Fumagalli, Laura1
  • Vandoorne, Tijs1
  • Baatsen, Pieter2
  • Kerstens, Axelle2
  • Giacomazzi, Giorgia3
  • Pavie, Benjamin2
  • Rossaert, Elisabeth1
  • Beckers, Jimmy1
  • Sampaolesi, Maurilio3
  • Van Damme, Philip4
  • Van Den Bosch, Ludo5
  • 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)
  • 2 VIB, Center for Brain & Disease Research, Research Group Molecular Neurobiology, Leuven, Belgium; KU Leuven - University of Leuven, VIB Bio Imaging Core, Leuven, Belgium. , (Belgium)
  • 3 KU Leuven - University of Leuven, Department of Development and Regeneration, Stem Cell and Developmental Biology, Leuven, Belgium. , (Belgium)
  • 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)
  • 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
Stem Cell Reports
Publisher
Elsevier
Publication Date
Sep 14, 2021
Volume
16
Issue
9
Pages
2213–2227
Identifiers
DOI: 10.1016/j.stemcr.2021.03.029
PMID: 33891869
Source
Medline
Keywords
Language
English
License
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.

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