Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Stem Cell Reports |
Volume | 16 |
Issue number | 9 |
Pages (from-to) | 2213-2227 |
Number of pages | 15 |
ISSN | 2213-6711 |
DOIs | |
Publication status | Published - 2021 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:
© 2021 The Authors
- amyotrophic lateral sclerosis, FUS, HDAC6, microfluidic device, neurite outgrowth, neurite regrowth, neuromuscular junction, Tubastatin A
Research areas
ID: 368622968