Rianne de Jongh1, Xandor M. Spijkers1,2, Svetlana Pasteuning‐Vuhman1,
Paul Vulto2 R. Jeroen Pasterkamp1
Neuromuscular Junction‐on‐a‐Chip:
ALS disease modeling and read‐out development in microfluidic devices
Journal of Neurochemistry
Open Access 31 December 2020
DOI: 10.1111/jnc.15289
1 Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
2 Mimetas B.V., Organ-on-a-chip Company, Leiden, The Netherlands
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease affecting upper and lower motor neurons with no cure available. Clinical and animal studies reveal that the neuromuscular junction (NMJ), a synaptic connection between motor neurons and skeletal muscle fibers, is highly vulnerable in ALS and suggest that NMJ defects may occur at early stages of the disease. However, mechanistic insight into how NMJ dysfunction relates to the onset and progression of ALS is incomplete, which hampers therapy development. This is, in part, caused by a lack of robust in vitro models. The ability to combine microfluidic and induced pluripotent stem cell (iPSC) technologies has opened up new avenues for studying molecular and cellular ALS phenotypes in vitro. Microfluidic devices offer several advantages over traditional culture approaches when modeling the NMJ, such as the spatial separation of different cell types and increased control over the cellular microenvironment. Moreover, they are compatible with 3D cell culture, which enhances NMJ functionality and maturity. Here, we review how microfluidic technology is currently being employed to develop more reliable in vitro NMJ models. To validate and phenotype such models, various morphological and functional read‐outs have been developed. We describe and discuss the relevance of these read‐outs and specifically illustrate how these read‐outs have enhanced our understanding of NMJ pathology in ALS. Finally, we share our view on potential future directions and challenges.
FIG: Overview of some of the morphological and functional read-outs that can be used
in NMJ-on-a-chip models for studying ALS disease mechanisms.
Acknowledgements: We thank Dr. Ewout Groen and Prof. Eran Perlson for carefully reading the manuscript, and Frederik Schavemaker for help with preparing the Figures. Work in the laboratory of R.J.P. is supported by the ALS Stichting Nederland (TOTALS, ALS-on-a-Chip) and by the MAXOMOD and INTEGRALS consortia under the frame of E-Rare-3, the ERANet for Research on Rare Diseases.
