Cell Stem Cell
Volume 26, Issue 2, 6 February 2020, Pages 172-186.e6
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Article
Self-Organizing 3D Human Trunk Neuromuscular Organoids

https://doi.org/10.1016/j.stem.2019.12.007Get rights and content
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Highlights

  • hPSC-derived neuromesodermal progenitors generate functional NMOs in 3D

  • Functional NMJs are generated in NMOs supported by terminal Schwann cells

  • NMOs contract and develop central pattern generator-like circuits

  • NMOs can be used to model key aspects of myasthenia gravis

Summary

Neuromuscular networks assemble during early human embryonic development and are essential for the control of body movement. Previous neuromuscular junction modeling efforts using human pluripotent stem cells (hPSCs) generated either spinal cord neurons or skeletal muscles in monolayer culture. Here, we use hPSC-derived axial stem cells, the building blocks of the posterior body, to simultaneously generate spinal cord neurons and skeletal muscle cells that self-organize to generate human neuromuscular organoids (NMOs) that can be maintained in 3D for several months. Single-cell RNA-sequencing of individual organoids revealed reproducibility across experiments and enabled the tracking of the neural and mesodermal differentiation trajectories as organoids developed and matured. NMOs contain functional neuromuscular junctions supported by terminal Schwann cells. They contract and develop central pattern generator-like neuronal circuits. Finally, we successfully use NMOs to recapitulate key aspects of myasthenia gravis pathology, thus highlighting the significant potential of NMOs for modeling neuromuscular diseases in the future.

Keywords

neuromesodermal progenitors
NMPs
neuromuscular organoids
NMOs
neuromuscular diseases
neuromuscular junction
myasthenia gravis
central pattern generators
skeletal muscles
spinal cord

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