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Cell Stem Cell. 2020 Feb 6;26(2):172-186.e6. doi: 10.1016/j.stem.2019.12.007. Epub 2020 Jan 16.

Self-Organizing 3D Human Trunk Neuromuscular Organoids.

Author information

1
Stem Cell Modelling of Development & Disease Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
2
Scientific Genomics Platforms, Laboratory of Functional Genomics, Nutrigenomics and Systems Biology, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
3
Electron Microscopy Core Facility, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
4
Developmental Biology and Signal Transduction Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
5
Muscle Research Unit, Experimental and Clinical Research Center (ECRC), Charité Medical Faculty, and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
6
Stem Cell Modelling of Development & Disease Group, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: mina.gouti@mdc-berlin.de.

Abstract

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:

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

PMID:
31956040
DOI:
10.1016/j.stem.2019.12.007

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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