Efficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells

Alessia Urzi, Ines Lahmann, Lan Vi N. Nguyen, Benjamin R. Rost, Angélica García-Pérez, Noemie Lelievre, Megan E. Merritt-Garza, Han C. Phan, Gary J. Bassell, Wilfried Rossoll, Sebastian Diecke, Severine Kunz, Dietmar Schmitz and Mina Gouti ()
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Alessia Urzi: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Ines Lahmann: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Lan Vi N. Nguyen: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Benjamin R. Rost: German Center for Neurodegenerative Diseases (DZNE)
Angélica García-Pérez: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Noemie Lelievre: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Megan E. Merritt-Garza: Emory University School of Medicine
Han C. Phan: University of Alabama
Gary J. Bassell: Emory University School of Medicine
Wilfried Rossoll: Mayo Clinic
Sebastian Diecke: Technology Platform Pluripotent Stem Cells
Severine Kunz: Technology Platform Electron Microscopy
Dietmar Schmitz: German Center for Neurodegenerative Diseases (DZNE)
Mina Gouti: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a robust and efficient self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells that can be maintained long-term in simple adherent conditions. The timely application of specific patterning signals instructs the simultaneous development and differentiation of position-specific brachial spinal neurons, skeletal muscles, and terminal Schwann cells. High-content imaging reveals self-organized bundles of aligned muscle fibers surrounded by innervating motor neurons that form functional neuromuscular junctions. Optogenetic activation and pharmacological interventions show that the spinal neurons actively instruct the synchronous skeletal muscle contraction. The generation of a soNMJ model from spinal muscular atrophy patient-specific iPSCs reveals that the number of NMJs and muscle contraction is severely affected, resembling the patient’s pathology. In the future, the soNMJ model could be used for high-throughput studies in disease modeling and drug development. Thus, this model will allow us to address unmet needs in the neuromuscular disease field.

Date: 2023
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DOI: 10.1038/s41467-023-43781-3

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