Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions

João D. Pereira, Daniel M. DuBreuil, Anna-Claire Devlin, Aaron Held, Yechiam Sapir, Eugene Berezovski, James Hawrot, Katherine Dorfman, Vignesh Chander and Brian J. Wainger ()
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João D. Pereira: Massachusetts General Hospital, Harvard Medical School
Daniel M. DuBreuil: Massachusetts General Hospital, Harvard Medical School
Anna-Claire Devlin: Massachusetts General Hospital, Harvard Medical School
Aaron Held: Massachusetts General Hospital, Harvard Medical School
Yechiam Sapir: Massachusetts General Hospital, Harvard Medical School
Eugene Berezovski: Massachusetts General Hospital, Harvard Medical School
James Hawrot: Massachusetts General Hospital, Harvard Medical School
Katherine Dorfman: Massachusetts General Hospital, Harvard Medical School
Vignesh Chander: Massachusetts General Hospital, Harvard Medical School
Brian J. Wainger: Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. Here, we generate sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and apply the model to different subgroups of amyotrophic lateral sclerosis (ALS). Using a range of molecular, genomic, and physiological techniques, we identify and characterize motor neurons and skeletal muscle, along with sensory neurons, astrocytes, microglia, and vasculature. Organoid cultures derived from multiple human iPSC lines generated from individuals with ALS and isogenic lines edited to harbor familial ALS mutations show impairment at the level of the NMJ, as detected by both contraction and immunocytochemical measurements. The physiological resolution of the human NMJ synapse, combined with the generation of major cellular cohorts exerting autonomous and non-cell autonomous effects in motor and sensory diseases, may prove valuable to understand the pathophysiological mechanisms of ALS.

Date: 2021
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DOI: 10.1038/s41467-021-24776-4

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