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Sensorimotor Organoids for Neuromuscular Disease

29 Pages Posted: 21 Feb 2019 Sneak Peek Status: Review Complete

See all articles by João D. Pereira

João D. Pereira

Harvard University - Department of Neurology

Anna-Claire Devlin

Harvard University - Department of Neurology

Daniel M. DuBreuil

Harvard University - Department of Neurology

Yechiam Sapir

Harvard University - Department of Neurology

Eugene Berezovski

Harvard University - Department of Neurology

Vignesh Chander

Harvard University - Department of Neurology

Brian J. Wainger

Harvard University - Department of Neurology

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Abstract

Human induced pluripotent stem cells (iPSCs) hold substantial promise for modeling diseases in the relevant human genetic backgrounds. Here, we leverage the shared developmental pathways of spinal neuroectoderm and paraxial mesoderm via neuromesodermal precursors to produce a sensorimotor organoid model, which we validate with single-cell RNA sequencing and physiology in multiple control and diseased human stem cell lines. The organoids contain motor neurons and skeletal muscle connected by physiologically functional neuromuscular junctions. We also generate additional neuronal and mesodermal derivatives, identified by RNA-seq cluster analysis and verified by staining, electron microscopy, and physiology. These cell types include astrocytes, endothelial cells, microglia, and sensory neurons, the last from which we record tetrodotoxin-resistant sodium currents and capsaicin-elicited calcium flux. The physiological resolution of the neuromuscular junction synapse combined with the generation of major cellular cohorts exerting autonomous and non-cell autonomous effects in motor and sensory diseases may prove valuable for more comprehensive disease modeling.

Suggested Citation

Pereira, João D. and Devlin, Anna-Claire and DuBreuil, Daniel M. and Sapir, Yechiam and Berezovski, Eugene and Chander, Vignesh and Wainger, Brian J., Sensorimotor Organoids for Neuromuscular Disease (February 16, 2019). Available at SSRN: https://ssrn.com/abstract=3335779 or http://dx.doi.org/10.2139/ssrn.3335779
This is a paper under consideration at Cell Press and has not been peer-reviewed.

João D. Pereira

Harvard University - Department of Neurology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Anna-Claire Devlin

Harvard University - Department of Neurology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Daniel M. DuBreuil

Harvard University - Department of Neurology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Yechiam Sapir

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Eugene Berezovski

Harvard University - Department of Neurology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Vignesh Chander

Harvard University - Department of Neurology

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Brian J. Wainger (Contact Author)

Harvard University - Department of Neurology ( email )

55 Fruit Street Boston
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

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