Functional connectivity under optogenetic control allows modeling of human neuromuscular disease

Cell Stem Cell, 2016 · DOI: 10.1016/j.stem.2015.10.002 · Published: January 7, 2016

Neurology Regenerative Medicine & Stem Cells

Simple Explanation

The study establishes optogenetic control in human pluripotent stem cell (PSC)-derived spinal motorneurons. These motorneurons are co-cultured with human myoblast-derived skeletal muscle to create a functional neuromuscular junction. This functional neuromuscular junction can be triggered to twitch upon light stimulation.

Study Duration

Not specified

Participants

Myasthenia gravis patients and healthy donors

Evidence Level

Not specified

Key Findings

1
Optogenetic stimulation produced calcium spikes in myofibers, which could be blocked by vecuronium.
2
MG IgG and complement significantly decreased contractility in co-cultures, mimicking myasthenia gravis.
3
Pyridostigmine application in MG cultures induced a significant therapeutic effect, increasing muscle contraction.

Research Summary

The study establishes optogenetic control in human PSC-derived spinal motorneurons and demonstrates functional connectivity with human skeletal muscle. The resulting neuromuscular junction can be triggered by light stimulation and used to model neuromuscular disease, specifically myasthenia gravis. The model recapitulates key aspects of myasthenia gravis pathology, including reduced muscle contraction amplitude and the therapeutic effect of pyridostigmine.

Practical Implications

Disease Modeling

The developed neuromuscular junction assay has significant potential for modeling neuromuscular diseases.

Regenerative Medicine

The study provides a platform for assessing neuronal connectivity in complex human culture systems, relevant to regenerative medicine.

Drug Discovery

The assay can be used for drug screening and the dissection of disease processes originating from either side of the neuromuscular junction.

Study Limitations

1
The neuromuscular co-cultures express the fetal gamma subunit of the acetylcholine receptor, not the adult epsilon subunit.
2
The system requires further refinement to induce full maturation of neuromuscular synapses.
3
The study used IgG fractions from only two MG patients.

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