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New neuromuscular model promises to revolutionize high-throughput drug screening studies

manhattantribune.com by manhattantribune.com
19 December 2023
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A human self-organized 2D neuromuscular junction model. Immunofluorescence analysis of the whole dish shows muscle cells (magenta) organized into bundles surrounded by spinal cord neurons (cyan). Credit: Alessia Urzi, Max Delbrück Center

In neuromuscular diseases, neurons and muscle cells no longer communicate properly. Researchers led by Mina Gouti can now model this in 2D in a culture dish. Writing about their findings in Natural communicationsThey say, the new model promises to revolutionize high-throughput drug screening studies.

Scientists have so far identified around 800 different neuromuscular diseases. These conditions are caused by problems in the way muscle cells, motor neurons, and peripheral cells interact. These disorders, including amyotrophic lateral sclerosis and spinal muscular atrophy, cause muscle weakness, paralysis and, in some cases, death.

“These diseases are very complex and the causes of dysfunction can vary considerably,” explains Dr. Mina Gouti, head of the laboratory for stem cell modeling of development and disease at the Max Delbrück Center. The problem could be with neurons, muscle cells, or the connections between the two. “To better understand the causes and find effective therapies, we need human-specific cell culture models, in which we can study how motor neurons in the spinal cord interact with muscle cells.”

Organoids are too big for high-throughput studies

Researchers working with Gouti had already developed a three-dimensional neuromuscular organoid (NMO) system. “One of our goals is to use our crops for drug testing on a large scale,” says Gouti. “Three-dimensional organoids are very large and cannot be cultured for a long time in the 96-well culture dish that we use to perform high-throughput drug screening studies.”






A human self-organized 2D neuromuscular junction model from human pluripotent stem cells. Credit: Gouti Lab, Max Delbrück Center

For this type of screening, an international team led by Gouti developed a self-organized neuromuscular junction model using pluripotent stem cells. The model contains neurons, muscle cells and the chemical synapse called the neuromuscular junction which is necessary for the two types of cells to interact.

The researchers published their results in Natural communication. “The 2D self-organizing neuromuscular junction model will allow us to perform high-throughput drug screening for different neuromuscular diseases and then study the most promising candidates in patient-specific organoids,” says Gouti.

To establish the 2D model of self-organized neuromuscular junction, researchers first had to understand how motor neurons and muscle cells develop in the embryo. Minas’ team does not conduct embryo research itself, but uses various human stem cell lines, licensed for research purposes under strict guidelines, as well as an induced pluripotent stem cell (iPSC) line. .

“We tested a number of hypotheses. We found that the cell types we needed for functional neuromuscular connections came from neuromesodermal progenitor cells,” says Alessia Urzi, doctoral student and lead author of the paper. Urzi found the right combination of signaling molecules that cause human stem cells to mature into functional motor neurons and muscle cells with the necessary connections between the two.

“It was exciting to see the muscle cells contract under the microscope,” says Urzi. “It was a clear sign that we were on the right track.” Another observation was that once differentiated, the cells organized themselves into areas composed of muscle cells and nerve cells, much like a mosaic.

An optogenetic switch for motor neurons

Muscle cells grown in the culture dish contract spontaneously due to their connection to neurons, but without a significant rhythm. Urzi and Gouti wanted to fix that. In collaboration with researchers from Charité—Universitätsmedizin Berlin, they used optogenetics to activate motor neurons.

Activated by a flash of light, the neurons fire and cause the synchronized contraction of muscle cells, bringing them closer to imitating the physiological situation of an organism.

Modeling spinal muscular atrophy in the dish

To test the validity of the model, Urzi used human iPSCs from patients with spinal muscular atrophy, a serious neuromuscular disease that affects children during the first year of life. Neuromuscular cultures generated from patient-specific induced pluripotent stem cells showed severe muscle contraction problems resembling the patient’s pathology.

For Gouti, 2D and 3D cultures are key tools to study neuromuscular diseases in more detail and test more effective and individualized treatment options.

As a next step, Gouti and his team want to perform high-throughput drug screening to identify new treatments for patients with spinal muscular atrophy and amyotrophic lateral sclerosis. “We want to start by seeing if we can achieve better results using new drug combinations to improve the lives of patients with complex neuromuscular diseases,” says Gouti.

More information:
Alessia Urzi et al. Efficient generation of a self-organized neuromuscular junction model from human pluripotent stem cells, Natural communications (2023). DOI: 10.1038/s41467-023-43781-3

Provided by the Max Delbrück Center for Molecular Medicine

Quote: New neuromuscular model promises to revolutionize high-throughput drug screening studies (December 19, 2023) retrieved December 19, 2023 from

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Tags: drughighthroughputmodelneuromuscularpromisesrevolutionizescreeningstudies
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