Creating a Human Nerve Circuit in a Dish to Study Movement Disorders

The Context: Neuromuscular disorders such as ALS arise from degeneration of brain cells that send signals to the muscles, and there are no treatments that address the root of the disease. This is partly because scientists do not have a human model of the nerve circuits that drive movement.

The Study: Scientists at Stanford University led by NYSCF – Robertson Stem Cell Investigator Sergiu Pasca, MD, have generated spheroids (3D clusters of human tissue made from stem cells) that represent the 3 major components of a human nerve circuit. These spheroids were able to fuse together to create a functional circuit in a lab dish, and the model is the first to accomplish this feat. The study appears on the cover of Cell.

The Importance: The circuit could help researchers better explore neurological disorders that affect movement and develop new treatments. The study also demonstrates that brain and body tissue can fuse together in the lab to form a functional circuit.

Studies of neuromuscular disorders such as ALS are typically carried out in mice due to the lack of human models, but these studies have been largely unsuccessful because a mouse’s nerve circuitry is different from a human’s.

“ALS has been cured in rodents dozens of times,” remarked Dr. Pasca, an associate professor of psychiatry and behavioral sciences, in a press release. “None of the cures have effectively translated to people. But now we can use patients’ own cells to generate personalized working models that will help us study these disorders in a dish.”

A Circuit in a Dish

The work leverages spheroids – 3D clusters of human tissue made from stem cells that allow scientists to study interactions between cells that drive biological functions. Dr. Pasca’s team has created spheroid models of many brain functions involved in a variety of diseases, including schizophrenia, depression, and addiction. His lab recently published a study in Nature Biotechnology in which they fused spheroids representing the cerebral cortex and the striatum, a brain structure that regulates pleasurable sensations and motivated behaviors.

So far, no one had been able to use spheroids to recreate nerve circuits. Dr. Pasca’s team modified their previous method for creating cerebral cortex spheroids from stem cells to create spheroids representing the other two major elements of a nerve circuit: spinal cord tissue and skeletal muscle. When placed next to each other in a lab dish, the spheroids fused together, creating a circuit similar to that found in our bodies.

 “We made the parts,” Dr. Pasca said, “but they knew how to put themselves together.”

A Promising Twitch 

In the human body, signals from the brain travel to the spinal cord, which then prompts a muscle to contract. The team was interested to see if their lab-grown circuit could do the same.

The team stimulated the brain spheroids and, excitingly, observed a twitch in the skeletal muscle.

“Skeletal muscle doesn’t usually contract on its own,” Dr. Pasca said. “Seeing that first twitch in a lab dish immediately after cortical stimulation is something that’s not soon forgotten.”

Additionally, connections between the spheroids can remain functional for at least 10 weeks.

“Remarkably, the longer they remain intact, the better the contraction is,” noted Dr. Pasca.

What’s next?

Dr. Pasca will continue using the circuit to understand movement disorders and explore new treatment options.

He is also embarking on a new project with Stanford’s Jan Carette, PhD, associate professor of microbiology and immunology, to use the spheroids to study the pathology of poliovirus and other crippling poliolike viruses.

Journal Article:

Generation of Functional Human 3D Cortico-Motor Assembloids
Jimena Andersen, Omer Revah, Yuki Miura, Nicholas Thom, Neal D. Amin, Kevin W. Kelley, Mandeep Singh, Xiaoyu Chen, Mayuri Vijay Thete, Elisabeth M. Walczak, Hannes Vogel, H. Christina Fan, Sergiu P. Paşca. Cell. 2020. DOI: https://www.cell.com/cell/fulltext/S0092-8674(20)31534-8

Cover image: A working model of a human brain-to-muscle nerve circuit in a dish.
Image credit: Jimena Andersen/Pasca lab