Stem cell-derived brain cells hold promise for Alzheimer’s, Parkinson’s research

Researchers at the University of Wisconsin-Madison have identified a protein key to the development of a type of brain cell believed to play a role in disorders such as Alzheimer’s and Parkinson’s diseases, and used the discovery to grow neurons from stem cells for the first time.

Stem cell-derived norepinephrine neurons of the type found in a part of the human brain called the locus coeruleus could enable research into many psychiatric and neurodegenerative diseases and provide a tool for developing new ways to treat them.

Yunlong Tao, a researcher at Nanjing University in China who was a research professor at UW-Madison’s Waisman Center when the study was conducted, and Su-Chun Zhang, a professor of neuroscience and neurology at UW-Madison, published their work on the cells. which they call LC-NE neurons, today in the journal Nature Biotechnology.

Norepinephrine neurons in the coeruleus regulate heart rate, blood pressure, arousal, memory, attention, and fight-or-flight responses. Humans have about 50,000 LC-NE neurons in the hindbrain, where the coeruleus is located. From there, LC-NE neurons reach all parts of the brain and spinal cord.

Norepinephrine neurons in the coeruleus are essential to our lives. We call it the center of life. Without these nerve cells, we would probably have disappeared from the Earth.”

Su-Chun Zhang, professor of neuroscience and neurology, UW–Madison

These neurons also play a role, albeit unknown, in various neurodegenerative and neuropsychiatric diseases. In many neurodegenerative diseases such as Alzheimer’s and Parkinson’s, neurons begin to degenerate at a very early stage -? sometimes years before other areas of the brain begin to falter.

“People have noticed this for a long time, but they don’t know what the function of the locus coeruleus is in this process. And partly because we don’t have a good model to mimic human LC-NE neurons,” he says. Tao, the first author of the study.

Previous attempts to generate these neurons from human stem cells followed a protocol based on growing LC-NE neurons in mouse models. For two years, Tao investigated why these efforts failed and how the development of neurons from stem cells was different in humans.

In the new study, he identified ACTIVIN-A, a protein belonging to a family of growth factors, as important for regulating neurogenesis in human NE neurons.

“We have some new understanding about the development of the locus coeruleus,” says Tao. “This is the important finding in this paper, and based on this finding, we are able to generate locus coeruleus norepinephrine neurons.”

To create LC-NE neurons, the researchers transformed human pluripotent stem cells into cells from the hindbrain. Then, using ACTIVIN-A and a series of additional signals, they directed the growth of the cells toward their fate as LC-NE neurons.

Once transformed, the cells showed typical characteristics of functional LC-NE neurons in the human brain, releasing the neurotransmitter norepinephrine. They also showed axial arborization -? extension of the long, branching arms of neurons that enable connections between brain cells – and reacted to the presence of carbon dioxide, which is vital for controlling breathing.

The new cells may serve as models for human disease, allowing scientists to screen drugs for potential treatments and answer questions such as why cells in the coeruleus die so early in neurodegenerative diseases.

“If this is somehow causative, then we could potentially do something to prevent or delay the neurodegeneration process,” Zhang says.

LC-NE cells may one day serve as a stem cell therapy.

“The application of these cells is quite broad in its significance,” says Zhang.

Next, the researchers plan to examine the detailed mechanisms by which ACTIVIN-A regulates LC-NE neuron growth. The team will also use the cells for translational drug screening and disease modeling work.