Human Norepinephrine Neurons from Stem Cells

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 like Alzheimer’s and Parkinson’s diseases and used the discovery to grow the neurons from stem cells for the first time.

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

The work was published in the journal Nature Biotechnology.

Norepinephrine neurons in the locus coeruleus regulate heartbeat, blood pressure, arousal, memory, attention and “fight or flight” reactions. Humans have approximately 50,000 LC-NE neurons in the hindbrain, where the locus coeruleus is. From there, the LC-NE neurons reach into all parts of the brain and the spinal cord.

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, the neurons start degenerating at a very early stage — sometimes years before other brain regions 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 the human LC-NE neurons,” says Tao, first author of the study.

Previous attempts at creating these neurons from human stem cells followed a protocol based on the development of LC-NE neurons in mouse models. For two years, Tao explored why these attempts were failing and how development of the neurons from stem cells was different in humans.

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

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

Once converted, the cells showed typical characteristics of functioning LC-NE neurons in the human brain, releasing the neurotransmitter norepinephrine. They also showed axonal arborization — extension of the long, branching arms of neurons that enable the connections between brain cells — and reacted to the presence of carbon dioxide, which is crucial for breathing control.

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

The LC-NE cells may someday serve as stem-cell therapy themselves.

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


Yunlong Tao, Xueyan Li, Qiping Dong, Linghai Kong, Andrew J. Petersen, Yuanwei Yan, Ke Xu, Seth Zima, Yanru Li, Danielle K. Schmidt, Melvin Ayala, Sakthikumar Mathivanan, Andre M. M. Sousa, Qiang Chang, Su-Chun Zhang. Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells. Nature Biotechnology, 2023; DOI: 10.1038/s41587-023-01977-4

University of Wisconsin-Madison. (2023, November 17). Alzheimer’s and Parkinson’s: Scientists produce human norepinephrine neurons from stem cells. ScienceDaily. Retrieved November 17, 2023 from

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