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August 29, 2018

Generating sympathetic neurons from stem cells

CiRA scientists report a new method that converts human iPS cells into sympathetic neurons, the cells that control heart rate, blood pressure and other vital signs.

As age spans rise, neurodegenerative diseases have become a great concern worldwide. In many cases, the neurodegenerative disease likely begins developing years or even decades before the patient shows signs of the disease. iPS cells have been a boon for the study of neurodegenerative diseases, because researchers can reprogram patient cells to observe how the disease develops in its early stages, well before the patient is symptomatic. A new study by CiRA researchers describes a method to efficiently create sympathetic nerve cells for the study of related neurodegenerative diseases.

iPS cells have already had an impact on neurodegenerative diseases that target other neurons. Motor neurons made from human iPS cells are the basis of a clinical trial on a drug to treat ALS, and dopaminergic neurons made from human iPS cells are the basis of a clinical trial on a cell therapy to treat Parkinson's disease. However, far less progress has been made converting iPS cells into sympathetic neurons.

"Sympathetic neurons cannot be differentiated efficiently from iPS cells. Sympathetic neurons regulate many unconscious activities like heart rate, blood pressure, and sweating," says CiRA Associate Professor Megumu Saito.

To solve this problem, his team of scientists investigated the expression of the gene PHOX2B during the differentiation of iPS cells.

"Animal studies have shown progenitor cells that express PHOX2B are committed to sympathetic neurons," says Saito.

Moreover, scientists have identified several intermediate stages in the development of sympathetic neurons. Pediatric surgeon Dr. Kosuke Kirino, the first author of the study, aimed to capture these intermediate cells.

"Sympathetic neurons are derived from trunk neural crest cells, which arise from neuromesodermal progenitor cells," he says.

The generation of neuromesodermal progenitor cells from human iPS cells and of neural crest cells from neuromesodermal progenitor cells is well established. However, the generation of neural crest cells leads to other cell types that contaminate the cell population. Therefore, to get a pure population of neural crest cells, Kirino looked for another marker in combination with PHOX2B.

"Neural crest cells express CD49d," he notes.

Indeed, capturing cells that expressed both CD49d and PHOX2B during the iPS cell differentiation resulted in the generation of sympathetic neurons at levels not seen previously.

Saito believes this discovery could open the door to new studies on poorly understood diseases.

"For many diseases of the sympathetic nervous system, there are no good human models. We hope our differentiation method can be used," he says.

Paper Details
  • Journal: Scientific Reports
  • Title: Efficient derivation of sympathetic neurons from human pluripotent stem cells with a defined condition
  • Authors: Kosuke Kirino1,2, Tatsutoshi Nakahata1, Tomoaki Taguchi2, Megumu K. Saito1
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. Department of Pediatric Surgery, Faculty of Medical Science, Kyushu University, Fukuoka, Japan
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