Details Discovered on How Human Stem Cells become Nerve Cells

Findings Suggest Routes to New ALS Therapies

January 30, 2005

[QUICK SUMMARY: In the first report showing that human embryonic stem cells can be made to form motor neurons in the lab, investigators find a precise sequence of molecular signals that guide cells into neuronal roles.]

Investigators funded by The ALS Association have shown for the first time that human stem cells can be made to become motor neurons, the cells of the nervous system destroyed by ALS. The research details the sequence of molecular events that guide embryonic stem cells into becoming motor neurons, the cells that make muscles contract.

The findings, published January 31 in the advance, online version of the journal, Nature Biotechnology, will guide researchers towards new therapies for the disease. According to ALSA science director, Lucie Bruijn, Ph.D., "the ability to produce human motor neurons in lab dishes is of immense value, not only for future therapy, but immediately, as a research tool to learn about new targets for motor neuron disease."

Su-Chun Zhang at the University of Wisconsin has been funded through ALSA for pioneering work on stem cells. ALSA has just awarded funds for a new project, where Zhang and his colleagues at the Waisman Center will proceed with plans to graft these motor neurons, derived from human embryonic stem cells, into spinal cord of chick embryos.

"We expect that the chick transplant study will at least tell us how human motor neurons mature histologically and functionally," Zhang said. Plans are to then transplant into the mouse model of ALS, and look for survival of grafted motor neurons, and any changes in the course of the disease in that animal.

A precisely timed pattern of signals determines what type of cell is formed from an embryonic stem cell. Zhang’s team found that the decision is made early in the process, to commit a cell to becoming a neuron. The crucial signals include retinoic acid, and the molecule called sonic hedgehog.

By knowing the exact sequence of signal molecules that steer stem cells to the motor neuron fate, scientists may be able to effect repairs in the nervous system damaged by ALS. "The motor neurons produced from the self-sustaining human stem cells provide a research tool to uncover new targets for motor neuron diseases and a target for screening pharmaceuticals designed for treating motor neuron-related disorders," Zhang said. "In the future," he added, "these cells may be used for replacing lost motor neurons."

The investigators found that there are two distinct stages to stem cell commitment to the fate of becoming a neuron, an early, and a late stage. In essence, a genetic program must be enabled to make the cells receptive to the pattern of signals that prompts formation of a motor neuron.

Treatment with retinoic acid turned out to be crucial for the cells to become motor neurons. Retinoic acid acts by allowing the molecule, sonic hedgehog, to steer the cells to express genes that specify the motor neuron fate.

The cells that took on the appearance of motor neurons also demonstrated electrical and chemical features that confirmed they were indeed functioning as such. These cells formed connections to neighboring cells, and in all aspects tested, acted like motor neurons. They even induce developing muscle cells to cluster their receptor molecules in the way that muscle fibers do to receive nerve cell signals at the neuro-muscular junction.

ALSA support for the projects is enabled through The Neil Brourman, M.D. ALS Research Fund, Hope for ALS, Inc., the Jeff Kaufman Fund, and the Wisconsin chapter of The ALS Association.