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Since the first human embryonic stem cells were isolated four years ago, researchers have wanted to convert these progenitor cells into replacement motor neurons for amyotrophic lateral sclerosis (Lou Gehrig's disease) patients. As motor neurons die in ALS, people with the disease lose control of their limb, mouth, and respiratory muscles.

But stem cell researchers have been unable to generate a batch of pure motor neurons, or other nerve cell types, and have not shown stem cell-derived neurons develop normally.

Now, Columbia Health Sciences researchers, using mouse embryonic stem cells and following the nerve cell's own developmental recipe, have produced and isolated motor neurons that make appropriate connections to muscle during development. The findings were published in the Aug. 9 issue of Cell.

Besides its impact on ALS research, the Columbia protocol can be applied to create better stem cell-derived cells for research into therapies for other neurodegenerative disorders, such as Parkinson's disease.

In the past few years, neuroscientist stem cell investigators have held out the hope stem cells could be used to restore coordinated movements in mouse models of motor neuron degenerative diseases, such as ALS.

But one potential problem with using stem cells to create neurons is obtaining defined populations of neurons in large enough numbers to have a therapeutic effect. Another concern is whether neurons derived from stem cells would behave normally. In an attempt to overcome some of these technical problems of cell type and cell maturation, Dr. Thomas Jessell, professor of biochemistry and biophysics, his postdoctoral researchers Drs. Hynek Wichterle and Ivo Lieberam, and Jeff Porter at Curis Inc. combined nature's own motor neuron instructions with some genetic engineering.

Starting with mouse embryonic stem cells growing in vitro, the scientists sequentially added two signaling proteins known to differentiate neural cells in vivo. Retinoic acid stimulated the formation of spinal cord cells and, then, sonic hedgehog changed the cord cells to spinal motor neurons. Throughout the process, the researchers monitored the cells' expressed proteins to ensure the cultured cells developed as they do in the mouse embryo.

The embryonic stem cells developed into motor neurons, but only 30 percent did so. To isolate the motor neurons, the researchers employed a unique tactic: They engineered embryonic stem cells to carry a genetic tag that would express a green fluorescent protein (GFP) in motor neurons. After the neurons differentiated, the researchers could then isolate GFP-fluorescing motor neuron cells.

But would the cells work like motor neurons? To test this, Dr. Wichterle inserted the neurons into a chick embryo's spinal cord and watched. The mouse motor neurons grew long axons that contacted intercostal muscles between the ribs and in the limbs.

"I was pleasantly surprised at how well the stem cell-derived neurons mimicked the chick's neurons," Dr. Jessell says. "But these experiments with embryonic stem cell-derived motor neurons are only a first step in our research for a potential treatment for ALS. They open the way for subsequent experiments to determine which cells should be introduced into an adult animal with a motor neuron degenerative disease."

Dr. Jessell says his future research will determine if implanted motor neurons work in an adult rather than in a developing embryo. But, he says, motor neurons may not even be the right cells. Glial cells, which surround, nourish, and protect neurons, could, perhaps, be more useful in a future therapy.

To help in other diseases, the method that produced the motor neurons can, in principle, be adapted to make a pure culture of any other type of brain cell, including the dopamine neurons damaged in Parkinson's. By changing the gene driving expression of the fluorescent tag, the method could isolate interneurons, or by changing the signaling molecules, the method could produce dopamine neurons. Columbia University has applied for a patent for the process of rational nerve cell generation and tagging specific nerve cell types.

"There's a lot of interest at Columbia to explore the potential of stem cells in clinical neurology," Dr. Jessell says. "Columbia is in the process of forming a Neural Stem Cell Scientific Advisory Committee to coordinate and direct the research. The $8 million gift from Bernard Spitzer and the $3 million gift from the Brunie Foundation for research into stem cell therapies make a stem cell center at Columbia a real possibility."

The stem cell research was supported by Project ALS, which raises money for ALS research. Dr. Thomas Jessell is a Howard Hughes Medical Institute investigator.