An Eye on the Shore
Centerwide stem cell research keeps hopes afloat in its early stages. But so far, every study answers questions that lead to more.

Nicholas Maragakis tests mouse upper-body strength—the same test he hopes to use on ALS animal models that’ve received glial stem cells.

Stem cell research for ALS is a bit like being thrown in the ocean a half-mile offshore but not knowing how to swim. Stay afloat, and you last longer. But should you figure out swimming’s basic principles, then purposeful strokes actually get you on land.

What’s going on at the Center for ALS Research, where scientists are studying perhaps a dozen different stem cell types, backs up the analogy. Each stem cell version, researchers believe, holds unique capabilities. And some of the earliest experiments with spinal cord or whole-animal ALS models have shown surprising, encouraging results. An eagerness runs through this work, prompted by small but real successes. They push Center research ahead at an unusually fast pace.

But, like any new science—or teaching yourself to swim—nobody knows yet what approaches work best. Therapy’s shore is still distant, the researchers say, until they learn the biology of what stem cells are doing.

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When neurologist Douglas Kerr, M.D., Ph.D., first tried stem cells on a new model of motor-cell injury he’d brought to the Center, he used mouse neural stem cells, largely because they create the various cell types in the nervous system.

Kerr’s mouse models, treated with a potent virus called Sindbis, quickly became paralyzed as they lost most of their lower motor neurons. (In ALS, both upper and lower motor neurons die.) Afflicted animals dragged their lower trunks and hind legs behind otherwise normal bodies.

Yet eight weeks after he injected stem cells into mouse spinal fluid, roughly half of the paralyzed mice could plant their feet.

In recent work with a Sindbis rat model, Kerr has used even more basic human stem cells salvaged from fetal tissue. Center biologist John Gearhart, Ph.D.,* bathed stem cells in agents that let them evolve faint characteristics of nervous system tissue—a chemical nudge. Three months after Kerr injected the cells, called “embryoid body-derived” or EBDs, into rat spinal fluid, most of the paralyzed rats could move their hips and plant their feet. A few could hobble.

“As thrilling as that was,” says Kerr, “the most dramatic finding was proof that stem cells migrated to the ventral horn of the spinal cord, exactly where motor neurons had died.” Moreover, some of the stem cells differentiated. They carried traits of more mature nerve cells, sending axons out into the rat’s leg, as do motor neurons.

For all that, however, Kerr doesn’t know what’s causing the rat improvement. The number of stem cells maturing into nerve cells isn’t enough, he says, to explain it. “It’s possible the stem cells trigger a protective effect on existing nerve cells.”

This work was supported in part by Project ALS.

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At left: a spinal cord slice from an ALS-model mouse holds few remaining motor neurons. At right, after glial stem cells are added, more survive..

Work by neurobiologist Vassilis Koliatsos, M.D., could help explain whether stem cells’ benefits lie in making new motor neurons or in supporting remaining ones.

Koliatsos is expert in trophic factors, chemical signals the body uses to keep nerve cells healthy or encourage regrowth of injured ones. He and others believe these factors—and many kinds abound—may be a key to stem cells’ action.

Different parts of the nervous system can vary in types and strength of trophic factors, Koliatsos says, creating many mini-environments. “So we not only test the various stem cells, but also check their behavior in different areas of the brain and spinal cord.”

Koliatsos has tested several stem cell types with his brand of rat model. In his version, certain nerves that extend from the spinal cord are severed, resulting in death of all motor nerve cells in that part of the cord. “It wipes the slate clean,” he says. “Then we know the added stem cells are responsible for anything that happens.” In one study, mouse cerebellar stem cells injected into spinal cords matured into Schwann cells, those that wrap around other nerve cells.

Recently, his team seeded human stem cells from prenatal spinal cords into motor-damaged rats. Maturitywise, the cells lay somewhere between the EBD cells Kerr used and neural stem cells that give rise to nervous system cells. “They’re ‘precursor-enriched,’” Koliatsos says, “like kids who enter first grade already knowing how to read.”

Like EBDs, precursor-enriched cells also apparently migrate to sites of injury. But, encouragingly, half of them grow into somewhat immature nerve cells. “Will they become motor neurons? I hope so. A half-year should tell.”

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The stem cell work that Mahendra Rao, Ph.D., and Nicholas Maragakis, M.D., undertake lies in one of the hottest areas of ALS research, dealing with nervous-system cells called astrocytes. Astrocytes in ALS patients have been shown, by Center scientists, to carry serious flaws that may contribute to the disease’s advance.

Specifically, patients’ astrocytes fail to transport excess glutamate away from neighboring neurons. Glutamate’s the excitatory chemical that tells motor neurons to fire. Too much of it, however, kills cells.

Rao has, for years, studied how astrocytes develop in the body. Most recently, he teased their “parent” cells, a type of stem cell called a glial restricted precursor (GRP), from rat embryos. He grew them in culture. Most important, Rao and Maragakis discovered GRPs are rich in the transporter molecules astrocytes use to “sop up” glutamate.

Could GRPs rescue tissue where motor neurons are dying? Could they take up some of the glutamate that ailing astrocytes couldn’t? Maragakis suspected as much. As his model of choice, he used the Center’s signature ALS culture, a thin, living slice of rat spinal cord treated with motor neuron poison.

Dropping the stem cells onto the cord, Maragakis gave them a week to engraft before he added the toxin. A month later, the cultures with added GRPs had almost double the number of surviving motor neurons than those without—a clear protective effect. “Can we deliver enough stem cells to the spinal cord to protect whole animals?” he asks.

This work was supported in part by Project ALS.

*Some of the research in this newsletter has corporate ties. For full disclosure information, call the office of Policy Coordination at 410-516-6248.

Next > The New Rat Model: Bigger Is Better
A new rat model of the disease that’s far easier to work with and more versatile than earlier mouse models.