[BobbyB]

Human Stem Cells Delay Start of Lou Gehrig's Disease in Rates


By Audrey Huang
Johns Hopkins Medicine

Researchers at Johns Hopkins have shown that transplanting human stem cells into spinal cords of rats bred to duplicate Lou Gehrig's disease delays the start of nerve cell damage typical of the disease and slightly prolongs life. The grafted stem cells develop into nerve cells that make substantial connections with existing nerves and do not themselves succumb to Lou Gehrig's, also known as amyotrophic lateral sclerosis, or ALS. The study is published in this week's issue of Transplantation.

"We were extremely surprised to see that the grafted stem cells were not negatively affected by the degenerating cells around them, as many feared introducing healthy cells into a diseased environment would only kill them," said Vassilis Koliatsos, an associate professor of pathology and neuroscience in the School of Medicine.

Although all the rats eventually died of ALS, Koliatsos said he believes that his experiments offer "proof of principle" for stem cell grafts and that a more complete transplant of cells, already being planned, along the full length of the spine to also affect upper body nerves and muscles might lead to longer survival in the same rats.

"We only injected cells in the lower spine, affecting only the nerves and muscles below the waist," he noted. "The nerves and muscles above the waist, especially those in the chest responsible for breathing, were not helped by these transplanted stem cells."

The research team used so-called SOD 1 rats, animals engineered to carry a mutated human gene for an inherited form of ALS. As in human ALS, the rats experience slow nerve cell death where all the muscles in the body eventually become paralyzed. The particular SOD 1 rats in the study developed an "especially aggressive" form of the disease.

Adult rats not yet showing symptoms were injected in the lower spine with human neural stem cells, which can, in theory, become any type found in the nervous system. As a comparison, the researchers injected rats with dead human stem cells, which would not affect disease progression. Both groups of rats were treated with drugs to prevent transplant rejection.

As weight loss indicates disease onset, the rats were weighed and tested for strength twice a week for 15 weeks. On average, rats injected with live stem cells started losing weight at 59 days and lived for 86 days after injection, whereas control rats injected with dead stem cells started losing weight at 52 days and lived for 75 days after injection.

The rats were coaxed to crawl uphill on an angled plank, and their overall strength was calculated by considering the highest angle to which they could cling for five seconds without sliding backward. While all the rats grew progressively weaker, those injected with live cells did so much more slowly than those injected with dead cells.

Close examination of the transplanted cells also revealed that more than 70 percent of them developed into nerve cells, and many of those grew new endings connecting to other cells in the rat's spinal cord.

"These stem cells differentiate massively into neurons, a pleasant surprise given that the spinal cord has long been considered an environment unfavorable to this type of transformation," Koliatsos said.

Another important feature of the transplanted cells is their ability to make nerve cell-specific proteins and growth factors. The researchers measured five times more of one particular factor known as GNDF (short for glial cell line-derived neurotrophic factor) in spinal cord fluid. The transformation of the transplanted cells also may allow them to deliver these growth factors to other cells in the spinal cord through physical connections.

Cautioning that clinical applications are still far from possible, Koliatsos said he hopes to take further advantage of his rodents with ALS to learn as much as possible about how human stem cells behave when transplanted.

The researchers were funded by the National Institutes of Health, Muscular Dystrophy Association and Robert Packard Center for ALS Research at Johns Hopkins.

Authors on this paper are Leyan Xu, Jun Yan, David Chen, Annie Welsh, Karl Johe, Glen Hatfield and Koliatsos, all of Johns Hopkins; and Thomas Hazel, of Neuralstem, Rockville, Md.



http://www.jhu.edu/~gazette/2006/11dec06/11gehrig.html

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