Neural stem cells take a step closer to the clinic.

by Terry Devitt

Scientists working with cells that may someday be used to replace diseased or damaged cells in the brain have taken neural stem cell technology a key step closer to the clinic.

Writing in the current online edition (June 2003) of the Journal of Neurochemistry, scientists from UW-Madison's Waisman Center and School of Pharmacy describe the first molecular profile for human fetal neural stem cell lines that have been coaxed to thrive in culture for more than a year.

The work is an in-depth analysis of global gene expression in human neural stem cells and demonstrates a method for prolonging the shelf life of cultured fetal stem cells, making it possible to generate enough cells to use to treat disease, says Lynda Wright, the lead author of the paper.

"We have now characterized long-term neural stem cells lines," she says. "That genetic characterization - and our ability to grow these lines for a year or more - is one of the major steps toward clinical application."
Unlike human embryonic stem cells, stem cells derived from fetal tissue are not capable of growing in culture indefinitely. But because neural fetal stem cells have been available to science for a much longer period than cells derived from embryos, their capabilities are better known to scientists and they may reach the clinic as therapies for disorders like Parkinson's and amyotrophic lateral sclerosis (ALS) much sooner.

In culture, the cells can be coaxed into becoming "neurospheres," aggregates of precursor brain cells that, when implanted, can migrate to different parts of the brain, integrate themselves and develop into many of the different types of specialized cells that make up the brain.
"These cells are the basis for future therapies. These are the cells we want to transplant," said Clive Svendsen, senior author of the Journal of Neurochemistry paper and a leading authority on neural stem cells.

But scientists have been limited by the tendency of these cells to peter out in culture, making it difficult to generate quantities that could be used therapeutically. The Wisconsin team reported work on three cell lines that were kept growing and dividing in culture for 50 weeks.
The Wisconsin researchers were able to extend the shelf life of the neural stem cell lines by adding a signaling chemical known as leukemia inhibitory factor to the medium in which the cells were grown.

In collaboration with Jiang Li, a member of Jeffrey Johnson’s laboratory in the School of Pharmacy, the cells were then subjected to "gene chip" analysis, a powerful method for scanning the activity of thousands of genes at once. Nearly 33,000 genes were monitored across the three cell lines to chart genetic activity.

The entire list of genes will be placed on Johnson’s website and made available to other researchers studying neural stem cells. Knowing what genes are at work is critical for characterizing and preparing cells for use in transplant therapy.
"This is the first real genetic analysis of neural stem cells," says Svendsen and Johnson. "It is like creating a library and a bank at the same time."

By tuning in to the genes that are at work in the neurospheres, scientists will be able to gain the molecular insight necessary to create cells that can be customized for therapy. For example, the Wisconsin group was able to monitor the activity of genes that influence immune response.

A critical hurdle for any cells or tissue used in transplants is finding ways to get around the body's immune system, which targets foreign cells and tissue for rejection. Through genetic manipulation, it may be possible to create cells that fool the immune system, obviating the need for drugs to suppress the immune system in order for the transplant to be accepted by the body.
"We saw a huge number of MHC (major histocompatibility complex) genes that were affected," Svendsen says. "This is how cell surfaces are influenced so that the immune system can recognize them."

Svendsen and Johnson both emphasize that while the new work represents necessary and key steps on the path to clinical use of stem cells, much work remains to be done before such cells are used in therapy.
"This gets us closer," they say. "But we still have a lot of work to do before these cells achieve their promise as treatments for neural diseases."

Other co-authors of the paper include Kyle Wallace, also of UW-Madison, and Maeve A. Caldwell of the University of Cambridge. The work was funded by grants from the Wellcome Trust, the Michael J. Fox Foundation and the National Institutes of Environmental Health Science Center.
 

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