Efforts produce human cells that might someday help repair damaged nerves
THURSDAY, April 9 (HealthDay News) -- U.S. scientists say they've coaxed human embryonic stem cells into generating cells that might someday be used to repair nerves damaged by multiple sclerosis.
The researchers pushed the stem cells to grow into critical nervous system support cells called oligodendrocytes, according to a report released Thursday.
Oligodendrocytes produce the myelin sheath that surrounds nerve fibers like wire insulation. The findings represent an important step toward embryonic stem cell-based therapies in general, experts say, and also for cell-based therapies for myelination disorders such as MS in particular. At the very least, the findings should lead to a laboratory model of the illness' pathology.
"They are definitely laying the groundwork for being able to apply these cells in terms of a therapeutic application," said Timothy Coetzee, executive director of Fast Forward, a wholly-owned subsidiary of the National Multiple Sclerosis Society, which partially funded the study.
Yet at the same time, he added, "It illustrated for me the critical importance of not assuming that because you can do something with a mouse cell, that a human cell is going to behave in the same manner."
The research was published in the May issue of the journal Development.
At the heart of this study is a fundamental question: What's the difference between mouse and man?
It's not as silly as it sounds. Human experimentation being both morally and legally forbidden, researchers often use model organisms such as mice as proxies for human development. The underlying assumption, of course, is that these organisms have fundamentally the same biology as we do. Sometimes, though, that assumption turns out to be wrong.
For years, researchers using mouse embryonic stem cells (ESCs) knew that if they added one of two proteins, FGF2 or SHH, to the cells' growth media, they could reliably induce those cells to become oligodendrocytes. The human application was obvious: ESC-derived oligodendrocytes could either be used directly as a cell therapy for MS and related diseases, or serve as research tools to study them.
But, when Dr. Su-Chun Zhang of the University of Wisconsin, Madison, who has been studying oligodendrocytes and myelination for nearly a quarter-century, tried to apply the culture conditions painstakingly worked out in rodents to human cells, oligodendrocytes failed to emerge.
"When we expand these [rodent] progenitor cells with FGF2 (and another factor called PDGF), these progenitor cells will become oligodendrocytes," Zhang said. But, "What we discovered was that when we did [the experiment] in the same way with human progenitor cells, they were blocked in this process."
By carefully dissecting the molecular events that occur as human ESCs differentiate first into neural stem cells, then neural progenitor cells, then pre-oligodendrocytes, and finally mature oligodendrocytes, Zhang and his team identified the source of the difference: While both rodents and humans control the process with the same regulatory circuitry and use the same molecules (including both FGF2 and SHH), FGF2 behaves differently in each species.
In mice, FGF2 promotes oligodendrocyte maturation; in humans, it inhibits the process.
"This finding is actually quite significant scientifically," said Zhang, "because even [though] the transcriptional network is more or less the same, yet they respond to the same factor in an opposite way. To me, that's quite extraordinary."
Once that simple fact was understood, the experiment could be tweaked so that human embryonic stem cells could, in fact, generate oligodendrocytes.
The study, said Coetzee, "just reinforces the absolute importance of being able to do some of this very fundamental biology and fundamental understanding of what human cells do, before you start experimenting with them to put them into people."
Dr. William Sheremata is professor of neurology at the University of Miami Miller School of Medicine. He sees many MS patients in his practice and called the study "an excellent example of work that is very carefully done by an expert group of people who really know what they are doing. So I think that the conclusion that FGF2 does not work to facilitate maturation of pre-oligodendrocytes is acceptable at face value. It is the first paper that has stated just that."
Sheremata questioned the therapeutic implications of the report, however, suggesting that therapies based on "autologous stem cells" (adult stem cells) were more likely to bear fruit.
Coetzee, though, called the findings "absolutely critical" to moving toward clinical applications for MS, whether directly by injection of mature oligodendrocytes or more primitive precursor cells, because it both enables researchers to grow large quantities of these cells and to molecularly define the process by which that happens.
"This actually begins to lay the foundation for envisioning having the ability to create the mass quantities of stem cells that you'd need in order to have a therapeutic application in MS," he said.
For more on multiple sclerosis, visit the National Multiple Sclerosis Society.
SOURCES: Su-Chun Zhang, M.D., Ph.D., professor, anatomy and neurology, University of Wisconsin, Madison; Timothy Coetzee, Ph.D., executive director, Fast Forward, New York City; William Sheremata, M.D., professor, neurology, Miller School of Medicine, University of Miami; May 2009. Development
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