New studies in mice have shown that immature stem cells thatproliferate to form brain tissues can function for at least a year —most of the life span of a mouse — and give rise to multiple types ofneural cells, not just neurons. The discovery may bode well for the useof these neural stem cells to regenerate brain tissue lost to injury ordisease.
Alexandra L. Joyner, a Howard Hughes Medical Instituteinvestigator at New York University School of Medicine, and her formerpostdoctoral fellow, Sohyun Ahn, who is now at the National Instituteof Child Health and Human Development, published their findings in theOctober 6, 2005, issue of the journal Nature. They said the techniquethey used to trace the fate of stem cells could also be used tounderstand the roles of stem cells in tissue repair and cancerprogression.
Joyner said that previous studies by her lab andothers had shown that a regulatory protein called Sonic hedgehog (Shh)orchestrates the activity of an array of genes during development ofthe brain. Scientists also knew that Shh played a role in promoting theproliferation of neural stem cells. However, Joyner said the preciserole of Shh in regulating stem cell self-renewal — the process wherebystem cells divide and maintain an immature state that enables them tocontinue to generate new cells — was unknown.
In the studiespublished in Nature, Joyner and Ahn developed genetic techniques thatenabled them to label neural stem cells in adult mice that areresponding to Shh signaling at any time point so they could study whichstem cells respond to Shh.
Other researchers had shown thattransient bursts of Shh signaling caused neural stem cells toproliferate and create new neurons. But a central question remained,said Joyner. At issue was whether resting, or quiescent, cells — whichare important for long-term function — responded to Shh signaling. Orwas the response limited to the actively dividing stem cells with ashort life span involved in building new tissue? To test these options,the researchers used a chemical called AraC that selectively killsfast-dividing cells, leaving only quiescent cells.
“This was animportant experiment, because by giving AraC, we could kill all thecells that were actively dividing for a week,” said Joyner. “And sincethe quiescent cells only divide every couple of weeks, they werespared.” The researchers' observations revealed that the quiescentcells did, indeed, respond to Shh signaling, expanding to produce largenumbers of neural cells. Even when the researchers gave the mice twodoses of AraC separated by a year, the quiescent cells recovered —demonstrating that the cells could still respond to Shh signaling.
Thatthe quiescent stem cells remained capable of self-renewal after a yearin both normal and AraC-treated mice was a central finding of thestudy, said Joyner. “It has been assumed that these cells probably livefor some time, but it has never really been known whether they keepdividing, or divide a few times and give out,” she said.
Theresearchers also found evidence that neural stem cells in vivoresponded to Shh signals by giving rise to other neural cell types,including glial cells that support and guide neurons. “An importantpoint is that earlier studies indicating that neural stem cells couldgive rise to multiple cell types had been done in vitro,” said Joyner.“Before our work, it had never been formally shown that they normallymake those different cell types in vivo.” Joyner and Ahn also foundthat the neural stem cell “niches” — the microenvironments in tissuethat support and regulate stem cells — were not formed until lateembryonic stages.
Joyner said that the new findings haveimportant clinical implications. “In terms of using neural stem cellsfor therapeutic purposes and to regenerate tissue, it's important thatthey can continue to proliferate, and that these stem cells can makedifferent cell types,” she said.
In further studies, theresearchers plan to use their technique of marking stem cells andtracing their fate to explore their role in repairing injured braintissue in animal models. Such studies, she said, could reveal whethergrowth factors that influence stem cell growth could be used to treatbrain injuries. “If these stem cells do produce cells that contributeto injury repair, it is fairly easy to infuse growth factors to coaxthese stem cells to do more in repairing injury,” she said.
Joynerand her colleagues are already discussing how to apply their geneticfate-mapping techniques to stem cells in the spinal cord and otherorgans. They are hopeful that since Shh signaling has been implicatedin spurring the metastatic progression of cancer, the technique mightalso be used to explore the role of Shh signaling in tumor progression.
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