Neural stem cells are long-lived (sonic hedgehog + growth factors)

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Neural stem cells are long-lived

http://www.medicalnewstoday.com/medicalnews.php?newsid=31681

New studies in mice have shown that immature stem cells that

proliferate 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

of neural cells, not just neurons. The discovery may bode well for

the use of these neural stem cells to regenerate brain tissue lost to

injury or disease.

andra L. Joyner, a Medical Institute investigator

at New York University School of Medicine, and her former

postdoctoral fellow, Sohyun Ahn, who is now at the National Institute

of Child Health and Human Development, published their findings in

the October 6, 2005, issue of the journal Nature. They said the

technique they used to trace the fate of stem cells could also be

used to understand the roles of stem cells in tissue repair and

cancer progression.

Joyner said that previous studies by her lab and others had shown

that a regulatory protein called Sonic hedgehog (Shh) orchestrates

the activity of an array of genes during development of the brain.

Scientists also knew that Shh played a role in promoting the

proliferation of neural stem cells. However, Joyner said the precise

role of Shh in regulating stem cell self-renewal -- the process

whereby stem cells divide and maintain an immature state that enables

them to continue to generate new cells -- was unknown.

In the studies published in Nature, Joyner and Ahn developed genetic

techniques that enabled them to label neural stem cells in adult mice

that are responding to Shh signaling at any time point so they could

study which stem cells respond to Shh.

Other researchers had shown that transient bursts of Shh signaling

caused neural stem cells to proliferate and create new neurons. But a

central question remained, said Joyner. At issue was whether resting,

or quiescent, cells -- which are important for long-term function --

responded to Shh signaling. Or was the response limited to the

actively dividing stem cells with a short life span involved in

building new tissue? To test these options, the researchers used a

chemical called AraC that selectively kills fast-dividing cells,

leaving only quiescent cells.

" This was an important experiment, because by giving AraC, we could

kill all the cells that were actively dividing for a week, " said

Joyner. " And since the quiescent cells only divide every couple of

weeks, they were spared. " The researchers' observations revealed that

the quiescent cells did, indeed, respond to Shh signaling, expanding

to produce large numbers of neural cells. Even when the researchers

gave the mice two doses of AraC separated by a year, the quiescent

cells recovered -- demonstrating that the cells could still respond

to Shh signaling.

That the quiescent stem cells remained capable of self-renewal after

a year in both normal and AraC-treated mice was a central finding of

the study, said Joyner. " It has been assumed that these cells

probably live for some time, but it has never really been known

whether they keep dividing, or divide a few times and give out, " she

said.

The researchers also found evidence that neural stem cells in vivo

responded to Shh signals by giving rise to other neural cell types,

including glial cells that support and guide neurons. " An important

point is that earlier studies indicating that neural stem cells could

give rise to multiple cell types had been done in vitro, " said

Joyner. " Before our work, it had never been formally shown that they

normally make those different cell types in vivo. " Joyner and Ahn

also found that the neural stem cell " niches " -- the

microenvironments in tissue that support and regulate stem cells --

were not formed until late embryonic stages.

Joyner said that the new findings have important clinical

implications. " In terms of using neural stem cells for therapeutic

purposes and to regenerate tissue, it's important that they can

continue to proliferate, and that these stem cells can make different

cell types, " she said.

In further studies, the researchers plan to use their technique of

marking stem cells and tracing their fate to explore their role in

repairing injured brain tissue in animal models. Such studies, she

said, could reveal whether growth factors that influence stem cell

growth could be used to treat brain injuries. " If these stem cells do

produce cells that contribute to injury repair, it is fairly easy to

infuse growth factors to coax these stem cells to do more in

repairing injury, " she said.

Joyner and her colleagues are already discussing how to apply their

genetic fate-mapping techniques to stem cells in the spinal cord and

other organs. They are hopeful that since Shh signaling has been

implicated in spurring the metastatic progression of cancer, the

technique might also be used to explore the role of Shh signaling in

tumor progression.

Medical Institute

http://www.hhmi.org