Segregation of Human Neural Stem Cells in the Developing Primate Forebrain
Published online July 26, 2001; Submitted on March 9, 2001; Accepted on July 16,
Vaclav Ourednik 1*, Jitka Ourednik 1, Jonathan D. Flax 1, Michael Zawada 2, Cynthia Hutt 3, Chunhua Yang 1, Kook I. Park 4, Seung U. Kim 5, Richard L. Sidman 6, Curt R. Freed 2, Evan Y. Snyder 1*
1. Departments of Pediatrics, Neurosurgery, and Neurology, Children's Hospital, Harvard
Medical School, 248 Ender Building, 300 Longwood Avenue, Boston, MA 02115, USA
2. Department of Medicine and Pharmacology and the Neuroscience Program, University of Colorado School of Medicine, 4200 East 9th Avenue, Denver, CO 80220, USA.
3. Department of Medicine and Pharmacology and the Neuroscience Program, University of Colorado School of Medicine, 4200 East 9th Avenue, Denver, CO 80220.
4. Departments of Pediatrics, Neurosurgery, and Neurology, Children's Hospital, Harvard Medical School, 248 Ender Building, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Yonsei University, Seoul, Korea.
5. Department of Neurology, University of British Columbia, Koerner Pavilion, 211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5.
6. Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, LMRC, 221 Longwood Avenue, Boston, MA 02115, USA.
* To whom correspondence should be addressed. E-mail: Snyder@a1.tch.harvard.edu
Many central nervous system regions at all stages of life contain Neural Stem Cells (NSCs). We explored how these disparate NSC pools might emerge. A traceable clone of human NSCs was implanted intraventricularly to allow its integration into cerebral germinal zones of Old World monkey fetuses. The NSCs distributed into two subpopulations: one contributed to corticogenesis by migrating along radial glia to temporally-appropriate layers of the cortical plate and differentiating into lamina-appropriate neurons or glia; the other remained undifferentiated and contributed to a secondary germinal zone (the subventricular zone) with occasional members interspersed throughout brain parenchyma. An early neurogenetic program allocates the progeny of NSCs either immediately for organogenesis or to undifferentiated pools for later use in the "post-developmental" brain.
Stem cells may
help in brain repair
AP Science Writer
July 27, 2001; Washington, D.C. (AP) -- Injecting stem cells into a fetus may correct organic problems in a developing brain, researchers say in the latest study showing promise for stem-cell science as President Bush weighs federal policy on funding the controversial work. The pioneering work explored the possibility of repairing a damaged brain during gestation. Researchers injected human neural stem cells into the skulls of three unborn monkeys and then showed that the cells were incorporated into the developing brains of the animals.
"This suggests we could repair the developing human brain in utero and have a child born normally that would otherwise have a defect that could lead to failure of the brain in the first few years of life." Freed and Dr. Evan Y. Snyder of Harvard Medical School led a team of researchers who developed a way to treat Parkinson's Disease in adults by injecting into their brains fetal neural cells that make dopamine, a brain chemical that is deficit in Parkinson's.
Although the researchers used stem cells from an aborted fetus, Freed said further research may show that repairing the brain could best be done using neural stem cells that are grown from embryonic stem cells. Embryonic stem cells are extracted from a human embryo. Researchers have shown those stem cells can be directed to transform into other types of cells. A plan to give Federal funding to embryonic stem-cell research has been delayed on the President's orders.
Some groups oppose the research because obtaining embryonic stem cells requires the death of a human embryo. These groups believe that adult stem cells, which can be isolated without the death of an embryo, should be studied instead. Many researchers, however, believe the embryonic stem cells hold greater promise for treating disease using techniques similar to that reported by Freed and his colleagues. Freed said he favors "Federal support of all the types of stem-cell research." "We need to find out which is the best source for treating any particular condition," he said. "All of the stem-cell possibilities need to be tested." Using a technique similar to one used for Parkinson's Disease, researchers now are exploring ways to correct a brain disorder before birth. Freed said the technique, years away from being ready for human clinical trials, holds promise for treating diseases of the brain that develop because of flawed brain cells.
He said an example would be Tay-Sachs Disease, an inherited enzyme deficiency disorder in which a child is born normally, but has brain failure in years after birth. The disorder occurs in about one out every 3,600 children born to European Jewish families and to French-Canadian families. It leads to mental retardation, blindness, and death by the age of four. Freed said that "in theory, injections of healthy neural stem cells could supplant the cells whose flaws cause Tay-Sachs and give the brain sufficient enzymes to develop normally after birth." "Diseases of this sort are the ones most likely to be treated by this kind of strategy," Freed said. Dr. Larry Goldstein, a stem cell researcher at the University of California, San Diego, said the work "establishes some important properties of these cells and shows that they can engraft and colonize and migrate" within the brain.
In the study, the researchers isolated neural stem cells from a human fetus that came from an elective abortion. The cells were cultured until they numbered several million. Then they were injected into the developing brain of a monkey fetus at three months gestational age. The monkey fetus was carried for another month and then removed by Caesarean section. The brain then was analyzed. "The remarkable thing we found is that the stem cells we put in did not produce a glob of cells in one place in the brain," Freed said. "Instead, they distributed themselves around the fluid-filled spaces and went into an orderly migration to the areas of the brain that were under development." In effect, the injected cells became an active, participating part of the young brain. By using human cells in the monkey, the researchers could easily identify the fate and development of the injected cells because they are clearly different in tests from those of the monkey.
Some of the injected stem cells joined pools or pockets of monkey stem cells. Researchers believe these may make up what Snyder has called "an organic tool box'' that the brain could use later in life to replace or repair damaged or injured neurons. The finding supports the idea that during development, the brain retains neural stem cells for future use.
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