Contributing Writer

Human stem cells transplanted into the brains of rats that have experimentally induced stroke can survive, a recent study showed. What's more, they can migrate toward the site of the stroke and differentiate into neurons.

The study brings closer the day - although still many years away - when it might be possible to restore brain function and repair neural tissue following disease or injury.

Gary Steinberg, Lacroute-Hearst professor of neurosurgery and neurosciences at Stanford University in Palo Alto, Calif., told BioWorld Today: "This is a huge step forward for researchers in this field. It has never been shown before that transplanted human neural stem cells can survive, migrate and differentiate in an animal model of stroke."

The results of the study imply, he added, that the microenvironment of the stroke has a profound influence on the survival, migration and differentiation of the transplanted cells.

"This work brings us closer to the clinical reality of a better treatment for stroke patients and others," Steinberg continued. "In the future, we envision being able to treat patients who have suffered devastating neurological disease or injury, for whom there is currently no hope, and help them to recover function."

Steinberg, with joint first co-authors Stephen Kelly and Tonya Bliss and other colleagues at Stanford and StemCells Inc., of Palo Alto, Calif., reported his experiments in a paper in the July 26, 2004, issue of the Proceedings of the National Academy of Sciences. The paper is titled "Transplanted human fetal neural stem cells survive, migrate and differentiate in ischemic rat cerebral cortex."

It now will be important, Steinberg said, to prove that the transplanted animals recover behaviorally, and that the impairment that developed as a result of the experimentally induced stroke could be remedied.

The team injected clusters of neural stem cells belonging to a cell line that originally had been derived from fetal tissue. Although federal funding for research on embryonic cell lines has been banned in the U.S., the cell line falls outside that category. It has the potential advantage that it would be easy to produce large quantities of cells for clinical treatments, if needed.

Earlier studies had shown that those cells had the capacity to turn into different types of brain cells, including neurons, astrocytes and oligodendrocytes.

When the researchers injected the cells into the stroke lesion itself, though, the cells did not survive. So they tried injecting them into healthy brain tissue adjacent to the affected area.

"Many cell lines, even rat neuronal cells, do not survive when you put them into another rat," Steinberg said. "In addition, the region of a stroke is a very hostile environment, with an inflammatory response that is not conducive to cell survival."

The cells survived, and the group was excited.

"While we were also hoping for cell migration and differentiation, we did not expect it, so these results are really quite remarkable," Steinberg said.

Tests showed that out of 300,000 cells put into each animal, on average, 100,000 survived. The more robust the inflammatory response following the stroke, the lower the survival of the transplanted cells. Steinberg said the team now is considering whether it might be possible to improve survival, migration and differentiation of the transplants by blunting the inflammatory response with standard anti-inflammatory agents.

While cells delivered to normal brains did not migrate much at all - and when they did it was in all directions - those that were transplanted a few millimeters away from the stroke migrated toward the stroke. On average, those cells moved 1.2 mm toward the lesion.

"Our hypothesis is that chemokines given off by the stroke are attracting the stem cells," Steinberg said.

Further investigations showed that many of the migrating cells expressed a chemokine cell-surface receptor called CXCR4, suggesting that those cells were responding to a gradient in that chemokine.

The cells that migrated also became differentiated. Of those that reached the edge of the lesion, almost half had become primitive neurons.

Ultimately, Steinberg envisages that it might be possible to transplant the cells into the brain of someone who has suffered a stroke, or into the ventricle, and allow the cells to migrate to the damaged tissue and repair it.

"But we don't know yet which is the best type of cell to transplant, or whether it may be better to try to enhance the native neurogenesis that occurs in the brain after a stroke," he said. "There is considerable work to be done before we can start to think about clinical trials."

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