13 Aug 2002

Research reported in the online Nature Medicine reinforces the potential of adult stem cells to repair the damaged or diseased brain, but it also points out the extent to which these cells are dependent on a healthy microenvironment.

After Stroke, Stem Cells Move to Replace Neurons
Researchers at Lund University in Sweden, led by Andreas Arvidsson, induced focal strokes in rats and looked for neurogenesis in the striatum. They found that the injury caused a marked increase in cell proliferation in the subventricular zone. This area along the lateral ventricles is one of two areas in the adult brain where significant adult neurogenesis occurs (the other being the subgranular zone of the dentate gyrus). The newly generated neural precursors, along with differentiated neuroblasts presumably generated before the injury, migrated from the ventricles into the damaged area of the striatum. Once there, they expressed the markers of the medium-sized spiny neurons native to that area of the brain. However, the vast majority of the new cells (about 80 percent) did not survive. Those that lasted for as long as 6 weeks post-ischemia were thus only able to replace some 0.02 percent of the dead striatal neurons.

Still, the fact that so many neurons were initially generated, "supports the notion that neurogenic response following stroke might be amplified," write the authors. The key will be to discover the trophic and connectional support systems required for the cells to survive, and also to limit the effects of inflammation and potentially destructive signals generated in response to the injury.

Radiation Can Be Fatal to Adult Stem Cells
The vulnerability of pluripotent neural precursors is also suggested by a well-known clinical phenomenon-the high incidence of cognitive deterioration in cancer patients who have undergone radiation to the cranium. As cancer treatments have become more effective, patients who survive the disease have shown alarmingly high rates of dementia as they age. One suspect mechanism, supported by animal research, is that the radiation interferes with ongoing neurogenesis in the hippocampal dentate gyrus.

Theo Palmer, Michelle Monje and colleagues at Stanford University and the University of California at San Francisco irradiated rats to determine whether the learning and memory deficits seen in such animals is caused solely by an acute destruction of neural progenitor cells, or whether there are permanent changes in the neurogenic microenvironment. In accordance with earlier results, they found that whole-brain irradiation comparable to a human clinical dose reduced hippocampal neural precursor proliferation. It does appear that there is irreparable genetic damage to more than half of the progenitor cells, as these were unable to carry on more than two or three mitotic passages in vitro. However, a significant number of the precursors were still around in vivo 2 months after the irradiation, although they failed to follow the usual course of differentiating into neurons.

When these irradiated precursor cells were cultured in vitro, they did in fact become neurons, suggesting that there is no intrinsic defect in the cells. Conversely, when non-irradiated precursor cells were grafted into irradiated brain, they were not able to differentiate into neurons, indicating that the extracellular environment is permanently damaged by the radiation. The most likely candidates for this damage include a chronic increased inflammatory response and alterations in the development of new blood vessels. The first possibility was demonstrated in this study by an increase in the number and activation status of microglia in the striatum of irradiated rats. The second was hinted at by perturbations in the microvascular angiogenesis typically seen as dentate gyrus neurons are replaced. Taken together, these studies raise new challenges and opportunities in inducing adult stem cells to differentiate to replace neurons lost by injury and disease.

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