Human stem cells transplanted in rat brain shown moving to damaged area
By illuminating the path taken by human neural stem cells as they were transplanted into the brains of rats and mice, medical school researchers have found the cells successfully navigate toward areas damaged by stroke.
The research group placed miniscule particles of iron inside stem cells to act as cellular beacons detected by magnetic resonance imaging. With the ability to monitor where the human stem cells go in real time, researchers will have an easier time learning the best way of using the cells to treat human neural disorders, such as stroke, traumatic brain injury, Parkinson's disease or radiation damage.
The findings, published in the June 4 advance online version of the Proceedings of the National Academy of Sciences, could eventually make it possible to track human stem cells that are transplanted into the brains of patients.
Gary Steinberg led a research group that transplanted human neural stem cells into the brains of rats, then inserted tiny particles of iron to illuminate the stem cells' path as they moved to areas damaged by stroke.
Gary Steinberg, MD, PhD, who led the research group, said the work also shows that the iron doesn't disrupt the normal function of the stem cells. 'This work is important because if a method of tracking the cells changes their biology, it will not be helpful,' said Steinberg, senior author of the paper and the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences.
In a 2006 study, Steinberg and his colleagues had shown that the same human stem cells used in this study were able to migrate toward a brain region in rats that mimicked a human stroke. They also found that those cells matured into the types of cells they would expect to find in that part of the brain.
The only problem was that in order to find out where the cells ended up, they had to kill the rats - not an approach that can be used for human clinical trials. What the researchers needed was a way of tracking the stem cells in real time to find out whether the cells migrated appropriately and survived.
Steinberg said that the iron particles, called superparamagnetic iron oxide or SPIO, have been used for more than a decade to track cells in living animals, including in rat neural stem cells. If the point is to use the technique in humans, he and postdoctoral scholar Raphael Guzman, MD, wanted to make sure that the particles worked in human cells as well.
'I think it's critical that we are applying this technique in human stem cells that can be used in human clinical trials,' said Guzman, who is lead author of the paper. He said that because they chose to work with those cells, their results can be directly translated to human trials.
They were reassured to see that putting the iron particles in the cells didn't change the stem cells' biological properties. Also, when the group placed those iron-filled human neural stem cells into the brains of rats - either healthy fetal and adult rats or those that had experienced a stroke - the cells behaved as expected in each case.
In fetal mice with brains still developing, the group injected stem cells into the fluid-filled brain regions called ventricles. From there, the iron-filled cells migrated along the path that stem cells normally take to populate the developing brain. Those stem cells also matured into the proper types of brain cells.
In adult rats that had a simulated stroke, the human stem cells migrated into the damaged region, matured into the appropriate type of neuron and support cells and appeared to integrate into the surrounding tissue. The research group is currently testing whether those transplanted cells repaired stroke-induced damage to the rats' ability to move or learn.
The only situation that rendered the neural stem cells immobile was the healthy adult rat brain. As with Steinberg's previous work, the group found that in the absence of any signals to beckon the stem cells, they stayed close to where the researchers implanted them.
All of this adds up to encouraging news for researchers hoping to use stem cells to treat human disease. For now, nobody knows the best way of inserting the cells, the conditions that are best for cell survival, or the optimal timing after an injury for when transplanting the cells is most effective. With the ability to watch the cells in real time, researchers can compare different techniques to learn what works best.
The cells used in this study were similar to those that are part of a clinical trial for a childhood disorder called Battens disease. Steinberg said he and others are interested in testing these or other stem cells as a way of treating a wide range of diseases.
Other Stanford researchers who participated in this work include Tonya Bliss, PhD, research associate; David Stellwagen, PhD, postdoctoral scholar; Joan Greve, graduate student; Robert Malenka, MD, PhD, professor of psychiatry and behavioral sciences; Michael Moseley, PhD, professor of radiology, and Theo Palmer, PhD, associate professor of neurosurgery.
The work was funded by grants from the National Institute of Neurological Disorders and Stroke, Russell and Elizabeth Siegelman, the Willian Randolph Hearst Foundation, Bernard and Ronni Lacroute and the Swiss National Science Foundation.
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