LA JOLLA, Calif. , December 16, 2004
A joint effort led by stem cell biologist Evan Y. Snyder, M.D., Ph.D., of The Burnham Institute, and Samia J. Khoury, M.D., of Harvard Medical School and Brigham and Women’s Hospital, report data suggesting that stem cells use inflammatory signals to “know” where they must home. Using a simulated stroke model, the collaborators found that the chemokine SDF-1 alpha, secreted by injured or inflamed neural tissue, acts like an SOS signal and summons implanted human neural stem cells to the site of injury, where the stem cells can assume the function of missing neurons. These results were published in the December 7th issue of Proceedings of the National Academy of Science.
To regenerate unhealthy tissue, stem cells must first move toward the effected area. It had never been known how stem cells--particularly those in the nervous system, but those in other systems, as well--are able to home precisely to the site of injury or disease, across long distances and using non-stereotypical pathways.
Previously, the authors observed that the pathology of many different types of diseases, including stroke, neurodegeneration, tumors, cell death, amyloid plaques, etc., seemed to draw stem cells to sites of abnormality where the stem cells encountered “niches” where “reparative signals” transiently resided (i.e., the stem cells would often shift their fates to replace missing or dying cells). In addition, the stem cells seemed to exert an anti-inflammatory, anti-scarring, and pro-regenerative response on the damaged tissue itself.
In the new study, the scientists selected a protein that is secreted by injured tissue, SDF-1 alpha, and tracked it by its attachment to the receptor CXCR4, which is known to bind only to SDF-1 alpha. When the SDF-1 alpha bound to the CXCR4 receptor on human neural stem cells cultured in Petri dishes, it triggered a series of intracellular processes associated with survival, cell proliferation, and migration—all steps required for stem cell mobilization, engagement, and repair.
The researchers then devised a test to see whether SDF-1 alpha would guide neural stem cells to the proper disease site in live animals--stem cell engagement with at the site of injury being the first critical step in repair. They set up a simulated stroke in mice. Before implanting human neural stem cells into the mice, they incubated the cells with a fluorescent dye that allowed them to trace the trajectory of the cells by microscopy.
The human neural stem cells traveled the distance from where they were implanted to the site of injury and intertwined with the SDF-1 alpha-expressing cells. There was a positive correlation between the amount of SDF-1 alpha expressed and the number of stem cells present. Furthermore, SDF-1 alpha was only found in damaged areas—not on the opposite, normal side of the brain, which failed to retain the implanted neural cells.
“The stem cells appear to migrate to the site of an injury by engaging in a special kind of movement called ‘chain migration’ in which the cells slide and guide on top of each other, laying down a path for each other, much like a colony of ants moving from their nest to a source of food,” says Dr. Evan Snyder. “This type of migration is important in development.”
The scientists performed a developmental study that produced results indicating that these same molecular mechanisms are present during the early birth of the brain, suggesting that “migration of stem cells during development” and “homing of stem cells to injury after development” employ many of the same mechanisms and molecules.
Snyder states that these results “could represent a paradigm shift in how we understand how stem cells of many types, from many organs, and in many disease states are ‘programmed’ to maintain homeostasis (or balance) within the body via repair. Inflammation is being recognized as a complex phenomenon with many ‘sides’ to it. Not only does inflammation play an important role in many disease processes–but it seems to use many of the same molecules that were needed for putting the body and its organs together in the first place (a process which itself employs stem cells).”
“Furthermore, this appears to be a strategy that is used by many organ systems,” continued Snyder, “and suggests a common inflammatory signature employed at some point by all diseases in their pathological process. Clearly, stem cell biologists working in the nervous system need to understand molecules that formerly were not thought to be ‘neural’. Similarly, stem cell biologists in other systems will need to look to the nervous system for some guidance in understanding principles relevant to stem cell biology in the broadest sense.”
Evan Y. Snyder, M.D., Ph.D., is Director of the Stem Cells and Regeneration Program in The Del E. Webb Center for Neuroscience and Aging at The Burnham Institute in La Jolla, CA.
Drs. Samia Khoury and Jaime Imitola, the first author on this paper, are with the Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School in Boston, MA.
This work was supported with by funding from the National Institutes of Health, the National Engineering Institute, Project ALS, Children’s Neurobiological Solutions, GMP Companies, and the Stem Cell Research Center of the Korean Ministry for Science & Technology.