Identifying Cellular Cues for Stroke Recovery
Brain Repair After Stroke
When a stroke strikes, the supply of blood to the part of the brain affected is interrupted, starving it of oxygen. Brain cells can be seriously damaged or die, impairing local brain function.
But the brain is a battler. Within weeks of a stroke, new blood vessels begin to form, and, like marching ants, newly born neurons migrate long distances to the damaged area to aid the regeneration process. What is not known, however, is what cellular environment and what cellular cues are necessary for this process of regeneration and migration to take place.
Now, in the Journal of Neuroscience currently online, Dr. S. Thomas Carmichael, assistant professor in the neurology department at the David Geffen School of Medicine at UCLA, and his colleagues report that in a mouse model, this neuron march is the direct result of signaling from the newly blooming blood vessels, thus causally linking angiogenesis - the development of new blood vessels - and neurogenesis, the birth of new neurons. Further, they have identified what these molecular signals are. The results hold promise for eventual clinical applications that may spur brain repair after stroke.
Stroke is the leading cause of adult disability, Carmichael said. And while much is known about the mechanisms of cell death in stroke, little is known about the mechanisms of neurological recovery after a stroke. Carmichael's lab studies the mechanisms of brain repair and the recovery of function after stroke.
Recent research has revealed that in the adult brain, new neurons form in a region of the forebrain known as the subventricular zone. After initiating strokes in mice in a part of the brain located far from this region, Carmichael and his colleagues used a combination of mitotic, genetic and viral labeling to track newly formed "neuroblasts" - immature brain cells from which mature adult neurons form - as they traveled from the subventricular zone through healthy brain tissue to the stroke area. Once there, these immature neurons wrapped themselves around the immature vascular cells that were in the process of forming new blood vessels in the damaged area. The neurons were found to arrive at the site within the first two to four weeks after the stroke.
Further, the researchers found that two proteins - stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1) - given off by these newly-forming blood vessels are what trigger the migration of thousands of immature neurons to the site of damage.
"The SDF1 and Ang1 proteins are what link the two processes of neurogenesis and angiogenesis together, by promoting post-stroke neuroblast migration," Carmichael said.
They also appear to effect behavioral recovery as well, he said. When researchers produced stroke in an area of the brain that controls a mouse's facial whiskers and then infused the mouse with Ang1 and SDF1, the function of the whiskers improved to the same level seen in the control (non-stroke) group of mice.
If harnessed properly, said Carmichael, the molecular mechanisms for neuronal regeneration hold the promise of regenerating and reconnecting brain cells near the area where stroke occurs. While the process may vary between mice and humans, he said, it's known that neurogenesis occurs in humans.
"We're hopeful that we can take advantage of the brain's plasticity," Carmichael said. "This work could lead to the development of new therapies that will promote brain repair after stroke."