So, you know how your mom always told you to wear a helmet when riding your bike because if you hit your head, you’ll lose brain cells that you can never get back? Well, back in the 90s, researchers discovered that adult neuronal stem cells (NSCs, cells which can become new neurons) do in fact exist, and what’s more, the brain never stops developing and incorporating new neurons! However, these NSCs have remained shrouded in mystery for some time. The big questions have included:
- “How are adult stem cells maintained in the adult?” and
- “What are the factors that control adult stem cell proliferation and differentiation?”
The first question was answered by Duke researchers in 2011 when they discovered the cells that keep the brain’s stem cells neurogenic, or able to form new neurons. When NSCs are harvested for culture in a dish, they don’t form new neurons; instead they form a type of cell called astrocytes, which if permitted to proliferate unchecked, can lead to brain tumor formation. This has been a major impediment to cultivating neurons for replacement therapies to treat brain injuries. But in their Neuron journal article, the researchers explain that neighboring cells called ependymal cells produce proteins involved in a pathway that is required for neurogenesis. When these genes were deleted from the ependyma, there was a dramatic depletion of neurogenesis. What’s special about these proteins? They instruct the ependymal cells to cluster around NSCs and morph into pinwheel-like architecture, providing what seems to be critical structural support. The study’s senior author, one Dr. Chay Kuo said, “We believe these findings will have important implications for human therapy,” and how could they not? With this new knowledge, cultivating neurons in a lab dish to implant in a damaged brain is much more feasible. Woo hoo!
The second question was answered at least in part by…the same Duke researchers. In an advance online publication released on June 1, 2014 (that’s like two weeks ago, guys!) they describe the discovery of an entirely new kind of brain cell called a ChAT+ neuron within the subventricular zone (SVZ) of the brain, an area where neurogenesis occurs. This region is hot stuff right now. A recent Medical Xpress article speaks of experiments in rodents with stroke injury which demonstrate migration of SVZ cells into the neighboring striatum (just a subcortical part of the forebrain that helps coordinate motivation with motor activity–don’t freak out), apparently aiding in the healing process. Additionally, a recent Cell paper identifies the striatum as a destination for new interneurons (connector brain cells) from this area. What’s more, the researchers write that “postnatally generated striatal neurons are preferentially depleted in patients with Huntington’s disease.” If only we could figure out how fix this! Now, thanks to the Duke scientists, we’re starting to put the puzzle together. The previously mentioned ChAT+ neurons were discovered to direct NSC differentiation–they use the neurotransmitter acetlycholine (ACh) to tell the stem cells to become neurons! When the ChAT+ neurons were stimulated by the researchers, there was an increase in nueroblast (dividing cells that will become neurons) formation. When they were inhibited, formation of neuroblasts was also inhibited. ChAT+ neurons are now a major target for medical research because the ability to stimulate new neuron formation will be invaluable in the treatment of traumatic brain injuries. The next step is to figure out what’s telling the ChAT+ cells to tell the stem cells to differentiate. What a beautiful and complex molecular bureaucracy!
Dr. Chay Kuo is on the ball lately, because he’s also behind some amazing recent discoveries about the brain’s response to injury. But first, some statistics. The CDC reports that in 2010, 2.5 million people suffered from a traumatic brain injury in the U.S. Additionally, 795,000 people a year suffer a stroke, the leading cause of death in the United States (it kills nearly 130,000 Americans each year). So it’s really exciting to be able to peek into the brain’s self-healing process, because the better we understand that, the better we can aid the process medically.
What Kuo and colleagues discovered in this 2013 study was surprising, given the scientific understanding at the time. Besides neurons, neural stem cells can differentiate into several different types of brain cells, including astrocytes (see pic at right), as mentioned previously. When astrogenesis occurs prolifically, it often leads to malignant astrocytic gliomas (e.g. glioblastoma), which are the most invasive, aggressive and lethal type of intracranial tumor, especially due to their resistance to most current therapeutic approaches (read about this kind of brain cancer here). So it was pretty crazy when the Duke researchers found that instead of producing new neurons to replace the damaged ones, the brain’s initial response after severe trauma is to up-regulate production of a certain kind of astrocyte that will migrate to the injured area in order to make a scar to stop the bleeding, which allows the tissue to start recovering. Importantly, when the scientists experimentally prevented mouse neural stem cells from differentiating into these astrocytes after a brain injury, it resulted in hemorrhaging and failure of the region to heal. But in fact, while this was an unexpected finding, it’s by no means counter-intuitive. Why would the brain produce new neurons to replace the dead ones when the brain is still bleeding? They wouldn’t have a chance.
So now we better understand the brain’s internal equivalent of a band-aid or scab, and we can use this knowledge to better treat brain traumas. According to this Medical Xpress article, the lead investigator Kuo commented, “We are very excited about this innate flexibility in neural stem cell behavior to know just what to do to help the brain after injury. Since bleeding in the brain after injury is a common and serious problem for patients, further research into this area may lead to effective therapies for accelerated brain recovery after injury.” And in the Nature letter itself the authors write, “We believe these results will have important implications for therapeutic interventions using transplanted and/or endogenous NSCs after brain injury28,29, as well as astrocytic tumors that can arise from the SVZ niche30.” Considering how many people are affected by brain trauma each year, this is a pretty big deal.
Of course, having said all that, you should still wear a helmet when you ride your bike.
Discussion Topic: What are some other things you thought were true ten years ago that you now know are completely false?