Human brain cells need plenty of oxygen and nutrients to survive. Whereas, a hibernating ground squirrel can survive with less nutrients. By tapping into the cellular mechanisms that keeps these animals’ brains healthy during the long winter months, IRP scientists have discovered a way to increase the survival of neuron-producing stem cells implanted into the brain after a stroke.
An ischemic stroke cuts off blood flow to part of the brain, by depriving the cells of essential substances. While clinicians can reduce the damage by restoring blood flow as quickly as possible, but till now there is no treatment that can regenerate lost neurons. One promising approach is to implant neural stem cells into the damaged area but unfortunately, like an oil spill that makes a patch of ocean uninhabitable, a stroke creates conditions that make it difficult for stem cells to survive.
In an attempt to overcome this shortcoming, the lab of IRP senior investigator John Hallenbeck, M.D., has been studying on a process called SUMOylation that the group discovered which helps brain cells survive the lack of blood flow that occurs when a certain species of squirrel hibernates. SUMOylation alters the activity and cellular location of proteins by attaching chemical tags called small ubiquitin-like modifiers (SUMOs) to them. In theory, activating SUMOylation process in stem cells could help them survive in the hostile environment of a post-stroke brain.
“Stroke therapy is a field ripe for innovation,” says Dr. Joshua Bernstock, who was involved in this study as part of his graduate research in Dr. Hallenbeck’s lab. “Stem cells are really dynamic molecular medicines that can react in real-time to the conditions in the focal diseased environment, so they’re kind of living drugs.”
Dr. Bernstock and his colleagues utilized transgenic mice that produce more of the enzyme that attaches SUMO tags to other proteins. The research team found that neural stem cells from the brains of these transgenic mice had higher levels of SUMOylation and less activity in genes involved in cell death. When cultured in a petri dish, these cells consumed less oxygen than neural stem cells from normal mice. Also, these cells more frequently developed into neurons rather than other types of brain cells.
Dr. Bernstock explains that, “The same phenomenon that we had seen in the petri dish took place in the brains of the mice. That’s very promising when you think about how to engineer a cell that you would ultimately hope to use in the context of regenerative medicine.”
Future studies are needed to completely understand how grafts of neural stem cells with greater SUMOylation affect functional recovery in mouse models of stroke. Scientists are also interested in developing new methods to boost SUMOylation without manipulating genes. Finally, if the approach is proven to be safe and effective in animals, clinicians in the future may implant neural stem cells with increased SUMOylation into the brains of stroke patients to help them regenerate lost neurons.
– Arpitha Shetty
Healthcare – Research Analyst