The neurons that are lost from stroke and traumatic brain injury are never replaced. Unfortunately, while many cells begin the process of regeneration, full activation occurs only in a small fraction of stem cells. As a result, few newly-made neurons are produced, and even fewer manage to survive and re-populate. Scientists at the Champalimaud Foundation sought to determine how to boost neural regeneration after stroke and traumatic brain injury. Their findings in flies and mice demonstrate a novel mechanism by which neurons and glia collaborate to drive the process.
Their results were published in the journal Developmental Cell in a paper titled, “Damage-responsive neuro-glial clusters coordinate the recruitment of dormant neural stem cells in Drosophila.”
“Recruitment of stem cells is crucial for tissue repair,” wrote the researchers. “Although stem cell niches can provide important signals, little is known about mechanisms that coordinate the engagement of disseminated stem cells across an injured tissue. In Drosophila, adult brain lesions trigger local recruitment of scattered dormant neural stem cells suggesting a mechanism for creating a transient stem cell activation zone. Here, we find that injury triggers a coordinated response in neuro-glial clusters that promotes the spread of a neuron-derived stem cell factor via glial secretion of the lipocalin-like transporter Swim.”
“We have revealed how neural stem cells sense injury and are recruited for tissue repair. These findings may be the first step towards developing drugs to promote the formation of new neurons following brain damage,” explained the study’s senior author Christa Rhiner, PhD, principal investigator, Champalimaud Foundation.
Rhiner and her team used fly and mouse models. “Just like ours, their brains also contain neural stem cells,” she explained. “In addition, many signaling molecules and forms of intercellular communication are common to humans, flies, and mice. Consequently, the insights we gain from these animal models are likely to be relevant for understanding human physiology.”
“It was Swim—a transporter protein that quite literally ‘swims’ across the tissue, helping molecules that normally act locally to spread out. Following a thorough investigation, we learned that Swim is critical for mounting a regenerative response to brain injury,” said Anabel Simões, a doctoral student in Rhiner’s lab.
The researchers sought to determine which molecule Swim was carrying. They found it was Wg/Wnt, a known activator of neural stem cells in flies and mammals.
“We found Wg in neurons in the damaged area, which is remarkable,” added Simões. “It meant that the neurons themselves sense the tissue’s distress and respond to it by trying to send a wakeup signal to dormant neural stem cells.”
The team found that when oxygen levels drop in the injured brain area, a certain type of glial cells produce Swim and secrete it into the extracellular space.
“One of the more striking aspects of this mechanism is that it’s collaborative,” said Simões, “Neurons and glia in the affected brain area work together to promote tissue repair.”
The team’s results reveal a novel, cooperative mechanism by which neurons and glia “join forces” to drive neural regeneration. How can these results help make this process more robust?
“Now that we know who the key players are and how they communicate with each other, we have a shot at giving neural regeneration a boost. First, we need to verify that a similar mechanism also exists in humans. Then, we can begin thinking about translating these findings into therapies,” said Rhiner. “These results also prompt many follow-up questions that we are looking forward to investigating next. For instance, how can we help new neurons survive in the tissue as it heals? It’s a fascinating journey, and we’re excited to see what we will find next,” she concluded.
