A piece of adult zebrafish gut in which immunostaining has been used to reveal the enteric nervous system (ENS) neurons in red and the ENS glia in green.
Researchers at the Francis Crick Institute have uncovered that glia cells, the maintenance cells of the nervous system, can generate new neurons in the intestine of zebrafish. Understanding how this process works could pave the way for future therapies that restore neurons in damaged guts.
The enteric nervous system, which regulates many functions of the digestive tract, includes two important types of cells, nerve cells and glia cells. If these enteric nerve cells do not develop properly or become damaged as a result of a disease, such as inflammation, healthy digestion is affected.
In their work, published in eLife, the Crick researchers identified and studied enteric glia cells in zebrafish. These cells could not be identified with labels commonly used for marking enteric glia in mice and humans, so the researchers applied a different strategy, which used zebrafish that expressed fluorescent labels in other types of glia, including radial glia in the brain.
They found that, in normal zebrafish, enteric glia cells can divide and create new neurons. This is very different to what happens in the gut of mammals, including humans, where new neurons are rarely generated in the gut.
Vassilis Pachnis, author and group leader of the Development and Homeostasis of the Nervous System Laboratory at the Crick, says: “If we can understand why enteric glia cells in zebrafish and in mammals behave differently, we may be able to find ways to mimic the fish’s regenerative potential in other species, including humans.
“Much more research is needed, but we hope that our new findings may eventually provide a new way to repair neuronal deficits that are linked to many gut diseases.”
This finding could also help other researchers who are studying neural regeneration in the brain because glia cells in the central nervous system of zebrafish can also proliferate and generate neurons, and may do so using similar mechanisms.
Tiffany Heanue, author and principal laboratory research scientist in the Development and Homeostasis of the Nervous System Laboratory at the Crick, says: “It’s really surprising that we’ve found this significant difference, as many of the genetic factors and processes related to the digestive system in zebrafish and in mammals are comparable. This is, in fact, why we use this fish species to study the digestive system of mammals.”
“We need to delve further into the mechanisms at work here, to fully understand why these cells have these different regenerative properties.”
Sarah McCallum, author and former Crick PhD student says: “We found that the enteric glia cells in zebrafish do not have the labels you’d usually expect to use to identify them. This meant we had to use a different approach, which was based on the application of genetic tools used to identify glia cells in the brain. Therefore, the glia cells of the brain and the gut are more similar than we thought.”
“Our work can also help us understand how the intestine can adjust the number of neurons it contains in order to maintain healthy digestion or repair damage due to injury or disease.”
The team will continue to study glia cells in the enteric nervous system in order to understand the mechanisms driving their proliferation into neurons in zebrafish, why this does not occur at such a high rate in mammals and whether disease may activate or suppress this process.