Astrocytes act as neuronal stem cells
In the late 1990s, scientists turned one of the central dogmas of neuroscience on its head: they showed that - even in aged adults - new nerve cells were still being born in certain brain areas. Previously we thought that in higher animals like us, neurogenesis stopped shortly after birth. Now scientists have made an even more extraordinary finding: that astrocytes, the non-neuronal supporting cells in the brain, can respond to injuries by transforming themselves into cell types resembling neural stem cells and produce new neurones. It’s early days, but it could have huge therapeutic potential. Chris Smith heard the story from Jens Magnusson…
Jens - The brain is very bad at replacing dead neurons in response to injuries. We had found previously that a very abundant type of support cell in the brain, which are called astrocytes, can activate a neuron-producing capacity in response to certain injuries in mice. But not all astrocytes appeared to have this ability. And we wanted to study the mechanism by which some astrocytes produce neurons, because we think that this might in the long term, enable us to recruit astrocytes as a sort of reservoir for new neurons that could be used therapeutically.
Chris - Traditionally, we think of astrocytes as these supporting cells, but if you injure the brain, you tend to find that they grow a lot and they produce almost like a scar. So that seems to be a little bit contradictory to what you're saying about them now being able to produce nerve cells instead. So are they different sorts of astrocytes that are doing this then?
Jens - We think that astrocytes have different programs so to say that they can turn on. It's true after an injury astrocytes can produce a scar. We found that after stroke injury astrocytes can also generate new neurons. And we wanted to understand the molecular program that creates this response.
Chris - How did you do the study then, talk us through what the method was and then we can perhaps unpick what those results are telling you.
Jens - We used a method called single cell RNA sequencing. So that's a way to read the entire gene expression profile of individual cells. Now, this is informative because cell types and cell states can be identified by the combinations of genes that they express. So we first triggered neuron production by some astrocytes in the mouse brain. And then we looked at their gene expression profiles as they initiated neuron production in mice. We found two things that are particularly interesting. The first thing was that as astrocytes initiated this neuron producing ability, they first underwent changes that made them extremely similar to neural stem cells. So there are neural stem cells in some parts of the brain that continuously make new neurons. And our astrocytes became very similar to them. The second thing that we found was that even though only a minority of astrocytes went on to generate neurons, all astrocytes appeared to initiate this neuron producing program, but then halted their development halfway. And we found that we could inject a type of growth stimulating protein into the brains of these mice and this helped some of the halted cells to resume their neuron production.
Chris - Does this therefore have a therapeutic potential in the sense that you could go into a sector of the brain, which is subject to some kind of trauma, some injury where there's perhaps been some selective vulnerability among a group of neurons where there's been loss, and stimulate the local astrocyte population to differentiate back into and repopulate that missing nerve compartment?
Jens - We hope that in the long term, this is exactly what we're going to be able to do. Now we're far from being there now, but if astrocytes can be viewed as dormant neural stem cells, we think this is really exciting because the capacity of the brain to replace dead neurons is extremely low. And if the brain turns out to be full of dormant neural stem cells, then if we can figure out how to unleash their potential, then that might represent a potential way for improving brain repair after injury and disease.
Chris - What about the phenotype of the nerve cells that you produce in this way? Are they just generic neurons or do you end up with neurons that resemble the native population that correspond to that part of the brain where those astrocytes were when you start starting to stimulate them in this way?
Jens - We don't find evidence that the astrocytes produce neurons that are of the same subtypes of the region that they're in. Astrocytes tend to generate interneurons that are not necessarily abundant in the tissue where they're generated. So we think that in order for this to be useful, therapeutically in the future, other bioengineering approaches are going to be necessary in order to steer the astrocytes towards certain types of neurons that are needed.
Chris - Do you know what the survivability though of those newborn nerve cells is? Because when people have studied the generation of new neurons in brains, cause that does go on in the adult brain, doesn't it, there are certain areas where neural stem cells continue to give rise to neurons throughout life, it's not a given that the new daughter nerve cells survive. So what proportion of the astrocyte derived nerve cells survive and how long for?
Jens - It's low, less than 1%. We don't know if this is a shortcoming of this neurogenic process, or if this is a built in mechanism.
Chris - And do you know if you can shift the survivability, are there common routes by which these cells try to die, that it may be possible to arrest?
Jens - Other groups have found that survivability can be increased by treating the brain with certain chemicals. So I think it's possible in principle.