Stem cells give anosmic mice a rat sense of smell

In a landmark in brain repair, scientists have used stem cells to regrow a missing part of the mouse brain. Two studies - published in the journal Cell - document how rat stem cells added to embryonic mice engineered to lack the normal smell circuitry, made their way to the brain, turned into the right sorts of nerve cells, and successfully wired themselves in, restoring the missing sense of smell. The study has important implications for how we might go about repairing damaged or diseased human brains in future. Kristin Baldwin is professor of genetics and development at Columbia University Irving Medical Center, and a corresponding author of one of the two papers…

Kristin - Fixing a brain that isn't working is probably the most difficult task that we have to face in medicine. And we would like to be able to understand how to replace parts of the brain that aren't working with other parts that do work. The goal of this study was to test that.

Chris - When I was little I watched a program and Anders Björklund was the guy from Norway and they were doing studies on human patients where they were putting in embryonic tissue to try to help people with Parkinson's disease. Is that the sort of thing you're talking about getting better at? Cell-based therapies, not necessarily with embryonic tissue but with cells that are capable of moving through the brain, turning into new cells to fix things.

Kristin - Exactly. We're trying to find the best way to get cells to go into the brain and actually help it function.

Chris - So how did you do it?

Kristin - We were able to take what are called early embryos in the mouse or blastocysts, which are balls of cells, a couple hundred cells and we can sneak into them about six cells from another species, a rat, that are early stem cells into that. And then they will co-develop in a mouse and become a whole mouse-rat chimaera where the rat cells are peppered throughout the mouse's body. And we can see them either because they cause different fur colours or because we engineer them to glow in the dark, red or green, and the mouse cells do not. So we can look under a microscope and see glow in the dark red rat cells in the brain all over the brain and also in the other tissues.

Chris - And how does this address your question of seeing how we can fix bits of the brain that we want to put cells into in the future?

Kristin - The first question is are there places rat cells can go in the brain and places they cannot? And we were able to clear the whole brain and look through it with a microscope and say basically the rat cells seem to be very good at going almost anywhere in the whole brain. That says this kind of approach has flexibility throughout the whole brain. Great. Now if we wanted to fix a broken brain, we at least think we could do it in a lot of different places. Question two then is, well if there was something wrong with the brain, could the rat cells go in and rescue it and fix it if the mouse's brain had a disease or had been injured?

Chris - And how did you test that?

Kristin - So we tested that by using genetic tricks. We made mouse brains that were missing important cells for the mouse, including those that are important for their sense of smell. So in one case we killed those cells and asked could the rat cells come in and restore that part of the nose? And in other cases, instead of killing them, we just made them very bad at talking to the rest of the brain so that the animal couldn't smell but the cells were still there. And those are sort of similar to things that happen to humans. Either they have a disease where you lose the neurons or you have a disease where they're just not working very well.

Chris - And the question is, you do this to the mouse and then see if the rat cells come in and make good. So before we think about whether they work, do they actually go to the right place and restore what's missing?

Kristin - That was remarkable that they actually go to the right place and the right kind of cells are there. They are adapting to that environment. They're born at the right time and they become the right size and shape to fit into the mouse brain, which is quite a bit smaller than the rat brain. So that is already great news that they can look like they're in the right place and be the right kind of neuron. And that was one of the most exciting early findings we had.

Chris - How did the rat cells know where the problem is in the mouse brain that you've caused and therefore how to fix it and also to look like mouse cells when they're doing it?

Kristin - Right. So all the cells go through the stages of development and they become something called a brain stem cell or neuro stem cell. And at that stage they start to listen to their environment, which tells them depending on where they're sitting, what kind of brain cell, what kind of neuron to become. So if they happen to be in the nose region, they'll become the kind of neurons that are important for smell. If they happen to be in an eye, they might become the kind of neurons that are important for vision.

Chris - So you get the smell system recapitulated, albeit built by rat cells in these mice.

Kristin - Exactly. And that was a wonderful result to see.

Chris - Indeed, because it kind of argues if we did this in a human with human cells, they might work even better. But there should be instruction sets there that will guide the cells to become the right thing. But the key question must be do they work? So if you test the smell system in the mice that have now got a rat sense of smell, do they seem to be smelling?

Kristin - That was the big experiment when we found that being in the right place at the right time could build a rat nose in a mouse. Would that mouse be able to use that nose to do what it likes to do, which is find a hidden cookie. And so we use this test, put a mouse in a cage where a mini Oreo is hidden and ask does it find it? How long does it take? And the mice that had disrupted their smell system wouldn't find the cookie. And when we put the rat cells into a mouse that had no mouse cells that could do this, the mice were able to find a cookie using a rat's nose. On the other hand, this is not just plug and play because if the mouse cells were there but quiet or silent, in that case the mouse couldn't use the rat cells. So we learned already that there are rules to how well your brain can take in different signals or signals for circuits that have been hurt and are now being repaired.

Chris - That sounds like it might be a stumbling block then. So if you have cells that are already there and they're not working properly, they can get in the way and frustrate the repair process.

Kristin - That is one possibility suggested by the work and something that we'd like to investigate further because that's very important to design appropriate cell therapies for humans.

Chris - I have to ask you the question, are there things that mice like the smell of that rats don't? And when you test your mice that <laugh> you find that there are things that they've developed a rat preference for that a mouse never would.

Kristin - Well that's my favourite experiment and we are gearing up to try to do that. It takes a few more tricks, but one thing is that mice actually smell a rat, a cat, or even a snake and are instantly afraid. They'll freeze. Rats are not afraid of rats. So what we'd really like to do is see if that mouse with a rat's nose is no longer afraid of a rat.