Paul Riley, University College London
Kat - Also this week, scientists have shown that the adult heart contains stem cells called epicardial stem cells that can be triggered by a signal called thymosin beta 4 to produce new muscle cells if part of the heart is damaged. This week, Chris spoke with the paper’s author, Professor Paul Riley from UCL...
Paul - The problem we were trying to address was the fact that the adult human heart is unable to repair itself following a heart attack, following injury. We were keen to exploit the fact that there is a cell type in the adult heart that is also found during development. They are found when the heart is actually forming during pregnancy and we wanted to try and recapture some of the potential of these cells, used during the building of the heart, to actually mend and repair the heart in the adult. The same as with that in a mouse.
Chris - So it sort of recapitulates the embryonic state in the disease state so that the damaged bit does regrow.
Paul - That's right. We’re not the first group to describe the potential for stem cells that might be existing in the heart, but the cells that have previously been described are very rare, and in fact, they don't become heart muscle or blood vessel cells very readily. If they do, they're very mature so they're not really functional. What we wanted to do was to find a much more tractable or better target cell type and the cell type we chose contributes to both the blood vessel development and also to muscle cells of the developing heart. These cells are called epicardial cells.
Chris - And they're there in the adult, so they could be potentially recruited in an injury.
Paul - That's right. They line the outside of the muscle of the heart in the adult, and they're thought to have basically stopped doing what they need to do because they contributed during development and then their sort of activity if you like, is switched off. So the key thing from our point of view is to try and reactivate that program and to try and get those cells to turn the clock back, behave more like they do in the embryo.
Chris - And how did you actually approach that?
Paul - We already knew from some previous work that a very important protein called thymosin beta 4, if its function was lost in mouse hearts, the heart failed to form properly and didn’t make the coronary blood vessels. The defect was at the level of these embryonic epicardial cells. What we then did was we took a huge leap of faith where we added thymosin beta 4 back to adult cells in preparations to try and see if thymosin beta 4 was both necessary during development, but also sufficient, to activate the adult cell type. Fortunately for us, thymosin beta 4 proved very good at making these cells divide, migrate and become in this instance smooth muscle cells, some fibroblast cells and also some endothelial cells. These are key cell types of both the coronary vessels and also the skeleton of the heart. What we didn’t know at that time was whether or not they had the potential to make heart muscle and that's been the nature of this particular study.
Chris - What did you actually do to try and track what these cells could do in context of an injury?
Paul - This study was really based on two findings back in 2008 that said that the embryonic epicardial cells could also contribute to the muscle of the heart. In that study, one of the groups used a transgenic mouse. This mouse was driving a green fluorescent protein in the epicardial cells during heart development by virtue of one of the embryonic genes that's expressed. This is switched off in the adults so we reasoned that if we’re reactivating any embryonic potential in these adult cells, maybe we’re also really restoring embryonic gene expression. We took that mouse and added thymosin beta 4 for a number of days and we were able to switch on this green label of the adult cells. So what we’ve done then is we’ve reactivated an embryonic gene program and we were able to watch what those cells did in response to an injury, where we induce the heart attack in the mice. In this instance, we were able to observe a proportion of them becoming new heart muscle.
Chris - And there's no way that these glowing green cells could’ve come from any other source.
Paul - Well that is actually a really good question. In fact, it’s a question posed to us by the reviewers of the study that we published in Nature. Their key point there is that we may have just been looking at existing muscle cells that have turned on the green fluorescent protein, so have just switched on the gene program in existing heart cells. What we have to do actually to disprove that completely was to do some cell transplantation experiments. We took cells that were labelled from a donor animal, that had undergone this thymosin beta 4 treatment and then injury, and put them into a non-transgenic unlabeled host mouse. That mouse had also undergone priming with thymosin beta 4 at injury. So we put green cells into, if you like, a white background within the heart and we were able to watch these cells then become heart muscles.
Chris - So the bottom line here is that you've identified there is a population of cells, all be it that they're in small numbers, and you can turn them on and they can locate the right place to go to and turn into the right sorts of cells to repair damage without people having to add new cells which has, up until now, been the dogma.
Paul - That's correct. So the key point was, yes, resident cells do exist in the heart that can be reactivated and when they do that they can repair significantly the damaged area. So we were also able to assess that functionally as well and assess heart function. That was done using magnetic resonance imaging studies where we showed that the heart function, as a result of this sort of treatment and so on, was improved by about 25%.
Chris - Which is a huge improvement and something no one even thought was feasible. That was Paul Riley from UCL and the next step in that research will be to produce an artificial form of thymosin beta 4 which is the agent that activates those stem cells.