The first heartbeat

14 November 2016

Interview with

Paul Riley, University of Oxford

The heart is one of the first organs to form during mammalian development and, in a human, was though to form a beating structure from 3 weeks following conception. Developing Mouse HeartBut now new imaging techniques have shown that the process occurs even earlier. By just 16 days there are already cells destined to form the future heart. These cells show surges of calcium that will later translate into heartbeats. The discovery is important because, with 1 in every 180 babies affected, congenital heart disease is one of the most common developmental disorders; it may also inform how we progress the use of stem cells to repair damaged adult hearts too. From the University of Oxford, Paul Riley explained the findings to Chris Smith...

Paul - Basically, we found that the heart beats earlier than was previously thought. So, it starts to beat with very early forming heart muscle cells as the heart forms a crescent shape. And this was before the stage that was previously thought, which was more like a linear heart tube which is in the mouse, at least a sort of day, day and a half later which equated to humans of about 5 days' time difference.

Chris - So in a human embryo, how early would we, if humans are analogous to the mice you've been studying begin to see a heartbeat.

Paul - So, if the analogy is exactly accurate then we have to take that with a slight grain of salt. The match up would be around about day 16 of human pregnancy.

Chris - Which is incredibly early, isn't it? I mean there's not very much to a human embryo  at that stage of development.

Paul - That's correct and certainly, the heart, in terms of a sort of organ we would perceive is a very early forming tissue and it really hasn't got all of the structure that we would normally associate with a heart at that stage.

Chris - How does the heart form?

Paul - Well, it forms for a whole series of cellular and molecular processes. But basically, there is this specification of cells either side of the embryo's midline. They come together at the middle of the embryo, they form this linear heart tube, that heart tube loops, and this looping aligns the chambers correctly and the inflow and outflow regions of the heart. Those chambers then specify, grow, they divide to make sure the blood flow is in one direction, and then there's further growth and expansion. So that's a simplistic way of looking at how the heart forms. So, we're talking about the very early stage when the heart exists as a few cells either side of the embryo's midline.

Chris - How did you find that these heart cells are effectively beginning to beat so early in development and why was it missed before?

Paul - Well, I think the issue here is the work that Shankar Srinivas has pioneered in imaging the life early mouse embryo. And so, what we're able to do is we're able to look very, very early stages and then appreciate that these cells were actually contracting. And then we're also able to look at the key events that are required for that contraction - how do these heart cells beat and what's the requirement for that? And it turned out to be calcium signals.

Chris - Why is calcium important?

Paul - Calcium is very important because it interacts with the contractile machinery of the heart muscle cell. And that enables the contractile process, so the beating. But what we found was actually, cells were positive if you like, for calcium signal before even the contraction event occurred.

Chris - So, are you saying then that these cells already know that they're going to be cardiac cells. They're already beginning to set up these fluxes or spikes of calcium which would normally coincide with a heartbeat but that then comes along a bit later so the calcium spikes might be in some way encouraging the cells to turn into heart cells.

Paul - Absolutely correct. The idea is that we think the calcium signal is an early defining event. It happens in a sort of random process within cells and we don't understand how that occurs and which cells tend to turn on the signal before others and also, how those cells then synchronize this calcium signal. But what we think happens is that calcium then is also important for the actual process of this heart muscle cell, differentiating and maturing properly.

Chris - Given how common the congenital heart problems are as a group, I suppose understanding this process and how heart cells get specified is going to be fundamental to understanding congenital heart disease but also, potentially putting hearts right.

Paul - That's correct. We think that two-fold application of the work if you extend it into the human setting and the disease setting, and that is one, understanding the fundamental processes of birth defects in congenital heart disease, i.e. at the level of how the heart starts to contract, what happens if that goes wrong. If for example, those cells that start to beat don't synchronise properly and don't communicate with each other properly. And we also think there's an important component here as applies to adult heart repair because if we're thinking about introducing new heart muscle into a patient who's had a heart attack for example then how that heart muscle needs to start to beat and integrate and communicate with the survived heart muscle of the patient is really important.

Chris - Do you know yet what those cells are doing in order to produce these interesting calcium signals and how are they doing that?

Paul - Well, we know that one of the key events is they need to express a particular ion channel which actually exchanges the calcium for sodium. Interestingly, there's an ionic balance of these different signals. And so, the expression of this channel which is called the NCX - so the sodium calcium exchanger is really important in these specifying heart muscle cells in this early stages. And what that enables then is for calcium to enter the cell. and so, that's the key event. We don't know why as I say, particular cells in this early forming heart start to do that early than others. The progression of events and how that becomes sort of synchronized that these heart cells communicate. And these are studies which are ongoing particularly in my colleague Shankar Srinivas's lab as he looks at single cell sequencing to determine key molecular profiles of these individual cells from this forming heart.

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