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4D heart imaging joins quest to tackle Europe’s biggest killer - Dr Miguel Torres

Dr Torres and Dr Mercader are looking at embryonic heart growth and regeneration in zebrafish and mice, which could lead to new treatments for heart disease. Image Credit - 4DHeart

Real-time imaging of embryonic heart growth and regeneration could uncover the cause of adult heart disease and lead to potential treatments, according to Dr Miguel Torres, a developmental biologist at the Spanish National Centre for Cardiovascular Research.

You are the coordinator of the EU-funded 4DHeart project, along with Dr Nadia Mercader, which is analysing heart regeneration and development in zebrafish and mice, respectively. Why is research into hearts so vital?

‘Heart disease is a big problem, especially in Europe with the standard of life we have here – heart failure is one of the most important issues in our society. The impacts of heart failure in terms of individual and social suffering, as well as the loss of working hours, are really very acute. The expenses for treating these issues are huge, and the calculations are that countries will not be able to support the expenses of treating all of the people that are expected to have a failure in the next 20 to 30 years. And the thing is that it cannot truly be cured – it can at best be stabilised. There’s no real solution, so any research that could lead to a new therapeutic approach for a regenerative cure would be a breakthrough.’

How does the 4DHeart project approach this issue?

‘The project is on heart imaging – applying different light analysis techniques to capture and model how hearts develop and function. We are looking at two models: one, the mouse, which is a very useful model as it’s a mammal and it’s the best model we have where we can do embryology (studying unborn or unhatched offspring). And the second model is the zebrafish, which is further away from humans but it’s a very useful model as it’s possible to look at an embryo’s heart development in real time. And why is real-time study important? Some conditions of the adult heart originate in this embryo stage and genetic analyses link heart development genes to adult heart disease.’

How have recent advances in the field of microscopy opened up cardiac research?

‘One particular approach we will use is called light-sheet microscopy, which was initially developed around 10 years ago and has recently become very useful as it now allows fast and quite deep imaging of tissues in live animals without disrupting the cells. If you wanted to go deep in tissue using conventional techniques, you would have to use such high laser energy that you’d destroy the cell, but in this case, you can look at the live development of the structures for prolonged periods using relatively low energy.’

‘Some conditions of the adult heart originate in this embryo stage and genetic analyses link heart development genes to adult heart disease.’

Dr Miguel Torres, Spanish National Centre for Cardiovascular Research

What is 4D analysis and did you have to develop special tools for this?

‘4D is 3D plus time, so we’re imaging heart development with time lapses – either at a very high frame rate keeping up with the fast heartbeat rate in zebrafish or longer, more dispersed observation over one or two days with mice. The informatics are very important as we need new software to connect and track cell development in three dimensions and time, giving an identity to this cell that can be tracked from one image to the next. There is software available, but it’s not optimal, so we’re creating a software toolbox for tracking this.’

Could the heart tissue regeneration seen in zebrafish also work in mammals?

‘Zebrafish are very popular for studying due to their heart regeneration properties and although it seemed this capacity existed only in the case of fish, a few years ago it was shown that new-born mice also have similar properties. It’s a matter of heart maturity – you can say a fish heart remains immature compared to mammal hearts, but you see the exact same heart cell regeneration in mice less than seven days old.’

So what exactly are you hoping to observe in embryonic mouse heart development?

‘In this particular project we’re not looking at regeneration of a mouse heart, but the early formation of a linear heart tube as a precursor to the four-chamber heart. It develops from tissue that is completely flat and organises to form a heart tube in about 16 hours. We don’t know how this happens because this process has only been observed in fixed embryos, so we want to capture the live dynamics of cells within the organ to understand its formation. We believe many congenital malformations appearing at birth may start to be generated by defects in linear heart formation and, using single cell tracking, we will be able to understand the cellular basis of this process.’

What are some possible applications which could arise from 4DHeart’s research?

‘There’s a field called organoid research with an increasing trend of looking at development in live tissues – i.e. looking at developing organs like kidneys and lungs in vitro (tests where groups of cells can be observed) and doing live analysis on the cellular processes. So even though we’re looking at the heart, the microscopy techniques we’re developing in this project might be of general use for research. On top of this, we might also be able to create hypotheses on how the linear heart tube develops in mouse embryos and how the adult zebrafish develops and regenerates.’

Looking to the future, what heart treatment options could lie on the horizon?

‘I see three possibilities. From a biology standpoint, a lot of emphasis is being put on cardiac stem cells, which may naturally exist in the heart, and can potentially be used as a source for creating other cells. Another path of research in biology is trying to regenerate mice hearts by stimulating cardiac muscle cell proliferation (rapid increase), and actually, we are starting to look at this in a project starting next year. But I do also see that there is increasing research in integrating robotic devices into human bodies, and when you think that the heart is actually a pump, I think that engineers will come up with optimised devices that function like the heart. In the long run, I tend to think that such mechanical solutions could be an important option.’

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