Who are the patients that your research benefits?
Jolanda van der Velden: Certain types of heart disease are caused by a gene mutation in the cardiac muscle cells. The people affected by it often develop symptoms, or have acute cardiac arrest, between the ages of 20 and 40. The outflow of blood from the heart to the body is via the aorta; patients who have this genetic condition develop a thickening of the heart muscle that obstructs this outflow.
As of yet, we don’t have a preventative treatment for this – but we can identify the people who are at risk because they carry a specific genetic defect. In addition, the timing of treatment of the symptoms is tricky. We’ve had to rely a lot on mouse models in the past, but a mouse’s physiology is different to a human’s physiology. So engineered heart tissue made from human stem cells is one tool to get closer to testing treatments to help these patients.
How does engineered heart tissue work?
JvdV: We collect a lot of cardiac muscle samples during heart surgery for research purposes. But to study the effect of a genetic mutation for a longer period of time, we wanted to engineer it in a dish. We therefore culture it from patient stem cells, using them to engineer heart muscle strips that can keep for several weeks in a dish. It’s essentially a mini-heart muscle based on human cells. The aim is to evaluate how well it resembles the patient situation, and to use it to unravel disease mechanisms and test drugs to treat the disease.
How does this compare with animal models?
Diederik Kuster: For diseases that originate in heart muscle cells, this engineered heart tissue is very helpful and physiologically relevant. We can make quite complex 3D models this way. But the disadvantage compared with animals is that the vasculature is not present, which is important in any cardiac condition. We can’t properly model the vasculature in a heart muscle strip yet, so we still need animals for this. The next step is to add not only the additional components of a heart with many different types of cells, but also other organs like the liver and kidneys. Until we can create this multi-organ physiology in a model, we can’t completely replace animal research. We still need animals to validate our research and perform studies in a more complex multi-tissue and multi-organ system.
JvdV: Cardiovascular diseases are complex, and therefore complex to model experimentally, as a diverse range of possible causes underlie malfunctioning of the heart and vessels; there are genetic causes, problems with vasculature, valvular defects and so on. When you use any model – whether a mouse model or an engineered human cell model – you need to be aware of the specific functional readout. Does the model accurately mimic the patient situation? That’s what you need to ask yourself, and every model has its advantages and limitations.
What are some of the things you can test and measure using engineered heart tissue?
DK: What we’re doing at the moment is measuring the function of heart muscle cells in different models. For example, how much force can the muscle generate, and how effectively can it contract and relax? Engineered heart tissue is one way to do this, but it’s difficult to achieve at the large scale that would be required for high throughput testing of different drugs or compounds.
So we’ve also been working on using isolated cardiac muscle cells from an animal heart, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in a dish. This is a 2D cell method to measure movement and translate that into contraction and relaxation. It’s a much higher throughput method to study compounds, and it hugely reduces (and in some cases replaces) the number of animals you need to use, as it increases the number of cells you can study in a day. Whereas before you could test only one compound per animal, now you can test 20. This method has the potential to take animals out of the equation for compound screening altogether.
Where are we going and where have we come from in the field of engineered heart tissue?
JvdV: If you look back, a lot has happened in the field already to reduce research in animal models. Around 30 years ago, an Australian scientist called Cris dos Remedios created an extensive cardiac tissue bank – this was truly visionary as a lot of knowledge was, and still is, obtained from this human cardiac tissue collection. And 10-15 years ago, a German scientist called Thomas Eschenhagen built the first engineered heart tissue. In our lab, we started engineering heart tissue about five years ago. It takes time to really set these things up – for instance, it takes six months to transform cells isolated from a patient’s blood to cardiomyocytes that we can study in a dish.
DK: The dream of personalised medicine is still some way off. Many aspects of it are there already, but it takes a long time to culture cells and it’s currently very expensive. At the moment, we’re still in the research arena – the next step is to scale up.
These iPSC-CMs are more foetal than animal cardiac muscle cells. We need to mature those cells and get them working more like a human heart. We also need to build vessels (and other cell types in general) into the system in order to be able to study that interaction and make the models more complex.
JvdV: The issue here is funding. We’ve set up all these models so far, but it’s a challenge to get funding to mature and innovate on these models. Grant-givers want to fund disease-curing treatments, but that’s one step ahead of where we’re at. First we need better models – then we can cure diseases. In the Netherlands especially, there is very little funding for science compared with countries like Germany, the UK and US – so we have to team up with scientists nationally and abroad. But overall, I expect a lot of things to move forward at a fast pace in the next five years.
Who are you collaborating with?
Dk: There are essentially three groups needed to work together on this: cardiologists, clinical geneticists and basic scientists. In the Netherlands, there’s a consortium on genetic heart diseases, which includes experts on iPSC-CMs and experts on metabolism in cells. We also collaborate with a team in Hamburg, Germany, which is where the work on engineered heart tissue began. It’s an international effort!
Where can people go to find more information?
- Amsterdam Cardiovascular Sciences works toward preventing and curing cardiovascular diseases. It interconnects excellence in clinical and basic research to provide a unique infrastructure for cardiovascular researchers.
- The Double Dose-consortium aims to unravel the mechanism by which cardiomyopathy-causing mutations lead to ultrastructural changes in cardiomyocytes. The consortium combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults.
- The Department of Physiology at the VUmc location of Amsterdam UMC recently crowdfunded 60,000 euro for heart research using engineered heart tissue.
Interview by Vicky Hampton, December 2021