Growing Specialized Heart Cells: Simulating a Heartbeat in a Dish

Detailed examinations of the heart revealed the pivotal role of the left ventricle – it’s the area of ​​the heart that develops first and provides the force to pump blood around our bodies. More importantly, it is the area most implicated in heart disease and heart attacks and is the area most susceptible to the cardiotoxic effects of some medications.

Crick researchers have now developed a way to grow specialized left ventricular heart muscle cells from stem cells, opening up new opportunities for research into heart disease, drug screening and possibly developing new therapies.

Their methods are published today in Cell Reporting Methods It has also been licensed to Axol Bioscience to market and sell a protocol for the production of cardiac muscle cells for research and development purposes and to provide contract research services, particularly in the field of drug screening and cardiotoxicity investigations.

Increased heart rate

This work was led by Andrea Bernardo, a Wellcome Trust Career Re-Entry Fellow at The Crick who recently started her own laboratory at Imperial College London. The development of left ventricular cardiomyocytes (heart muscle cells) is a complex process, and is based on a detailed understanding of developmental biology, explains Andrea.

“In order to encourage cells to specialize, you have to understand the process of normal development. We set out to understand the different chambers of the heart — how they are formed, and what genes and pathways are involved in their development.

“Only with this detailed understanding of early embryonic changes can we apply the knowledge in stem cell models, starting with the formation of the correct mesoderm lineage, which is the first stage in cell specialization. We also found that blocking the retinoic acid pathway acts like a fail-stop, preventing types of different from the myocardium of formation.

“What we end up with is a near-homogeneous group of left ventricular cardiomyocytes that beat in sync. It’s like a Mexican wave across a dish. We can study these cells functionally in 2D cultures and we can also make prepared heart tissue, measure their strength, and study them in this 3D environment.” Surprisingly, we show that left ventricular cardiomyocytes or engineered heart tissue generated from them are stronger and have improved structural, functional, and metabolic maturation compared to standard cardiomyocyte models.”

The way it was made is 30 years old

Andrea’s work is rooted in research conducted over 30 years ago. Jim Smith, emeritus scientist at Crick, examined the molecules that drive embryonic development in an early amphibian embryo using the frog Xenopus laevis as a model.

Andrea and Jim met when they were both working at the University of Cambridge, and began collaborating on research on mouse embryos, which led to work progressing toward human stem cells, a partnership that would continue when Jim became director of the MRC National Institute for Medical Research, one of the Crick Institutes’ founders.

Culture of synchronously pulsed left ventricular cardiomyocytes. Credit: Francis Crick Institute

“When I was an early career researcher, I had no idea how I would one day apply my findings,” Jim says. “It’s very exciting to see molecules that we first observed in frogs are now part of this process.

“This really highlights the value of exploratory research – you never know where that might lead.”

It was the partnership between Andreia and Jim that pushed the research forward through challenges over the years.

“I took a long time off work to take care of my baby who was very sick, and without Jim’s support, I don’t know if I would have gone back,” Andrea says.

“And recently, while we were improving our methods, we had to stop our research because of the pandemic. Many cultures were lost and this set us back about a year.”

But fortunately, their team returned to Crick and with the support of Crick’s translation team, found a partner in Axol Bioscience.

Ranmali Nawaratne, Senior Business Manager of the Crick Translation Team, said, “When Andreia and Jim introduced this protocol to our team, the potential was clear. We were able to file a patent and provide internal translation funding that they could use to generate more data about the nature of these muscle cells.”

“It has been great work translating this laboratory discovery into a marketable method. It is exciting to see how these specialized muscle cells will be applied in future research and possibly in cell therapy, in the time to come.”

future applications

The new agreement with Axol Bioscience will allow more laboratories around the world to use these specialized heart cells in their own research. This could be testing the safety of different drugs or developing new drugs to treat specific diseases of the left ventricle.

Andrea also recently set up her own research group at Imperial College where her team will use cells to study left ventricular growth, maturation and disease. Better models of diseases such as hypertrophic cardiomyopathy, a congenital heart condition affecting the left ventricle specifically, will be designed using this method. Her team will also explore whether these cells have therapeutic value for treating heart failure.