Investigating human heart diseases is the main aim of this EC3R project under the leadership of Prof. Michael Gotthardt and Dr. Sebastian Diecke. Their research team develops artificial heart tissue in order to shed light on disease mechanisms, test drugs and reduce the number of animal experiments in accordance with the 3R principles.
Cardiovascular diseases are still the leading cause of death worldwide. The majority of patients are affected by heart failure with preserved ejection fraction (HFpEF). In this case, the elasticity of the heart is impaired, rather than its ability to pump. The heart muscle's impaired ability to adequately fill with blood results in a systemic shortage of oxygen and nutrients, affecting the body's overall function. Affected patients are less physically resilient, retain water in their lungs and experience shortness of breath. There is no effective medication to alleviate the symptoms.
Professor Gotthardt wants to change this. One of the goals of his research group "Translational Cardiology and Functional Genomics " at the Max Delbrück Center for Molecular Medicine in Berlin, is to discover novel drugs that could be used to treat cardiovascular diseases more efficiently. Scientists in Gotthardt’s group are working with artificial heart tissue (Engineered Heart Tissue, EHT), along with animal models for heart disease. With the EC3R project "Engineering of human heart tissue for functional diagnostics, drug testing and therapy", they would like to further develop EHT technology and make it available to researchers worldwide. His partner, Dr. Sebastian Diecke, is head of the "Pluripotent Stem Cells" technology platform at the Max Delbrück Center.
For their experiments, Gotthardt’s research team is using heart muscle cells, also known as cardiomyocytes, which are created in the laboratory. First, Sebastian Diecke reprograms human cells, derived from e.g., blood or tissue samples, into stem cells capable of development. These so-called induced pluripotent stem cells (iPS cells) can then differentiate into any given cell of the human body - liver cells, neurons, intestinal cells and even cardiomyocytes. Individual heart muscle cells are assembled into a shimmering pink, three-dimensional tissue structure. "The artificial heart tissue mimics the interconnected network and communication of cardiomyocytes within the heart muscle," explains Prof. Michael Gotthardt. "EHTs enable us to replicate key aspects of various cardiovascular diseases in vitro, offering a realistic representation within a Petri dish."
To provide resistance and study its mechanical properties, artificial heart tissue is connected to small plastic rods. The EHT has the ability to rhythmically contract and relax - just like cardiomyocytes in their natural environment. The movement of the plastic rods, resulting from cardiomyocyte contractions, are recorded and analyzed computationally. Utilizing these measurements, the researchers are able to draw conclusions about cardiac function in the human organism. "We want to understand the heart’s responses to different external stimuli and adjust its elastic properties to achieve the best possible therapeutic effect.", says Prof. Michael Gotthardt. Furthermore, the researchers use EHTs to develop active compounds that improve metabolism and pumping function of the heart.
To cope with different stressors, cardiomyocytes employ alternative splicing, a process allowing them to create diverse protein variants from a single gene. Thus, different isoforms of titin, the largest protein in the human body, are produced. Alongside actin and myosin, this giant protein is a building block of the sarcomere, the smallest mechanical unit of the muscle cell. It determines the elastic properties and therefore has a significant impact on the mechanical properties of cardiomyocytes.
"Our goal is to decipher how cardiac splicing is regulated and how to target it therapeutically in order to improve the life of patients suffering from heart failure with preserved ejection fraction," says Gotthardt. Last year, he received an Advanced Grant from the European Research Council (ERC) endowed with 2.5 million euros. In HFpEF, cardiac wall stiffness increases, so that the heart is no longer able to sufficiently fill with blood. Drugs targeting the production of sarcomeric and cardiac signaling proteins could help improve the filling capacity of a diseased heart muscle and therefore enhance its overall function.
Here, artificial heart tissue has several crucial advantages. "We can generate almost any number of genetically identical EHTs from a single sample, allowing us to increase throughput and run more comparative analyses," says Gotthardt. "It also paves the way for precision medicine," adds Pragati Nalinkumar Parakkat, a doctoral student in Gotthardt's team. "Thanks to the EHTs, we can analyze patient-specific heart tissue more easily. This has not been possible for a long time, as access to human heart tissue is very limited." The iPS cell technology in combination with the engineering of heart tissue now makes it possible to grow heart tissue specific to any individual. This advancement opens doors to testing personalized medication, recognizing the unique response of different individuals to drugs.
Artificial heart tissue also helps to reduce the number of animal experiments. "EHTs are very well suited as models for select aspects of heart disease, facilitating the analysis of how drugs effect human cardiomyocytes," explains the scientist. In order to fully understand the systemic effects of therapeutic interventions, researchers still have to rely on animal models, as these provide insights into the intricate interplay among various cells in the body. "But the experiments with artificial heart tissue enable us to carry out better, more refined animal experiments," says Prof. Michael Gotthardt. "Results of EHT experiments provide us with critical information that enhances our ability to develop better therapies."
Original text (German): Jana Ehrhardt-Joswig, May 2023.
