Cardiac progenitor cells generate healthy tissue after a heart attack

Following a heart attack, the human body is unable to repair lost tissue due to the heart’s inability to generate new muscle. However, treatment with cardiac progenitor cells could lead to the formation of functional cardiac cells at injured sites. This new therapeutic approach is introduced by an international team in Cell Biology Nature. The objective is to start clinical studies within two years.

How can heart function be restored after a heart attack? With approximately 18 million deaths each year worldwide due to cardiovascular disease according to the World Health Organization (WHO), this is being researched around the world. One possible answer could be treatment with an enriched pool of ventricular progenitors derived from human pluripotent stem cells, or HVP for short. An international team comprising the Technical University of Munich (TUM) and its university hospital Klinikum rechts der Isar, Sweden’s Karolinska Institutet, Swedish biotech startup Procella Therapeutics and biopharmaceutical company AstraZeneca investigated this approach in a study published in the journal Cell Biology Nature.

Many heart diseases cause heart muscle cells and blood vessels to die. They are replaced by fibrous scar tissue, which leads to further deterioration of heart function. Some animals, especially amphibians and fish, can repair such damage, an ability almost entirely absent from the heart of an adult human. An experimental approach to restoring lost heart tissue is stem cell therapy. Previous studies have included the use of heart cells derived from stem cells, in particular: cardiomyocytes. However, common side effects such as irregular heartbeat and life-threatening arrhythmia have occurred.

Cardiac progenitor cells instead of differentiated cardiac cells

In contrast, the team working with Karl-Ludwig Laugwitz, professor of cardiology at TUM, is studying human ventricular progenitor cells. These cells play a crucial role in the formation of the heart during development. Over time, they differentiate into different types of heart cells, including cardiomyocytes. The team succeeded in producing a large number of these HVPs from human embryonic pluripotent stem cells. “This represents the culmination of two decades of our work trying to find the ideal cell to rebuild the heart,” says Kenneth R. Chien, professor of cardiovascular research at Karolinska Institutet.

Complex molecular mechanisms

With these cells, scientists studied the complex molecular processes involved in repairing damaged areas of heart muscle. “In laboratory investigations, we were able to show how HVPs can, in a sense, stalk damaged regions of the heart, migrate to sites of injury and become active heart cells. They also actively prevent the formation of scar tissue by interacting. with fibroblasts, as we call the cells that form the structural framework of non-functional connective tissue, says Professor Laugwitz, who heads the first medical department at TUM’s Klinikum rechts der Isar.

Successful processing of pig hearts

In the next step, the interdisciplinary team used pigs to study the effectiveness of treating a damaged heart with HVPs. Physiologically, pig hearts are quite similar to human hearts. As a result, experiments with pigs are often conducted shortly before human patient studies begin. The results show that heart damage can be reliably repaired, even in large animals, with no serious side effects observed. “The treatment has successfully demonstrated the formation of new heart tissue and, most importantly, the improvement of heart function and the reduction of scar tissue,” said Dr. Regina Fritsche-Danielson, head of research and early development at AstraZeneca.

Researchers aim to start clinical studies within the next two years

In the months and years to come, scientists plan to apply the results of their current research to develop a treatment for heart patients. An important intermediate step is the development of hypoimmunogenic lines of HVP. Currently, it is necessary to inactivate the recipient’s immune system to prevent it from destroying the treatment cell. Hypoimmunogenic cells would eliminate the need for this step, as they would not be identified as foreign bodies to the recipient. Further research will be conducted on hypoimmunogenic cells and possible side effects. The objective is to start clinical studies on the therapeutic use of HVP within two years.

“The new knowledge on the therapeutic use of HVPs represents an important step in the treatment of various patients with severe heart failure”, says Professor Karl-Ludwig Laugwitz. “In particular, older patients with co-existing conditions, for whom major heart surgery would represent undue hardship, would benefit from treatment with HVPs.”

Reference: Poch CM, Foo KS, DeAngelis MT, et al. Migratory and anti-fibrotic programs define the regenerative potential of human cardiac progenitors. Nat Cell Biol. 2022;24(5):659-671. doi:10.1038/s41556-022-00899-8

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