New treatment repairs heart damage after heart attack without side effects

Researchers at the Technical University of Munich find that treatment with cardiac progenitor cells can lead to the formation of functional heart cells in damaged areas after a heart attack.

Following a heart attack, cardiac progenitor cells produce healthy tissue

A heart attack, also known as a myocardial infarction, occurs when part of the heart muscle does not get enough blood. The longer it goes on without restoring blood flow, the more the heart muscle is damaged.

The most common cause of heart attack is coronary artery disease. A strong spasm or sudden constriction of a coronary artery, which can cut off the blood supply to the heart muscle, is another reason, although less common.

The human body is unable to rebuild damaged tissue following a heart attack due to the heart’s inability to produce new muscle. However, treatment with cardiac progenitor cells could lead to the production of functional cardiac cells in injured regions. A global team introduced this new method of treatment in Cell Biology Nature May 12. Clinical trials are expected to begin within the next two years.

How to restore heart function after a heart attack? With an estimated 18 million deaths worldwide from cardiovascular disease each year, according to the World Health Organization (WHO), this is a global research goal. Treatment using an enhanced pool of human pluripotent stem cell-derived ventricular progenitors, or HVP for short, could be a viable approach. In a study published in the journal Cell Biology Naturean international team consisting of the Technical University of Munich (TUM) and its university hospital Klinikum Rechts der Isar, the Swedish Karolinska Institute, the Swedish biotech startup Procella Therapeutics and the biopharmaceutical company AstraZeneca evaluated this approach.

Heart muscle cells and blood vessels die as a result of many heart diseases. They are replaced by fibrous scar tissue, which worsens heart function. Some animals, especially amphibians and fish, can heal such wounds – a talent that is almost entirely lacking in the heart of an adult human. Stem cell therapy is an experimental strategy to regenerate missing heart tissue. Previous research has used heart cells derived from stem cells, specifically cardiomyocytes. However, many side effects occurred, including abnormal heartbeats and life-threatening arrhythmia.

Tissue cutting fourteen days later

A tissue section shows that after fourteen days already, cardiac progenitor cells (green) almost completely colonize the damaged areas of the heart. Credit: Poch et al., Nature Cell Biology

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.

Karl Ludwig Laugwitz, Alessandra Moretti, Christian Kupatt Jeremias, Christine Poch

Three TUM chairs involved: Prof. Karl-Ludwig Laugwitz (right), Prof. Alessandra Moretti (2nd from right) and Prof. Christian Kupatt-Jeremias (left) with first author Dr. Christine M. Poch. Credit: Daniel Delang / TUM

Complex molecular mechanisms

With these cells, scientists studied the complex molecular processes involved in repairing damaged areas of heart muscle. “During laboratory investigations, we were able to show how HVPs can, in a sense, localize 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. of the 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 in 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. “Especially older patients with co-existing conditions, for whom major heart surgery would represent undue hardship, would benefit from treatment with HVPs.

Reference: “Migratory and anti-fibrotic programs define the regenerative potential of human cardiac progenitors” by Christine M. Poch, Kylie S. Foo, Maria Teresa De Angelis, Karin Jennbacken, Gianluca Santamaria, Andrea Bähr, Qing-Dong Wang, Franziska Reiter, Nadja Hornaschewitz, Dorota Zawada, Tarik Bozoglu, Ilaria My, Anna Meier, Tatjana Dorn, Simon Hege, Miia L. Lehtinen, Yat Long Tsoi, Daniel Hovdal, Johan Hyllner, Sascha Schwarz, Stefanie Sudhop, Victoria Jurisch, Marcella Sini , Mick D. Fellows, Matthew Cummings, Jonathan Clarke, Ricardo Baptista, Elif Eroglu, Eckhard Wolf, Nikolai Klymiuk, Kun Lu, Roland Tomasi, Andreas Dendorfer, Marco Gaspari, Elvira Parrotta, Giovanni Cuda, Markus Krane, Daniel Sinnecker, Petra Hoppmann , Christian Kupatt, Regina Fritsche-Danielson, Alessandra Moretti, Kenneth R. Chien and Karl-Ludwig Laugwitz, May 12, 2022, Cell Biology Nature.
DOI: 10.1038/s41556-022-00899-8

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