Following a heart attack, cardiac progenitor cells produce healthy tissue
A heart attack, also known as a myocardial infarction, occurs when a part of the heart muscle does not get enough blood. The longer it goes without restoring blood flow, the more damage is done to the heart muscle.
The most common cause of a heart attack is coronary artery disease. A strong spasm, or abrupt constriction, of a coronary artery, which may cut off blood supply to the heart muscle, is another, although less frequent reason.
The human body is incapable of rebuilding damaged tissue following a heart attack due to the heart’s incapacity to produce new muscle. Treatment with cardiac progenitor cells, however, could result in the production of functional heart cells in injured regions. A global team introduced this new treatment method in Nature Cell Biology on May 12th. Clinical trials should begin within the next two years.
How can heart function be restored after a heart attack? With an estimated 18 million deaths worldwide from cardiovascular diseases each year, according to the World Health Organization (WHO), this is a focus of worldwide research. Treatment using an enhanced pool of human pluripotent stem cell-derived ventricular progenitors, or HVPs for short, might be one viable approach. In a study published in the journal Nature Cell Biology, an international team comprised of the Technical University of Munich (TUM) and its university hospital Klinikum Rechts der Isar, the Swedish Karolinska Institutet, 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 fibrotic scar tissue, which worsens cardiac function. Some animals, particularly amphibians and fish, can heal such injury — a talent that an adult human’s heart lacks almost entirely. Stem cell treatment is one experimental strategy for regenerating missing cardiac tissue. Previous research used heart cells derived from stem cells, specifically cardiomyocytes. However, numerous side effects occurred, including abnormal heartbeats and deadly arrhythmia.
Cardiac progenitor cells instead of differentiated heart cells
In contrast, the team working with Karl-Ludwig Laugwitz, Professor of Cardiology at TUM, is investigating human ventricular progenitor cells. These cells play a crucial role in the formation of the heart during development. Over time, they differentiate into the various cell types in the heart, including cardiomyocytes. The team has succeeded in producing large numbers of such 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, the scientists studied the complex molecular processes involved in the repair of damaged areas of the heart muscle. “In laboratory investigations, we were able to show how HVPs can, in a sense, track down damaged regions in the heart, migrate to injury sites, and mature into working heart cells. They also actively prevent the formation of scar tissue by cross-talking with fibroblasts, as we call the cells that form the structural framework for the non-functional connective tissue,” says Prof. Laugwitz, who heads the First Medical Department of TUM’s Klinikum Rechts der Isar.
Successful treatment of pig hearts
As 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 those of humans. As a result, experiments with pigs are often conducted shortly before the start of studies in human patients. The results show that damage to the heart can be reliably repaired even in large animals with no serious side effects observed. “The treatment successfully demonstrated the formation of new cardiac tissue and importantly, improved cardiac function and reduced scar tissue,” says Dr. Regina Fritsche-Danielson, Head of Research and Early Development at AstraZeneca.
Researchers aim at starting clinical studies within the next two years
In the coming months and years, the scientists plan to translate their current research findings to develop a treatment for heart patients. An important intermediate step in the development of hypoimmunogenic lines of HVPs. Currently, it is necessary to inactivate the recipient’s immune system to prevent it from destroying the cell treatment. Hypoimmunogenic cells would eliminate the need for this step because they would not be identified as foreign bodies to the recipient. Further research will be conducted on hypoimmunogenic cells and possible side effects. The aim is to start clinical studies on the therapeutic use of HVPs within the next two years.
“The new insights on the therapeutic use of HVPs represent a milestone in the treatment of diverse patients with serious heart failure,” says Prof. Karl-Ludwig Laugwitz. “Especially older patients with coexisting conditions, for whom major heart surgery would represent an excessive strain, would benefit from treatment with HVPs.”
Reference: “Migratory and anti-fibrotic programmes 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, 12 May 2022, Nature Cell Biology.