Cardiac Regeneration & Aging

Cardiac regeneration and aging influence cardiac function drastically. Our vision is to therapeutically exploit non-coding RNA (ncRNAs) and telomere biology to enhance mammalian cardiomyocyte proliferation and thus cardiac regeneration to combat heart disease. NcRNAs are currently emerging as key players in virtually all biological processes where they are believed to contribute significantly to diversity and disease susceptibility, including cardiovascular development and disease. Our group is interested in identifying functional ncRNAs that play critical roles in cardiac regeneration and aging processes. Since telomere biology is directly related to aging and regeneration, we are also interested in telomere dynamics.

Aging is associated with telomere shortening and regulation of certain ncRNAs involved in development and proliferation which are identified by high-throughput sequencing of regenerative cardiac tissue samples or actively proliferating cardiomyocytes from our reporter cell lines. We are focusing on using relevant ncRNAs or telomerase as therapeutic targets in heart failure by promoting cardiac regeneration. While tissue engineering in the form of patches and external biomaterials is an additional focus to promote cardiac tissue growth and function after detrimental cardiac injury, our less invasive strategies include telomerase reactivation and modulation of ncRNAs that have cardioprotective effects or promote cardiomyocyte proliferation and cell cycle progression. Our research involves the modulation of functional RNAs involved in cell cycle pathway modulation, regulation of oxidative stress, and prevention of apoptosis.

These therapeutic ncRNA strategies or telomerase therapy are then tested in our in vitro reporter cell line, which can serve as a screening platform to monitor increased cardiomyocyte proliferation. In addition to this novel system, we also have in vivo tools to evaluate pro-regenerative ncRNAs in a neonatal model of myocardial infarction. Tissue regeneration, fibrotic scar formation, cardiomyocyte proliferation and cardiac functional data can be assessed in this neonatal mouse model in which the left anterior descending coronary artery (LAD) is ligated within the first week after birth. These tools allow us to validate novel candidates and therapeutically exploit ncRNA and telomere biology to enhance mammalian cardiomyocyte proliferation and thus cardiac regeneration to combat heart disease.

Key references:

Costa A, Hunkler HJ, Chatterjee S, Cushman S, Hilbold E, Xiao K, Lu D, Leonardy J, Juchem M, Sansonetti M, Hoepfner J, Thum T, Bär C. (2024) A reporter system for live cell tracking of human cardiomyocyte proliferation. Cardiovasc Res. 120(14):1660-1663. https://doi.org/10.1093/cvr/cvae175

Costa A, Cushman S, Haubner BJ, Derda AA, Thum T, Bär C. (2022) Neonatal injury models: integral tools to decipher the molecular basis of cardiac regeneration. Basic Res Cardiol. 117(1):26. https://doi.org/10.1007/s00395-022-00931-w

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