Investigating mechanisms underlying cardiomyocyte invasion of fibrotic scar tissue during zebrafish cardiac regeneration.

• Applicant: Dr. Arica Beisaw
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553991203

Despite numerous advances in our understanding of cardiovascular biology, cardiac disease and heart failure remain the leading causes of morbidity and mortality in industrialized nations. Following myocardial infarction, billions of cardiomyocytes (CMs) are lost in the human heart and replaced with a fibrotic scar. While this scar is essential to maintain the function of the heart, its presence eventually leads to heart failure. There remains an urgent need to replace this fibrotic scar tissue with functional CMs, in order to increase the quality of patient lives and decrease the burden on our healthcare systems. Cell-based therapeutic approaches to remuscularize the infarcted mammalian heart are currently under intense investigation, as it has been shown that providing exogenous sources of CMs can improve the functional output of the heart following injury. However, integration of these exogenous CMs into host fibrotic tissue is low and there remains a need to increase engraftment efficiency into host tissue. Zebrafish, a teleost fish species, exhibit a remarkable ability to regenerate their heart following cryoinjury, an injury model whereby a liquid nitrogen-cooled probe placed on the heart leads to cell death, activation of an inflammatory response, and deposition of a collagen-containing scar, similar to myocardial infarction in humans. While research efforts in the last two decades have led to an immense increase in our knowledge of the mechanisms of cardiac regeneration, it remains unclear how CMs at the wound border invade, and eventually replace, the fibrotic scar tissue following cryoinjury. We have characterized the process of CM invasion during heart regeneration in zebrafish and find that both CM-intrinsic mechanisms and cell:cell/cell:ECM interactions are important regulators of this process. Here, we propose to test the use of microfluidics to allow us to visualize and quantify CM invasion ex vivo long-term. Further, we propose to use genetic mutant and cell ablation models to understand CM-intrinsic mechanisms underlying CM invasion and how regenerative fibroblasts contribute to CM invasion of injured tissue. Ultimately, our goal is to use knowledge of the mechanisms underlying the replacement of fibrotic scar tissue by cardiomyocytes in zebrafish regeneration to guide the development of cell-based therapeutic approaches to remuscularize the human heart following infarction.

• DFG Programme: Research Grants