The project “Leveraging mechanisms from zebrafish to promote engraftment of transplanted human cardiomyocytes” was carried out at the Max‑Planck Institute for Heart and Lung Research (Rhein‑Main) in cooperation with the Institute for Experimental Pharmacology and Toxicology in Hamburg (Hamburg/Kiel/Lübeck). It was funded under the German Heart Center (DZHK) Pillar B for pre‑clinical research with a budget of €24 266,50 and ran from 1 April 2022 to 31 March 2023. Dr. Arica Beisaw served as project leader and coordinated the work across the two DZHK partner sites.
The scientific aim was to harness the natural invasion of cardiomyocytes into fibrotic scar tissue observed during zebrafish heart regeneration and apply this knowledge to improve the engraftment of human induced pluripotent stem cell (iPSC)‑derived cardiomyocytes in a mammalian myocardial infarction model. To identify key regulators, single‑cell RNA sequencing was performed on the border zone of regenerating zebrafish hearts. This analysis highlighted the matrix‑metalloproteinase gene mmp14b as a candidate mediator of cardiomyocyte invasion. Genetic knockout of mmp14b in zebrafish revealed a reduced capacity of cardiomyocytes to infiltrate the scar, confirming its functional importance. In parallel, an inducible overexpression system was established in human iPSCs. Using a tetracycline‑controlled promoter, the system was first validated by driving expression of a green‑fluorescent protein after cardiac differentiation; the construct was then adapted to overexpress MMP14. Preliminary data show that MMP14‑overexpressing human cardiomyocytes display enhanced migration into fibrotic tissue in ex‑vivo assays, suggesting a promising strategy to boost engraftment in the infarcted myocardium.
The project also produced a set of high‑resolution single‑cell transcriptomic datasets that will serve as a resource for future studies on cardiac regeneration and for the preparation of grant applications to the German Research Foundation (DFG), the Boehringer Ingelheim Foundation, and the FEBS Excellence Award. The work was completed within the planned 12‑month period, with no significant deviations in the research plan. The inducible system’s successful validation with GFP demonstrates the feasibility of controlled protein expression in human cardiomyocytes, a critical step toward translational application.
Results and insights from the study are slated for submission to a peer‑reviewed cardiovascular journal in September 2023. The team has already disseminated findings at several international conferences: a talk on “Macrophage‑Cardiomyocyte interaction in the regenerating heart” at the CPI Scientific Symposium in Frankfurt (2022), and posters titled “Macrophages regulate cardiomyocyte repopulation of fibrotic tissue during zebrafish heart regeneration” presented at the Weinstein Cardiovascular Development and Regeneration Conference in Marseille (2022) and the Gordon Research Conference for Cardiac Regulatory Mechanisms in New London (2022). These presentations highlight the collaborative nature of the project and its relevance to the broader cardiovascular research community.