B06: LncRNA function in cardiac resident macrophages

Cardiac resident macrophages (CRM) have a critical role in the orchestration of immune cell recruitment, wound healing and cardiac function after myocardial injury. The project aims at characterizing conserved human lncRNA with impact on macrophage function as already proven in mice. For this, a selection of the top ten identified lncRNAs will be characterized in hiPSC-derived macrophages in vitro. Novel hiPSC-derived 2D and 3D models for advancing investigation of tissue resident macrophage will be established, such as derivation of macrophages with yolk sac origin and cardiac organoids containing macrophages. CRISPR/Cas9 or Cas13 hiPSC lines will be used to facilitate the investigation of lncRNA mechanisms modulating macrophage properties, e.g. phagocytosis, chemotaxis, and cytokine secretion. The lncRNA impact on tissue function will be analyzed in human/ pig heart slices following radiofrequency ablation, an ex vivo model for acute heart injury. Resulting changes in macrophage function and intercellular communication will be assessed by live-imaging, single-cell and spatial transcriptomics. Finally, a mouse model for acute myocardial infarction will be established to fathom the role of the top three lncRNAs more deeply in vivo.