Optical steering of cellular biophysics in native myocardium: illuminating interstitial and myeloid cell contributions to cardiac electrophysiology

• Applicant: Dr. Franziska Schneider-Warme
• Subject Area: Cardiology, Angiology ; Anatomy and Physiology ; Biophysics
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 412853334

Cardiac function relies on complex interactions of diverse cell populations. While cardiomyocytes are the key cell type responsible for the electromechanical activity of the heart, they are embedded within an extensive and intricate network of non-myocytes, including cardiac interstitial cells, mainly fibroblasts, and resident myeloid cells, mainly macrophages. During cardiac remodeling, for example following cardiac injury, non-myocytes proliferate and change their phenotype, a process with fundamental relevance for cardiomyocyte activity. Understanding biophysical interactions between cardiac myocyte and non-myocyte populations is crucial for assessing structural and functional mechanisms underlying cardiac homeostasis and disease progression. The here proposed project focusses on the bidirectional nature of electrophysiological coupling between cardiomyocytes, fibroblasts and resident cardiac macrophages, and the relevance of this signalling for cardiac function in both health and disease. To this end, I will use optogenetics, a powerful method allowing me to unravel specific heterocellular electrical interactions in native myocardium. I will genetically drive the expression of light-activated ion channels and fluorescent reporter proteins in the cells of interest to allow optical manipulation and monitoring of cell-type specific behavior. I will develop suitable optogenetic animal models to specifically modulate, visualize and measure the membrane potential of cardiomyocytes, fibroblasts and macrophages in cardiac tissue from mice, rabbits and humans. Optogenetic approaches will be combined with imaging of non-myocyte proliferation and differentiation, and with assessment of cellular electrophysiology – all combined in computational models of heterocellular electrical interactions. To investigate the relevance of this coupling in cardiac disease, I will use ischemia-reperfusion models in mice and rabbits to mimic the structural and electrophysiological remodeling that occurs following myocardial infarction in patients. I will study altered single-cell activity, multi-cellular coupling and electrical conductance during cardiac scar formation and maturation. The obtained data will be quantitatively integrated to identify key principles of heterocellular electrical crosstalk and to assess its impact on cardiac function with the end goal of providing novel insights into future treatment options for reversing and/or delaying pathological electrical remodeling in cardiac disease.

• DFG Programme: Independent Junior Research Groups