Project Details
Projekt
P3: Effects of Cardiac Electro-Mechanical Activity on Interstitial Non-Myocytes
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Biophysics
Cell Biology
Anatomy and Physiology
Biophysics
Cell Biology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
The heart functions as an electrically driven pump, whose activity is not solely determined by cardiomyocytes (CM) but is critically dependent on their complex interplay with interstitial non-myocytes (NM), particularly fibroblasts (FB) and tissue-resident macrophages (MΦ). NM regulate and support cardiac excitability, tissue structure, and signalling through structural, electrical, and mechanical coupling. While NM are known to respond to biophysical cues, we have a limited understanding on how the continuous electromechanical activity from CM, particularly under pathological conditions, shapes NM structure, function, and signalling, and how NM activity in turn modulates CM behavior. This project is based on the central hypothesis that cyclic electrical and mechanical stimulation modifies intrinsic properties of interstitial NM, thereby triggering feedback mechanisms that influence CM function and overall myocardial performance. To test this hypothesis, the proposed research project, P3, aims to systematically and quantitatively investigate electromechanical communication between CM and NM at the cellular level. We will implement an integrated optogenetic and biomechanical experimental programme, structured into four working packages (WP): In WP1, we will generate transgenic hiPSC lines expressing optogenetic fast K-BiPOLES variants to enable precise, contact-free control of membrane potential in CM, FB, and MΦ. WP2 will apply defined rhythmic and arrhythmic depolarization-repolarization cycles to NM to analyze effects of temporally defined voltage dynamics on cellular architecture, ion channel activity, and functional adaptation. In parallel, cyclic stretch and release (achieved with the Flexcell system) will be used to mimic (patho-)physiological mechanical loading conditions acting on NM. WP3 will focus on how electrical and mechanical cues modulate paracrine and biochemical signaling between NM and CM. Finally, WP4 will re-evaluate these findings in 2D and 3D co-culture, and in engineered heart muscle systems to assess synergistic effects of electromechanical coupling within functional myocardial tissue models. In conclusion, the project adopts an innovative strategy to decipher bidirectional electromechanical communication between cardiac muscle and the interstitium, an aspect of heart physiology that remains poorly understood. The outcomes will provide fundamental insights into how NM contribute to the electrical and mechanical stability of the heart, and how dysregulation of these communication processes promotes cardiac dysfunction. Ultimately, the project will lay the foundation for future development of interstitium-targeted therapeutic approaches to preserve or restore cardiac function in heart disease.
DFG Programme
Research Units
