Nano-Structural Basis for Mechanical Fibroblast-Cardiomyocyte Cross-Talk (B11 (P11))

• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422681845

We propose that fibrotic lesion remodeling is associated with extracellular matrix (ECM) accumulation not only in the bulk myocardium outside cardiomyocytes, but also deep inside the transverse/axial tubular system (TATS) - the cardiomyocytes’ membranous nanodomains whose lumens are continuous with the extracellular space. Based on insight gained in first funding period, we suggest that ECM accumulation in TATS is facilitated by fibroblasts-borne tunneling nanotubes (TNT). We propose that the presence of such 'nano-fibrosis' has negative effects on cardiomyocyte function. We will perform an unbiased analysis of TATS contents in post-ischaemic injury in human and pig tissue. We will correlate TATS content with the electrical function of TATS elements. We will also assess how accumulation of ECM components in TATS affects membrane topology and luminal fluid homeostasis in TATS, as well as the coupling of TATS to intracellular organelles. Finally, we will attempt to modulate fibroblasts-TNT activity (based on interventions identified in the first funding period) and assess the effects on TATS content. This work may ultimately reveal a novel spatial dimension of fibrotic remodeling and will allow us to investigate the nanodynamic structural and functional interplay of fibroblasts, ECM components, and cardiomyocytes, as well as the effects of this interaction on lesion properties.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1425: Heterocellular Nature of Cardiac Lesions: Identities, Interactions, Implications
• Applicant Institution: Albert-Ludwigs-Universität Freiburg
• Project Heads: Privatdozentin Eva Rog-Zielinska, Ph.D.; Professor Dr. Alexander Rohrbach, until 6/2024