Project Details
Projekt
P2: ECM Deposition at the Fibroblast–Cardiomyocyte Nano-Interface
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Cell Biology
Anatomy and Physiology
Cell Biology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
The nano-scale integration of cardiomyocytes into the extracellular matrix involves complex interactions between the cardiomyocyte sarcolemma, the basement membrane, the fibrillar and non-fibrillar extracellular matrix, and the fibroblasts. It is however unknown how exactly extracellular matrix elements are positioned and dynamically maintained in the vicinity of the cardiomyocytes. Furthermore, while the detrimental impact of ‘bulk’ fibrosis on cardiac function is clear, the nano-scale fibrotic processes in pathologically remodeling hearts are yet to be described. One of the recently described nano-fibrotic events in diseased hearts is the extracellular matrix accumulation inside cardiomyocyte’s transverse-axial tubular system, a network of surface membrane invaginations; such accumulation of extracellular matrix in the cardiomyocyte nano-domains could disturb efficient excitation-contraction coupling. We hypothesize that extracellular matrix deposition in cardiomyocyte transverse-axial tubular system is driven by fibroblast membrane nanotubes, recently described by us as mediators of the interactions between fibroblasts and their environment. We aim to (i) explore the mechanistic links between fibroblast membrane nanotubes and extracellular matrix deposition in the vicinity of cardiomyocytes; (ii) modulate the peri-cardiomyocyte extracellular matrix deposition by targeting fibroblast membrane nanotubes, and (iii) validate and modulate the reversible mechanisms of extracellular matrix deposition in the transverse-axial tubular system in rodent models of progressive versus reversible fibrosis, and in native human heart slice cultures. We will use human induced pluripotent stem cell-derived cardiomyocytes and fibroblasts to track extracellular matrix deposition in the vicinity of cardiomyocytes and in cardiomyocyte transverse-axial tubular system using super-resolution light and electron microscopy. We will perform proteomic analysis of fractionated fibroblast membrane nanotubes to identify targeting strategies to modulate the extracellular matrix deposition at fibroblast–cardiomyocyte interfaces, and we will test these, together with recently published anti-fibrotic approaches, in vitro and in native human cardiac slice cultures. We will furthermore explore the functional consequences of extracellular matrix accumulation in cardiomyocytes transverse-axial tubular system on intraluminal ion diffusion, electrical properties of the membrane, and physiological deformation in rodent models of fibrosis. In summary, we will establish a novel concept of nano-scale fibrotic remodeling at the interface between fibroblasts and cardiomyocytes. Our long-term vision is to specifically target the local mechanisms in the progression of extracellular matrix deposition and/ or accelerate its regression. This will allow us to protect the transverse-axial tubular system and cardiomyocyte function from the negative effects of interstitial remodeling.
DFG Programme
Research Units
