CRC Distinguished Lecturer Seminar

This is a virtual seminar; link will be made available by email.

Prof Michelle Tallquist

Cardiac Fibroblast Depletion and Tissue Matrix Stability

The extracellular matrix (ECM) network generated by cardiac fibroblasts provides structural support and regulates extracellular signalling. Cardiomyocytes are enclosed by a basement membrane comprised of ECM and sarcomeres, the fundamental contractile unit of the myocyte, connect to the ECM for transmission of lateral force. Despite their suspected importance in maintaining homeostatic balance, few studies have examined the effect of altering fibroblast dynamics. We hypothesised that depletion of cardiac fibroblasts would alter myocyte function due to alterations in ECM components. To investigate this, we generated mice with a 70-80% reduction in fibroblast numbers. Fibroblast reduction resulted in basement membrane irregularities in protein localisation and abundance, including laminin, collagen IV, and collagen VI. Interestingly, structural ECM components, such as type I collagen and fibronectin remain relatively normal in quantity. However, scanning electron microscopy of decellularised hearts show disorganised collagen fibers, suggesting that fibroblast loss disrupts collagen fiber organisation. Proteomic analysis also identified enhanced proteolysis of sarcomeric proteins. Investigation of calcium handling and contractility in myocytes showed reduced peak calcium amplitude and calcium re-uptake, as well as reduced sarcomere shortening during contraction in fibroblast deficient hearts compared to controls. Taken together, these data indicate that cardiac fibroblasts maintain basement membrane and disruption in the basement membrane may result in myocyte dysfunction and slippage. Further evaluation of how fibroblasts reshape the myocardium during physiological conditions will provide a better understanding of the remodelling that occurs during pathology.