TBEP Research Seminar: Defining the cardiac fibroblast and its role in health and disease

Jeffery Molkentin, Ph.D.

Division Director of Molecular Cardiovascular Biology and Heart Institute Co-Director, Cincinnati Children’s Hospital

Professor of Pediatrics, University of Cincinnati Children’s Hospital Medical Center

Register for the seminar via Zoom

Abstract: Collagen production in the adult heart is primarily mediated by the tissue resident interstitial fibroblast. Indeed, adult fibroblast-specific deletion of the molecular chaperones required for procollagen biosynthesis, heat-shock protein 47 (Hsp47), prevents new fibrillar collagen production in the adult heart. More specifically, myofibroblast-specific ablation of Hsp47 blocked fibrosis and deposition of collagens type-I, -III and -V following pressure overload, which unexpectedly significantly reduced cardiac hypertrophy. These results suggested that an inability to generate new supportive ECM material by cardiac fibroblasts in response to pressure overload was sensed by the cardiomyocyte as it attempted to hypertrophy. To examine this potential mechanism further we also generated Col1a2-loxP targeted mice so that fibroblast specific deletion could be performed to then examine the hypothesis that reduced structural rigor of the newly synthesized type I fibrillar collagen network in the pressure loaded mouse heart would not support the same degree of cardiac hypertrophy. Indeed, myofibroblast- specific deletion of Col1a2 in the adult heart following 1 week of pressure overload compromised the hypertrophic response. Importantly, deletion of Col1a2 from the heart resulted in reduced stiffness and structural integrity, at both baseline with developmental deletion as well as in the adult heart with inducible deletion. Unexpectedly, developmental deletion of Col1a2 from the mouse heart resulted in a secondary fibrotic response with increased fibroblast number, which is likely a compensatory response to the decreased stiffness of the ECM due to defective type I collagen. Collectively our results suggest that the cardiac fibroblast communicates with the cardiomyocyte in the heart through the integrity of the ECM, which also effects fibroblast dynamics.