Dr F.A. van Nieuwenhoven

Cardiomyocyte-fibroblast interaction

Cardiac fibroblasts perform essential functions in the healthy human heart, such as the maintenance of the myocardial architecture which is crucial in the transmission of force generated by the cardiomyocytes. Fibroblasts are abundantly present throughout the myocardium and communicate with cardiomyocytes through paracrine mechanisms, but also through mechanical and electrical signals that can be transferred by the ECM or through direct cell-cell interactions. Injurious stimuli to the heart, such as hypertension, can cause activation, proliferation and differentiation of cardiac fibroblasts to myofibroblasts resulting in excessive deposition of extracellular matrix (ECM) proteins (fibrosis). During the structural remodeling process, cardiomyocytes will hypertrophy and show detrimental changes in important cellular processes such as calcium handling, eventually leading to cardiomyocyte dysfunction.

Cardiac fibrosis is a prominent contributor to cardiac disease as it reduces myocardial compliance and leads to electrical dissociation in the myocardium. The increase in passive stiffness of the heart, which is mainly attributed to the increased collagen volume fraction, impairs cardiac relaxation, resulting in increased filling pressures, aberrant ventricular filling and diastolic dysfunction. The electrical conduction disturbance associated with cardiac fibrosis plays an important role in
predisposing the heart to arrhythmias. The changes in both fibroblasts and cardiomyocytes are important in the deterioration of cardiac function during adverse cardiac structural remodeling.  Aside from the effect of the initial detrimental stimulus to the heart on fibroblast and cardiomyocyte function, unfavourable signaling between these two important cell types significantly contributes to cardiac disease progression. This research line is dedicated at improving our understanding of the paracrine interaction between cardiac fibroblasts and cardiomyocytes in health and disease.

During cardiac disease, multiple growth factors are involved in the adverse structural remodeling of the heart. Some of these factors are derived from infiltrating immune cells, but both the cardiomyocytes and fibroblasts release a number of proteins and peptides, such as angiotensin II (AngII), transforming growth factor β (TGFβ), fibroblast growth factor-2 (FGF2), insulin-like growth factor-1 (IGF1), cardiotrophin-1 (CT-1) and connective tissue growth factor (CTGF) to regulate their local environment through autocrine or paracrine mechanisms. Systemic factors that initiate aberrant paracrine signaling between the cardiomyocytes and fibroblasts can be mechanical, electrical or neuro-endocrine in nature.

Mechanical interaction between cardiac fibroblasts and cardiomyocytes occurs through the ECM and through direct cell-cell interaction. During the cardiac cycle both cell types are subject to mechanical stretch. On top of this physiological cyclic stretch, pressure and/or volume overload lead to a significant increase in mechanical load on the cardiac cells. In vitro studies have shown that both cardiomyocytes and fibroblasts react to stretch. We recently showed that cyclic 10% biaxial stretch of isolated adult rabbit cardiomyocytes resulted in a clear hypertrophic response, including increased cell surface area, protein synthesis and BNP expression. Stretching cardiomyocytes also induced connective tissue growth factor (CTGF) expression, which is known to affect fibroblast function and cardiac
fibrosis. Several studies have reported activation of cardiac fibroblasts by mechanical stimulation, resulting in increased ECM turnover and release of many growth factors that function as autocrine and paracrine mediators in cardiac structural remodelling In our lab, we use isolated adult cardiomyocyte and fibroblast cultures and investigate their response to stretch and electrical stimulation. Cells are cultured separately and in co-culture to distinguish between direct effects of stretch and electrical stimulation, and true paracrine signaling. While electrical stimulation of the myocytes results in force development in the heart and thereby mechanical load on the fibroblasts, electrical stimulation of lower intensity has been shown to affect fibroblast function directly. The latter effect may play a role in the high frequency stimulation as occurring during atrial fibrillation. Alternatively, therapies employing artificial stimulation, such as pacing, may employ this property to modulate fibroblast function and, potentially through paracrine effects, also myocyte function. Endpoints will be extracellular matrix production and (myo)fibroblast differentiation for effects on fibroblasts and myocyte hypertrophy as well as contractile function and calcium handling for the myocytes.

Identification of autocrine or paracrine mediators importantly determining fibroblast and  cardiomyocyte function may lead to new biomarkers for development and progression of cardiac reactive fibrosis and hypertrophy, and novel therapeutic strategies for intervening in this adverse structural remodeling of the heart. We will test such novel approaches in animal models of cardiac structural remodeling, such as pressure-overload hypertrophy, ventricular pacing and atrial fibrillation.

Scientific output (1991-2018)

54 publications in international scientific journals

H-index: 31

Co-supervisor PhD thesis Dr. P. Roestenberg, January 9, 2007

Co-supervisor PhD thesis Dr. A. Daniels, December 11, 2012

Co-supervisor PhD thesis Dr. L.B. van Middendorp, September 4, 2015