Follistatins are extracellular inhibitors of the TGF-β family ligands including activin A, myostatin and bone morphogenetic proteins. Follistatin-like 3 (FSTL3) is a potent inhibitor of activin signalling and antagonises the cardioprotective role of activin A in the heart. FSTL3 expression is elevated in patients with heart failure and is upregulated in cardiomyocytes by hypertrophic stimuli, but its role in cardiac remodelling is largely unknown. Here, we show that the production of FSTL3 by cardiomyocytes contributes to the paracrine activation of cardiac fibroblasts, inducing changes in cell adhesion, promoting proliferation and increasing collagen production. We found that FSTL3 is necessary for this response and for the induction of cardiac fibrosis. However, full activation requires additional factors, and we identify connective tissue growth factor as a FSTL3 binding partner in this process. Together, our data unveil a novel mechanism of paracrine communication between cardiomyocytes and fibroblasts that may provide potential as a therapeutic target in heart remodelling.British Heart Foundation [PG/08/084/25827]; Heart Research UK; National Institute for Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton; Harefield NHS Foundation Trust; Imperial College; European Union [ERG-239158, ITN-289600]; Spanish Ministry of Science and Innovation [BFU2009-10016, CP08/00144]; Regional Government of Madrid [S2010/BMD-2321 'Fibroteam']S
