Follistatin-like 3 mediates paracrine fibroblast activation by cardiomyocytes.
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.
Heart Science Centre, Imperial College London, Hill End Road, Middlesex, UB9 6JH, UK.
Kalyani D
KD
Panse
Leanne E
LE
Felkin
Marina M
MM
López-Olañeta
Jesús
J
Gómez-Salinero
María
M
Villalba
Lucía
L
Muñoz
Kazuto
K
Nakamura
Masayuki
M
Shimano
Kenneth
K
Walsh
Paul J R
PJ
Barton
Nadia
N
Rosenthal
Enrique
E
Lara-Pezzi
D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D038702:Follistatin-Related Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors
D038702:Follistatin-Related Proteins; C498620:Fstl3 protein, mouse; D011506:Proteins; D055513:Connective Tissue Growth Factor; D003094:Collagen