Skip to Main content Skip to Navigation
Journal articles

Cardiac fibroblasts regulate sympathetic nerve sprouting and neurocardiac synapse stability.

Céline Mias 1 Christelle Coatrieux 1 Colette Denis 1 Gaël Genet 1 Marie-Hélène Seguelas 1 Nathalie Laplace 2 Charlotte Rouzaud-Laborde 1 Denis Calise 3 Angelo Parini 1 Daniel Cussac 1 Atul Pathak 1, 2 Jean-Michel Sénard 1, 2 Céline Galés 1, *
* Corresponding author
IPBS - Institut de pharmacologie et de biologie structurale, CREFRE - Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales, GENOTOUL - Génopole Toulouse Midi-Pyrénées [Auzeville]
Abstract : Sympathetic nervous system (SNS) plays a key role in cardiac homeostasis and its deregulations always associate with bad clinical outcomes. To date, little is known about molecular mechanisms regulating cardiac sympathetic innervation. The aim of the study was to determine the role of fibroblasts in heart sympathetic innervation. RT-qPCR and western-blots analysis performed in cardiomyocytes and fibroblasts isolated from healthy adult rat hearts revealed that Pro-Nerve growth factor (NGF) and pro-differentiating mature NGF were the most abundant neurotrophins expressed in cardiac fibroblasts while barely detectable in cardiomyocytes. When cultured with cardiac fibroblasts or fibroblast-conditioned medium, PC12 cells differentiated into/sympathetic-like neurons expressing axonal marker Tau-1 at neurites in contact with cardiomyocytes. This was prevented by anti-NGF blocking antibodies suggesting a paracrine action of NGF secreted by fibroblasts. When co-cultured with cardiomyocytes to mimic neurocardiac synapse, differentiated PC12 cells exhibited enhanced norepinephrine secretion as quantified by HPLC compared to PC12 cultured alone while co-culture with fibroblasts had no effect. However, when supplemented to PC12-cardiomyocytes co-culture, fibroblasts allowed long-term survival of the neurocardiac synapse. Activated fibroblasts (myofibroblasts) isolated from myocardial infarction rat hearts exhibited significantly higher mature NGF expression than normal fibroblasts and also promoted PC12 cells differentiation. Within the ischemic area lacking cardiomyocytes and neurocardiac synapses, tyrosine hydroxylase immunoreactivity was increased and associated with local anarchical and immature sympathetic hyperinnervation but tissue norepinephrine content was similar to that of normal cardiac tissue, suggesting depressed sympathetic function. Collectively, these findings demonstrate for the first time that fibroblasts are essential for the setting of cardiac sympathetic innervation and neurocardiac synapse stability. They also suggest that neurocardiac synapse functionality relies on a triptych with tight interaction between sympathetic nerve endings, cardiomyocytes and fibroblasts. Deregulations of this triptych may be involved in pathophysiology of cardiac diseases.
Document type :
Journal articles
Complete list of metadata
Contributor : Marie Francoise Simon Connect in order to contact the contributor
Submitted on : Thursday, July 31, 2014 - 2:45:27 PM
Last modification on : Wednesday, October 20, 2021 - 3:44:03 AM

Links full text




Céline Mias, Christelle Coatrieux, Colette Denis, Gaël Genet, Marie-Hélène Seguelas, et al.. Cardiac fibroblasts regulate sympathetic nerve sprouting and neurocardiac synapse stability.. PLoS ONE, Public Library of Science, 2013, 8 (11), pp.e79068. ⟨10.1371/journal.pone.0079068⟩. ⟨inserm-01053600⟩



Record views