title: Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators.
abstract: OBJECTIVE
  Crosstalk between cardiomyocytes and fibroblasts in physiological conditions and during disease remains poorly defined. Previous studies have shown that fibroblasts and myocytes interact via paracrine communication, but several experimental confounding factors, including the use of immature myocytes and the induction of alpha-smooth muscle actin (α-SMA) expression in fibroblasts by prolonged culture, have hindered our understanding of this phenomenon. We hypothesize that fibroblasts and myofibroblasts differentially affect cardiomyocytes viability, volume, and Ca(2+) handling via soluble mediators. More specifically here: (i) we compare the effects of freshly isolated fibroblasts and cultured fibroblasts from normal rat hearts on adult cardiomyocytes; (ii) we compare the effects of (freshly isolated) normal fibroblasts and myofibroblasts from pressure-overloaded hearts; and (iii) we study the contribution of TGF-β and the importance of the crosstalk between the two cell types.
  
  
  RESULTS
  We used co-culture methods and conditioned medium to investigate paracrine interaction between fibroblasts and cardiomyocytes. All fibroblast types reduce cardiomyocyte viability and increase cardiomyocyte volume but α-SMA-negative fibroblasts increase cardiomyocyte Ca(2+) transient amplitude, whereas cultured fibroblasts and myofibroblasts from pressure-overloaded hearts decrease Ca(2+) transient amplitude. In turn, cardiomyocytes release soluble mediators that affect fibroblast proliferation. Using SB431542 to block TGF-β type 1 receptors, we determined that TGF-β directly causes cardiomyocyte hypertrophy and participates in bi-directional regulatory signalling between fibroblasts and cardiomyocytes.
  
  
  CONCLUSIONS
  Fibroblasts have different roles during physiology and disease in regulating myocardial function via soluble mediators. A crosstalk between fibroblasts and cardiomyocytes, controlled by TGF-β, is crucial in this interaction.
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Cartledge
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kane
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Priyanthi
authors.initials: P
authors.lastname: Dias
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Meron
authors.initials: M
authors.lastname: Tesfom
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Clarke
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mckee
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK King Fahad Cardiac Center, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Samha
authors.initials: S
authors.lastname: Al Ayoubi
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Chester
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Camelliti
authors.affiliation: Imperial College London, National Heart and Lung Institute, London, UK c.terracciano@imperial.ac.uk.
authors.forename: Cesare M
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D019899:Paracrine Communication; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011917:Rats, Inbred Lew; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
keywords: Calcium handling; Fibroblasts; Paracrine communication; TGF-β