title: The Notch pathway controls fibrotic and regenerative repair in the adult heart.
abstract: OBJECTIVE
  In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling.
  
  
  RESULTS
  We generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells.
  
  
  CONCLUSIONS
  We conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cells.
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Nemir
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Metrich
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plaisance
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Lepore
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland.
authors.forename: Steeve
authors.initials: S
authors.lastname: Cruchet
authors.affiliation: Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Berthonneche
authors.affiliation: Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sarre
authors.affiliation: Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne, Switzerland.
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland thierry.pedrazzini@chuv.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000503:physiopathology / Q000628:therapy; D049109:Cell Proliferation / Q000502:physiology; D048429:Cell Size; D003250:Constriction; D005355:Fibrosis / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D012038:Regeneration; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015291:Transforming Growth Factors / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D058570:TOR Serine-Threonine Kinases; D015291:Transforming Growth Factors; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C546843:mTOR protein, mouse; C487757:Pten protein, mouse