Mohamed Nemir1, Mélanie Metrich1, Isabelle Plaisance1, Mario Lepore1, Steeve Cruchet1, Corinne Berthonneche2, Alexandre Sarre2, Freddy Radtke3, Thierry Pedrazzini4. 1. Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Rue du Bugnon 27, CH-1011 Lausanne, Switzerland. 2. Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland. 3. Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne, Switzerland. 4. 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.
Abstract
AIMS: 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. METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Hidemasa Oh; Steven B Bradfute; Teresa D Gallardo; Teruya Nakamura; Vinciane Gaussin; Yuji Mishina; Jennifer Pocius; Lloyd H Michael; Richard R Behringer; Daniel J Garry; Mark L Entman; Michael D Schneider Journal: Proc Natl Acad Sci U S A Date: 2003-10-06 Impact factor: 11.205
Authors: D S Sohal; M Nghiem; M A Crackower; S A Witt; T R Kimball; K M Tymitz; J M Penninger; J D Molkentin Journal: Circ Res Date: 2001-07-06 Impact factor: 17.367
Authors: D Orlic; J Kajstura; S Chimenti; I Jakoniuk; S M Anderson; B Li; J Pickel; R McKay; B Nadal-Ginard; D M Bodine; A Leri; P Anversa Journal: Nature Date: 2001-04-05 Impact factor: 49.962
Authors: Karl Toischer; Wuqiang Zhu; Mark Hünlich; Belal A Mohamed; Sara Khadjeh; Sean P Reuter; Katrin Schäfer; Deepak Ramanujam; Stefan Engelhardt; Loren J Field; Gerd Hasenfuss Journal: J Clin Invest Date: 2017-10-30 Impact factor: 14.808
Authors: Van K Ninh; Elia C El Hajj; Alan J Mouton; Milad C El Hajj; Nicholas W Gilpin; Jason D Gardner Journal: Alcohol Clin Exp Res Date: 2018-05-30 Impact factor: 3.455
Authors: Hilde M Norum; Kaspar Broch; Annika E Michelsen; Ida G Lunde; Tove Lekva; Aurelija Abraityte; Christen P Dahl; Arnt E Fiane; Arne K Andreassen; Geir Christensen; Svend Aakhus; Pål Aukrust; Lars Gullestad; Thor Ueland Journal: J Cardiovasc Transl Res Date: 2017-05-04 Impact factor: 4.132
Authors: Guanhua Xie; Gamze Karaca; Marzena Swiderska-Syn; Gregory A Michelotti; Leandi Krüger; Yuping Chen; Richard T Premont; Steve S Choi; Anna Mae Diehl Journal: Hepatology Date: 2013-09-30 Impact factor: 17.425