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Role of the Notch pathway in cardiac multipotent mesenchymal stromal cells

English title Role of the Notch pathway in cardiac multipotent mesenchymal stromal cells
Applicant Pedrazzini Thierry
Number 143355
Funding scheme Project funding
Research institution Lab, Division of Neprology and Hypertension Department of Medicine CHUV
Institution of higher education University of Lausanne - LA
Main discipline Cardiovascular Research
Start/End 01.10.2012 - 30.09.2015
Approved amount 445'000.00
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Keywords (6)

Stem cells; Knockout; Heart; Transgenic; Regeneration; Physiology

Lay Summary (English)

Lead
Lay summary

In high-income countries, chronic heart failure is expected to remain a major burden on health care. Ultimately, transplantation remains the only therapeutic option. However, the lack of organ donors limits the access to transplantation to a small number of patients each year. In this context, controlled induction of cardiac regeneration could represent an attractive therapeutic approach.

The adult mammalian heart has limited regenerative potential. Nevertheless, multipotent cells, demonstrating a capacity to differentiate into functional cardiomyocytes in vitro and in vivo, have been identified in the heart. Our research aims at identifying therapeutic pathways that could be used to induce cardiac regeneration via mobilization of mesenchymal multipotent stromal cells in situ.

In the past years, we have identified the Notch pathway as pivotal during the adaptation of the heart to damage. We have strong evidence that Notch targets in particular the mesenchymal stromal cell population. Our main hypothesis is that, depending on endogenous signaling events, this population can give rise preferentially to fibroblasts or to cardiac precursors. In turn, the heart produces either a fibrotic scar or a new myocardium. The Notch signaling pathway, when activated, could tip the balance towards regeneration. Indeed, activation of the Notch pathway decreases the differentiation of fibroblasts into myofibroblasts, and thus limits the development of fibrosis. Second, Notch stimulates the production of multipotent mesenchymal stromal cells. Third, Notch regulates the commitment of precursors into the cardiogenic lineage. Finally, Notch controls terminal differentiation of cardiac transient amplifying cells into cardiomyocytes. Via the Notch pathway, we might have therefore a way of controlling the outcome of cardiac disease by stimulating regenerative repair.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart
Metrich Mélanie (2015), Jagged1 intracellular domain-mediated inhibition of Notch1 signalling regulates cardiac homeostasis in the postnatal heart, in Cardiovascular Research, 108(1), 74-86.
The Notch pathway controls fibrotic and regenerative repair in the adult heart.
Nemir Mohamed (2014), The Notch pathway controls fibrotic and regenerative repair in the adult heart., in European Heart Journal, 35(32), 2174-2185.
Mapping Genetic Variants Associated with Beta-Adrenergic Responses in Inbred Mice
Hersch Micha, Peter Bastian, Kang Hyun Min, Schüpfer Fanny, Abriel Hugues, Pedrazzini Thierry, Eskin Eleazar, Beckmann Jacques S., Bergmann Sven, Maurer Fabienne (2012), Mapping Genetic Variants Associated with Beta-Adrenergic Responses in Inbred Mice, in PLoS ONE, 7(7), e41032-e41032.
Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice
Pellieux C., Montessuit C., Papageorgiou I., Pedrazzini T., Lerch R. (2012), Differential effects of high-fat diet on myocardial lipid metabolism in failing and nonfailing hearts with angiotensin II-mediated cardiac remodeling in mice, in AJP: Heart and Circulatory Physiology, 302(9), H1795-H1805.
Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice
Wang Q., Domenighetti A. A., Schafer S. C., Weber J., Simon A., Maillard M. P., Pedrazzini T., Chen J., Lehr H.-A., Burnier M. (2012), Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice, in AJP: Regulatory, Integrative and Comparative Physiology, 302(9), R1025-R1033.
Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1
Rosenblatt-Velin N., Ogay S., Felley A., Stanford W. L., Pedrazzini T. (2012), Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1, in The FASEB Journal, 26(1), 229-239.

Collaboration

Group / person Country
Types of collaboration
Christian Siebel, Genentech, Inc., San Francisco, CA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Freddy Radtke, Swiss Institute for Experimental Cancer Research, EPFL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Associated projects

Number Title Start Funding scheme
128129 Identification of miRNAs modulating the regenerative response of the heart in the zebrafish and the mouse 01.06.2010 NRP 63 Stem cells and regenerative medicine
150837 MicroSPECT/PET/CT for preclinical molecular imaging 01.12.2013 R'EQUIP
127590 Importance of the Notch pathway in cardiac tissue homeostasis 01.10.2009 Project funding
130505 A systematic and functional analysis of HIF-dependent splice regulator expression and pre-mRNA alternative splicing in pathologic stress-induced cardiac hypertrophy 01.01.2011 Sinergia

Abstract

In high-income countries, chronic heart failure is expected to remain a major burden on health care. Ultimately, transplantation remains the only therapeutic option. However, the lack of organ donors limits the access to transplantation to a small number of patients each year. In this context, controlled induction of cardiac regeneration could represent an attractive therapeutic approach.The adult mammalian heart has limited regenerative potential. However, resident cardiac stem cells, demonstrating a capacity to differentiate into functional cardiomyocytes in vitro and in vivo, have been identified. Recent evidence demonstrates that new cardiomyocytes are produced in the adult heart after injury, and cardiac stem cells contribute to myocyte renewal. This suggested that myocytes could be replaced through a process involving cell replication and differentiation.Nevertheless, upon tissue damage, fibroblast proliferation far exceeds cardiac precursor expansion. Therefore, compensatory molecular and cellular mechanisms result in cardiomyocyte hypertrophy, fibroblast proliferation and fibrosis. In other words, the default pathways, which are activated in the mammalian heart under stress, lead to fibrotic repair and not to regeneration. This creates a detrimental situation contributing to the development of heart failure.The Notch signaling pathway is pivotal in the healing process of the injured adult heart. In particular, Notch limits the extent of the hypertrophic response in cardiomyocytes, and improves cell survival. In addition, Notch facilitates the expansion of cardiac stem cells during the response to stress. Recently, we have shown that Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair. Altogether, these findings indicate that Notch could represent a unique therapeutic target for inducing regeneration via mobilization of cardiac stem cells in situ.However, the molecular and cellular mechanisms underlying the effects of Notch signaling in the adult cardiac mesenchyme are largely unknown. Besides its anti-hypertrophic action on cardiomyocytes, we hypothesize that Notch acts in several different ways to improve the adaptation of the adult stressed heart. First, activation of the Notch pathway could decrease the differentiation of fibroblasts into myofibroblasts, and thus decrease matrix production and the development of fibrosis. Second, Notch could modulate the production of multipotent mesenchymal stromal cells, possibly via a regulation of cardiac epithelial-to-mesenchymal transition in the epicardium. Third, Notch could regulate the commitment of mesodermal precursors into the cardiogenic lineage and favor their proliferation. Finally, Notch could control terminal differentiation of cardiac transient amplifying cells into cardiomyocytes. It is, therefore, the main goal of the present project to investigate these different mechanisms.For this purpose, we will take advantage of a series of transgenic mice, in which we will systematically assess the role of Notch in multipotent stromal cells. Since truly specific markers for each cardiac mesenchymal subpopulation are lacking, gene deletion or overexpression restricted to these different lineages cannot be easily achieved in transgenic animals. Therefore, we will use complex genetic models to follow the fate of Notch-activated mesenchymal cells in the adult heart. Furthermore, we propose to isolate and study multipotent precursors in vitro. Altogether, these experiments should contribute to our knowledge of the mechanisms leading to regeneration in the adult heart.
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