Project

Heart; Remodeling; Stem cells; Physiology; Transgenic; Knockout; Myocardial infarction; Heart failure; Regeneration; Cell therapy; Transgenic mice; Notch

Lead
Lay summary
In high-income countries, coronary artery disease is one of the most frequent cardiovascular disorders, and leads to acute myocardial infarction. Myocardial infarction frequently progresses into maladaptive cardiac remodeling and heart failure. 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, induction of cardiac regeneration in the damaged heart could represent an attractive therapeutic approach. This will only be possible if the pathways important for inducing repair and their associated regulatory mechanisms are identified.In the damaged heart, compensatory myocyte hypertrophy maintains cardiac output. Recent evidence suggests, however, that myocytes could be replaced continuously through a process involving replication, differentiation, senescence and death. Along these lines, resident cardiac stem cells have been identified. Together, this indicates that, akin of prototypic self-renewing tissues, the heart could possess the basic and necessary elements for tissue regeneration.The Notch pathway has crucial roles in the embryonic life of metazoans, and is essential during development of the cardiovascular system in mammals. It is also involved in regeneration of adult self-renewing tissues. We recently demonstrated that the Notch pathway is activated in the stressed adult heart. Notch1-receptor signaling takes place in cardiomyocytes and in cardiac precursors, and is activated secondary to stimulated expression of the Notch receptor ligand Jagged1 on the surface of cardiomyocytes. In cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response and contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and facilitates the expansion of a transient amplifying cell compartment. These results suggest that controlled activation of the Notch pathway during the adaptation of the heart to stress should produce beneficial effects via induction of cardiac stem cell expansion, control of cardiogenesis, improvement of cardiomyocyte survival, and reduction of cardiac fibrosis. Therefore, we propose to test this hypothesis using different approaches in vitro and in vivo. In particular, we will use transgenic mouse models, in which the Notch pathway can be transiently or chronically activated, and conditional and inducible knockouts, in which the Notch pathway can be inhibited.

Direct link to Lay Summary

Last update: 21.02.2013

Number	Title	Start	Funding scheme

In the Western world, cardiovascular diseases account for fifty percents of hospitalizations and deaths. In high-income countries, the increasing average age of the population has altered the spectrum of cardiac diseases towards heart failure. Heart failure is a progressive disease that is initiated by a loss of functional cardiomyocytes. Heart transplant remains the ultimate therapy but the lack of donor organs limit the access to a few thousands of patients each year. In this context, therapies aimed at inducing cardiac repair could propose attractive alternatives. There are basically two approaches. First, cardiac stem cells are transferred into the damaged heart to produce a new myocardium. Second, endogenous cardiac stem cells are induced to proliferate and differentiate in situ to heal the heart. In both cases, however, the understanding of the precise molecular mechanisms controlling the expansion of the stem pools and those regulating cardiogenic differentiation is required. The Notch signaling pathway is implicated in adult tissue renewal and our recent experiments suggest that it may play a similar role in the heart. Therefore, the Notch pathway represents an interesting therapeutic target to obtain clinical benefit in heart failure patients.Our previous data demonstrate the importance of the Notch pathway in the adaptive response of the heart to stress. Signaling in Notch-receptor expressing cardiac cells is triggered by the Notch ligand Jagged1. These results suggest also that activation of the Notch pathway should produce beneficial effects in the damaged heart via induction of cardiac stem cell expansion, control of cardiogenesis, improvement of cardiomyocyte survival, and reduction of cardiac fibrosis. Therefore, we propose to test this hypothesis using different approaches in vitro and in vivo. In particular, we will use transgenic mouse models, in which the Notch pathway can be transiently or chronically activated, and conditional and inducible knockouts, in which the Notch pathway can be inhibited. Furthermore, we propose to investigate the role of the Notch pathway in the cardiogenic differentiation of embryonic stem cells, as prototypes of undifferentiated progenitors, and of cardiac stem cells isolated from the postnatal heart. The potential role of cardiomyocytes as accessory cells belonging to a Jagged1-expressing cardiac stem cell niche will be also investigated. Finally, the importance of microRNAs in the regulation of cardiogenesis by the Notch pathway will be evaluated.