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Pathways important for the mobilization of resident cardiac precursors cells in the diseased heart

English title Pathways important for the mobilization of resident cardiac precursors cells in the diseased heart
Applicant Pedrazzini Thierry
Number 114026
Funding scheme Project funding
Research institution Département de Médecine CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2006 - 30.09.2009
Approved amount 377'000.00
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Keywords (6)

heart; hypertrophy; failure; stem cells; transgenic; physiology

Lay Summary (English)

Lead
Lay summary
In the western world, cardiovascular diseases account for fifty percent of hospitalizations and deaths. Today, around five percents of the population over forty years old suffer from heart failure. Although significant advances were made in the management of patients, heart transplant remains ultimately the only therapeutic option. However, due to a lack of donor organs, the transplantation capacity is very limited. For instance, in the United States, each year about 2,000 patients with end-stage heart failure receive heart transplant but 400,000 individuals develop heart failure.

Recent evidence suggests that myocytes could be replaced continuously in the heart through a process involving replication, differentiation, aging, and death. Indeed, several groups have identified resident cells in the heart with properties of cardiac progenitors. The overall concept provides a mechanism by which cardiac function and the capacity of the left ventricle to adapt to hemodynamic overload could be altered in the diseased heart. Indeed, the presence of a stem cell pool in the heart, which could participate to a cardiac repair system, suggests that integrity depends on the persistence of this pool. Therefore, heart failure could be viewed as a consequence of a loss of the self-renewing capacity of the heart. In this context, cell replacement therapies aimed at restoring the stem cell pool could represent attractive therapeutic approaches.

Different types of progenitors have been assessed for their capacity to participate to cardiac regeneration. Cardiac progenitor cells represent the ideal cell type for cell therapies of cardiac diseases. Nevertheless, several problems need to be addressed before therapies can be envisaged.

First, sample collection is not simple. In addition, these cells, once isolated, require periods of extensive expansion to produce sufficient numbers. A simpler alternative would be to stimulate in situ the recruitment of resident cardiac progenitor cells by delivering specific soluble factors. However, this will require a precise understanding of the molecular mechanisms that control the level of the cardiac progenitor pool and its commitment toward the cardiogenic lineage.

In the present application, we propose to identify pathways that could be instrumental in maintaining cardiac integrity during the development of cardiac hypertrophy and failure. We will focus on pathways that have been implicated in adult tissue renewal, and that might play a similar role in the heart. In particular, the Notch signaling pathway is crucial in many developmental processes and has also been implicated in adult tissue repair. Basically, Notch controls the level of progenitor pools by maintaining an undifferentiated state in progenitor cells, and regulates cell-fate decisions via lateral or inductive signaling. Therefore, in our research, we will take advantage of several transgenic models in which we can expect to observe enhanced production of cardiac progenitors, and we will address specifically the importance of the Notch pathway using gain and loss of function approaches in vivo and in vitro.

Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
102154 Maintaining cardiac integrity in angiotensin II-dependent renovascular hypertension 01.10.2003 Project funding
127590 Importance of the Notch pathway in cardiac tissue homeostasis 01.10.2009 Project funding

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