Project

Back to overview

Identification of miRNAs modulating the regenerative response of the heart in the zebrafish and the mouse

English title Identification of miRNAs modulating the regenerative response of the heart in the zebrafish and the mouse
Applicant Pedrazzini Thierry
Number 128129
Funding scheme NRP 63 Stem cells and regenerative medicine
Research institution Service de Cardiologie Département de Médecine CHUV
Institution of higher education University of Lausanne - LA
Main discipline Cardiovascular Research
Start/End 01.06.2010 - 31.05.2015
Approved amount 940'139.00
Show all

All Disciplines (3)

Discipline
Cardiovascular Research
Cellular Biology, Cytology
Pathophysiology

Keywords (6)

Myocardial infarction; Cardiac regeneration; microRNAs; long non-coding RNAs; Mouse; Zebrafish

Lay Summary (English)

Lead
The human heart has limited potential for regeneration after infarction. In contrast, lower vertebrates like zebrafish have the ability to generate a new myocardium after damage. This capacity is a consequence of the differential utilization of gene regulatory networks, which are controlled in part by microRNAs and long non-coding RNAs. Characterization of these regenerative circuits will lead to the identification of new therapeutic targets for inducing regeneration in the human heart.
Lay summary

Background In the Western world, cardiac disease represents a main cause of mortality. Indeed, cardiac hypertrophy and fibrosis develop in the adult mammalian heart after infarction, leading to heart failure. In sharp contrast, organisms such as the Zebrafish can produce a completely new heart following injury. The animal model is therefore a great source of inspiration for identifying pathways leading to regeneration.

Aim The aim of this project is to systematically characterize the gene regulatory networks, which are differentially utilized in the regenerating heart of the Zebrafish as compared to the non-regenerating heart of the mouse. We postulate that that gene networks that activated in the Zebrafish heart but not in the mouse heart represent candidate pathways for stimulating regeneration.

Results In the past months, we have generated global expression profiles in the injured mouse and Zebrafish hearts. We examine particularly the role of microRNAs, which are small RNA molecules that can modulate the activity of their target genes. We found many microRNA-dependent gene networks that are differentially modulated in the regenerating Zebrafish heart. Interestingly, some of these networks control epigenetic chromatin remodeling in the heart during the response to injury. There are increasing data indicating that organisms are capable of plasticity to cope with stress. These adaptive responses involve epigenetic mechanisms. Along these lines, long non-coding RNAs are non-coding transcripts, which are able to mediate epigenetic changes by recruiting chromatin remodeling complexes to specific genomic loci. We identified thousands of novel long non-coding RNAs in the mouse heart, of which, hundreds were significantly modulated post myocardial infarction. Each one of these microRNAs and long non-coding RNAs represent putative therapeutic targets, which will need to be validated in relevant model system in vitro and in vivo.

Significance Each year, coronary heart disease, myocardial infarction and heart failure are the cause of thousands of deaths in Switzerland. Currently, heart transplantation remains the only therapeutic option. However, the lack of organ donors limits the access to transplantation to a small number of patients. In this context, induction of cardiac regeneration in the damaged heart via activation of microRNAs- or long non-coding RNA-dependent gene regulatory networks would represent a very attractive therapeutic approach.

Direct link to Lay Summary Last update: 10.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
[In the heart of noncoding RNA: a long way to go].
Pedrazzini Thierry (2015), [In the heart of noncoding RNA: a long way to go]., in Médecine sciences : M/S, 31(3), 261-7.
Long noncoding RNAs in cardiac development and ageing.
Devaux Yvan, Zangrando Jennifer, Schroen Blanche, Creemers Esther E, Pedrazzini Thierry, Chang Ching-Pin, Dorn Gerald W, Thum Thomas, Heymans Stephane, Cardiolinc network (2015), Long noncoding RNAs in cardiac development and ageing., in Nature reviews. Cardiology, Epub ahead of print(1), 1-1.
Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease
Ounzain Samir, Pezzuto Iole, Micheletti Rudi, Burdet Frédéric, Sheta Razan, Nemir Mohamed, Gonzales Christine I., Sarre Alexandre, Alexanian Michael, Blow Matthew J., May Dalit, Johnson Rory A., Dauvillier Jérôme, Pennacchio Len A., Pedrazzini Thierry (2014), Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease, in Current Therapeutic Research - Clinical and Experimental, 76, 55-70.
The Notch pathway controls fibrotic and regenerative repair in the adult heart.
Nemir Mohamed, Metrich Mélanie, Plaisance Isabelle, Lepore Mario, Cruchet Steeve, Berthonneche Corinne, Sarre Alexandre, Radtke Freddy, Pedrazzini Thierry (2014), The Notch pathway controls fibrotic and regenerative repair in the adult heart., in European heart journal, 35(32), 2174-85.
The promise of enhancer-associated long noncoding RNAs in cardiac regeneration
Ounzain Samir, Pedrazzini Thierry (2014), The promise of enhancer-associated long noncoding RNAs in cardiac regeneration, in Trends in Cardiovascular Medicine, Epub ahead of print(1), 1-1.
Small and long non-coding RNAs in cardiac homeostasis and regeneration.
Ounzain Samir (2013), Small and long non-coding RNAs in cardiac homeostasis and regeneration., in Biochim Biophys Acta, 1833, 923-933.
Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long noncoding RNAs
Ounzain Samir, Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long noncoding RNAs, in European Heart Journal.

Collaboration

Group / person Country
Types of collaboration
Swiss Institute of Bioinformatics Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Firalis Biotechnology Company France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Centre for Genomic Regulation Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Maastricht University Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Luxemburg Institute of Health Luxembourg (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
CELLULES SOUCHES: L'ORIGINE DE LA VIE Performances, exhibitions (e.g. for education institutions) 25.09.2014 Lausanne, Switzerland Pedrazzini Thierry; Micheletti Rudi; Ounzain Samir;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Interview Rts Western Switzerland 2014

Associated projects

Number Title Start Funding scheme
143355 Role of the Notch pathway in cardiac multipotent mesenchymal stromal cells 01.10.2012 Project funding
150837 MicroSPECT/PET/CT for preclinical molecular imaging 01.12.2013 R'EQUIP
163476 Regenerative therapy for heart disease via modulation of long noncoding RNAs 01.10.2015 Project funding

Abstract

Cardiovascular diseases, and in particular heart failure, are leading causes of death. Heart failure is a progressive disorder initiated by a loss of cardiomyocytes. The primary event can be either acute, for instance after myocardial infarction, or gradual, for instance in patients suffering from chronic hypertension. The mammalian heart adapts to new hemodynamic conditions via induction of hypertrophy in viable cardiomyocytes. However, evidence suggests that myocytes could also be replaced continuously in the heart through a process involving replication, differentiation, aging, senescence and death. This indicates that, akin of prototypic self-renewing tissues, the heart could possess the basic and necessary elements for tissue regeneration. Regeneration may rely on populations of resident cardiac stem cells that could be activated upon cardiac damage to produce committed cardiac precursor cells. Despite the mobilization of cardiac stem cells, the adult mammalian heart has limited regenerative capacity. Instead, lost myocytes are mostly replaced by fibrotic scar tissue. In sharp contrast to mammals, organisms such as the zebrafish can regenerate their amputated heart. Regeneration of the zebrafish heart requires a complex action of mechanisms including progenitor recruitment, myocyte dedifferentiation, undifferentiated cell proliferation, pattern generation and cardiogenic differentiation. Regeneration replaces lost cardiac tissues in about a month, and, consequently, little or no fibrosis is observed. Recently, miRNAs have emerged as new regulators of gene expression. These non-coding RNA molecules regulate gene expression by either inducing messenger RNA degradation or by inhibiting translation. In the heart, modulation of miRNAs controls the development of cardiac hypertrophy and fibrosis in both the non-regenerating mammalian heart and in the regenerating zebrafish heart. Therefore, miRNAs could be used to shift the response to injury in the mammalian heart towards cardiomyocyte proliferation, stem cell recruitment and cardiogenic differentiation. It is, therefore, the goal of the current project to identify such miRNAs by comparing the cardiac response to injury in two relevant animal models, the mouse and the zebrafish. This project will take advantage of the latest technology in deep sequencing, transcriptomics and bioinformatics analysis to identify the miRNAs and their target genes that are differently modulated after myocardial infarction in the mouse and after ventricular resection in the zebrafish. The biological relevance and therapeutic potential of the identified miRNAs and target genes will be evaluated in vitro and in vivo.
-