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Reduction Of Left Ventricle Remodeling After Cell-Based Therapy: A Pre-Clinical Study

English title Reduction Of Left Ventricle Remodeling After Cell-Based Therapy: A Pre-Clinical Study
Applicant Giraud Marie-Noëlle
Number 149986
Funding scheme Project funding (Div. I-III)
Research institution Département de Médecine Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Cardiovascular Research
Start/End 01.01.2014 - 31.08.2017
Approved amount 337'214.05
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Keywords (5)

Tissue engineering; Myocardial infarction; pre-clinical; Cell-based therapy; Ventricle remodeling

Lay Summary (French)

Lead
Le projet consiste à étudier l’efficacité thérapeutique d’un nouveau traitement cellulaire pour l’infarctus du myocarde, basé sur l’administration d’un mélange de cellules et de matrice gélatineuse appliqué directement sur la zone infarcie du cœur.
Lay summary

L'objectif du projet est d'explorer l'application épicardiale de cellules souches mésenchymateuses et d’un gel composé de fibrine.
Nous allons consolider nos premiers résultats en étudiant des paramètres importants pour l'administration du traitement comme par exemple définir le meilleur moment pour l’administration du traitement après l’accident cardiaque , évaluer l'efficacité à long terme, optimiser la qualité des cellules.
Par ailleurs, nous étudierons les mécanismes moléculaires impliqués dans l'efficacité du traitement et la régénération cardiaque
Enfin, le traitement optimisé sera validé chez le cochon avant les essais cliniques .


Contexte scientifique et social :
Le remodelage ventriculaire pathologique est la marque de l'insuffisance cardiaque après un infarctus du myocarde chronique. Actuellement, aucun traitement curatif n'existe. La thérapie cellulaire cardiaque n’a pas encore répondu à toutes les attentes. Affiner le traitement et la compréhension des mécanismes est primordiale afin de définir un traitement optimal et efficace.

Ce projet est une étude préclinique qui pourra déboucher sur la mise en place d’essais cliniques.
Les résultats attendus jettera un nouvel éclairage sur la capacité de régénération du cœur associées è un remodelage adaptatif.


Direct link to Lay Summary Last update: 18.11.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Myocardial infarction does not affect circulating hematopoietic stem and progenitor cell self-renewal ability in a rat model.
Kröpfl J M, Spengler C M, Frobert A, Ajalbert G, Giraud M N (2017), Myocardial infarction does not affect circulating hematopoietic stem and progenitor cell self-renewal ability in a rat model., in Experimental physiology.
Cardiac bone marrow-derived cell-based therapy associated with scaffold for heart regeneration
Borrego I., Frobert A., Valentin J., Ajalbert G., Roth V., Fellay B., Cook S., Giraud M.N. (2017), Cardiac bone marrow-derived cell-based therapy associated with scaffold for heart regeneration, in European Heart Journal, 38(suppl_1), 502-2536, 38(suppl_1), 502-2536.
Myocardial Tissue Engineering: A 5 Year---Update
Giraud Marie-Noelle, Borrego Inês (2017), Myocardial Tissue Engineering: A 5 Year---Update, in Pham Phuc Van (ed.), Springer International Publishing, new york, 197-209.
Histological Quantification of Chronic Myocardial Infarct in Rats.
Valentin Jérémy, Frobert Aurélien, Ajalbert Guillaume, Cook Stéphane, Giraud Marie-Noëlle (2016), Histological Quantification of Chronic Myocardial Infarct in Rats., in Journal of visualized experiments : JoVE, (118), e54914.
Prognostic Value of Troponin I for Infarct Size to Improve Preclinical Myocardial Infarction Small Animal Models.
Frobert Aurélien, Valentin Jérémy, Magnin Jean-Luc, Riedo Erwin, Cook Stéphane, Giraud Marie-Noëlle (2015), Prognostic Value of Troponin I for Infarct Size to Improve Preclinical Myocardial Infarction Small Animal Models., in Frontiers in physiology, 6, 353-353.

Collaboration

Group / person Country
Types of collaboration
Cardiovascular surgery, Inselspital, Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Hopital cantonal de Fribourg Switzerland (Europe)
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Chapter Meeting of the Tissue Engineering and Regenerative Medicine International Society Poster Cardiac Bone Marrow-Derived Cell-based Therapy associated with scaffold for Heart regeneration 26.06.2017 davos, Switzerland Giraud Marie-Noëlle;
Cardiovascular and metabolic research meeting 2016 Poster Bone Marrow-Derived Mesenchymal Stromal Cells Heterogeneity and Implications for Tissue repair 14.01.2016 Fribourg, Switzerland Valentin Jérèmy;
Cardiovascular and metabolic research meeting 2016 Poster Speckle-tracking echocardiography (STE) for radial and longitudinal strain estimation of the infarcted heart using high-frequency ultrasound 14.01.2016 Fribourg, Switzerland Valentin Jérèmy;
Termis eu 2014 Poster Early predictor of myocardial infarction extent in a mouse model 10.06.2014 genova, Italy Giraud Marie-Noëlle;
TERMIS EU 2014 Poster Cell and matrix treatment potentiates myocardial repair and regulates neurotrophic factors 10.06.2014 genova, Italy Giraud Marie-Noëlle;
Cardiovascular and metabolic research meeting 2014 Poster Double thoracotomy for myocardial infarction and epicardial application of cell therapy in a rodent model. 16.01.2014 Fribourg, Switzerland Valentin Jérèmy;


Self-organised

Title Date Place
Cardiovascular and metabolic research meeting 2017 19.01.2017 Fribourg, Switzerland
Cardiovascular and metabolic research meeting 2016 14.01.2016 Fribourg, Switzerland
Cardiovascular and metabolic research meeting 2015 23.01.2015 Fribourg, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions WINS, WOMEN IN SCIENCE Western Switzerland 2017
Talks/events/exhibitions WINS Western Switzerland 2016
Media relations: radio, television La régénération des cellules du cœur après un infarctus rts Western Switzerland 2015

Awards

Title Year
Best Poster Award Ines Borrego- AGLA and Cardiovascular biology meeting (5th edition) - Fribourg, Switzerland 2016

Associated projects

Number Title Start Funding scheme
122334 Design of a contractile artificial muscle for cardiac repair using electrospun nanofibers. 01.08.2009 Project funding (Div. I-III)
157658 High frequency, high resolution Ultrasound imaging platform (Vevo2100) for preclinical imaging 01.12.2014 R'EQUIP
122334 Design of a contractile artificial muscle for cardiac repair using electrospun nanofibers. 01.08.2009 Project funding (Div. I-III)

Abstract

Background. Ischemic heart disease is the most frequent causes of death in industrialized countries like Switzerland. The urgent need for new therapies fostered the development of strategies that focus on the recovery of the cardiac structure and function. Past decade, cell therapy has provided encouraging results. The treatment of the damaged myocardium relies on the administration of a large number of exogenous cells. Beneficial outcomes such as improved heart function and reduced remodeling may be mediated via the secretion of cytoprotective factors that stimulate revascularization, increase the recruitment of host progenitors cells and trigger in situ repair mechanisms. Nevertheless, the key players and pathways have not yet been identified. Further advance of cell therapy is, however, limited by several challenges. Poor retention of the administered cells represents a major issue. An interesting solution relies on the concomitant implantation of cells and exogenous matrix. Accordingly, we previously assessed the epicardial administration of different biografts in rodent model of myocardial infarction. We provided evidence that improved cell retention, increased and sustained therapeutic effects depend on the nature of the matrix. In light with this finding, we have identified fibrin glue associated with mesenchymal stem cell (MSC) as the most efficient biograft (named MFG) for cardiac function recovery. Last 8 years, we accumulated experimental successes for MI treatment with biografts. We have now reached an essential step: we have identified a very efficient way to regenerate the myocardium. Our efforts must be pursued in order to fine-tune the biograft-based therapy, characterize induced adaptive remodeling, identify repair mechanisms and translate these key findings obtained in animal models to a clinical reality.Aims. In the current proposal, we will pursue the ongoing project that was previously supported by the SNF, and expand our expertise in tissue engineering gained over the past 8 years into translational research. We therefore propose a clinically oriented investigation of MFG. We will first address two important shortcomings of cell therapies: (a) the time frame of cellular administration, and (b) the quality of the cells to be administrated. To answer this request, we will first compare the efficiency of MFG in acute and chronic myocardial infarction (MI) models (Specific aim 1). Secondly, we plan to evaluate the therapeutic efficiencies of MFG composed of cells isolated from either healthy or infarcted animals (Specific aim 2). Thirdly, we propose a molecular analysis to identify mechanism involved in myocardial regeneration and cardiac innervation remodeling (Specific aim 3). Finally, we aim to investigate MFG in large animal model of MI (Specific aim 4) and collect documents and data to prepare the clinical trial (Specific aim 5).Experimental design. To fulfill our aims, we will use different in vivo models. Briefly, acute and chronic MI will be performed in mice that undergo respectively a temporary (ischemia/reperfusion) or a permanent coronary ligation. Heart harvesting and mRNA isolation from remote and infarcted areas will allow identification of differential expression of markers of myocardial regeneration (with emphasis on genes involved innervation). Finally, the knowledge accumulated in both small animal models will be tested in a preclinical model (balloon-induced coronary occlusion and epicardial administration of MFG, minipig).
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