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S100A4 is a key player of smooth muscle cell phenotypic transition: implications for atherosclerosis

English title S100A4 is a key player of smooth muscle cell phenotypic transition: implications for atherosclerosis
Applicant Bochaton-Piallat Marie-Luce
Number 166357
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Pathophysiology
Start/End 01.07.2016 - 30.06.2019
Approved amount 351'780.00
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Keywords (6)

Apelin; Macrophages; Atherosclerosis; Smooth muscle cells; S100A4; Restenosis

Lay Summary (French)

Lead
Lors de la formation de la plaque d’athérome et de la lésion resténotique, les cellules musculaires lisses (CMLs), normalement présentent dans un phénotype différencié dans la media, s’accumulent dans l’intima et acquièrent un phénotype synthétique. Nous avons isolé deux populations différentes de CMLs de la coronaire du porc in vitro, les CMLs fusiformes et rhomboïdes. Les CMLs rhomboïdes sont typiques du phénotype synthétique et expriment la S100A4. En utilisant un milieu conditionné riche en S100A4 (collectée de CMLs transfectées avec le gène de la S100A4) nous avons aussi montré que la forme extracellulaire de la S100A4 pourrait jouer un rôle primordial dans le développement du phénotype synthétique et dans l’acquisition par les CMLs de propriétés pro-inflammatoires.
Lay summary

Objectif 1. La S100A4 recombinante sous forme multimérique est connue pour être la forme active de la S100A4. Nous allons étudier si elle est exclusivement responsable de la transition phénotypique des CMLs vers un phénotype pro-inflammatoire. Ces résultats seront confirmés en utilisant un anticorps neutralisant de la S100A4 dans le milieu conditionné riche en S100A4. Pour déchiffrer les mécanismes de signalisation induits par la S100A4 extracellulaire nous allons explorer l’implication de différents récepteurs et leur codépendance. L’activation possible des monocytes par les CMLs au phénotype pro-inflammatoire sera aussi examinée.

Objectif 2. Nous allons investiguer si l’expression altérée de la S100A4 est associée à la formation de la lesion resténotique et athérosclérotique. Nous allons induire avec un cathéter à ballonnet une lésion (un modèle de resténose) dans les carotides de souris S100A4-/-ApoE-/- et ApoE-/- mice simultanément traitée avec un anticorps S100A4 neutralisant. De plus des souris S100A4-/-ApoE-/- sous un régime riche en cholestérol seront étudiées pour le développement de la plaque athérosclérotique.

Objectif 3. L’apeline, dont le rôle dans l’athérosclérose n’est pas démontré, est exprimée dans le noyau des CMLs rhomboïdes. Nous aimerions étudier le rôle de l’apeline dans le changement phénotypique des CMLs et en particulier si elle est corrélée à l’expression de la S100A4.

L’étude de la S100A4 devrait permettre d’élucider certains mécanismes d’accumulation des CMLs dans l’intima. Notre but ultime est le développement d’outils influençant l’évolution des lésions athérosclérotiques et resténotiques.

Direct link to Lay Summary Last update: 17.05.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Sudden coronary death in the young: Evidence of contractile phenotype of smooth muscle cells in the culprit atherosclerotic plaque
Rizzo Stefania, Coen Matteo, Sakic Antonija, De Gaspari Monica, Thiene Gaetano, Gabbiani Giulio, Basso Cristina, Bochaton-Piallat Marie-Luce (2018), Sudden coronary death in the young: Evidence of contractile phenotype of smooth muscle cells in the culprit atherosclerotic plaque, in International Journal of Cardiology, 264, 1-6.
Expression of α-smooth muscle actin in the periodontal ligament during post-emergent tooth eruption
Dorotheou Domna, Bochaton-Piallat Marie-Luce, Giannopoulou Catherine, Kiliaridis Stavros (2018), Expression of α-smooth muscle actin in the periodontal ligament during post-emergent tooth eruption, in Journal of International Medical Research, 46(6), 2423-2435.
Novel concepts for the role of smooth muscle cells in vascular disease: towards a new smooth muscle cell classification
Bochaton-Piallat Marie-Luce, Bäck Magnus (2018), Novel concepts for the role of smooth muscle cells in vascular disease: towards a new smooth muscle cell classification, 114(4), 477-480, Oxford University Press, Oxford 114(4), 477-480.
Smooth muscle cell fate and plasticity in atherosclerosis
Allahverdian Sima, Chaabane Chiraz, Boukais Kamel, Francis Gordon A, Bochaton-Piallat Marie-Luce (2018), Smooth muscle cell fate and plasticity in atherosclerosis, in Cardiovascular Research, 114(4), 540-550.
Human Bone Marrow Contains Mesenchymal Stromal Stem Cells That Differentiate In Vitro into Contractile Myofibroblasts Controlling T Lymphocyte Proliferation
Bochaton-Piallat Marie-Luce, Kindler Vincent, Lecarpentier Yves, Schussler Olivier, Sakic Antonija, Rincon-Garriz José Maria, Soulie Priscilla (2018), Human Bone Marrow Contains Mesenchymal Stromal Stem Cells That Differentiate In Vitro into Contractile Myofibroblasts Controlling T Lymphocyte Proliferation, in Stem Cells International, 2018, 1-15.
Microvesicles in vascular homeostasis and diseasesPosition Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology
Ridger Victoria C., Boulanger Chantal M., Angelillo-Scherrer Anne, Badimon Lina, Blanc-Brude Olivier, Bochaton-Piallat Marie-Luce, Boilard Eric, Buzas Edit I., Caporali Andreas, Dignat-George Francoise, Evans Paul C., Lacroix Romaric, Lutgens Esther, Ketelhuth Daniel F. J., Nieuwland Rienk, Toti Florence, Tuñon Jose, Weber Christian, Hoefer Imo E. (2017), Microvesicles in vascular homeostasis and diseasesPosition Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology, in Thrombosis and Haemostasis, 117(07), 1296-1316.
Cell-specific diversity in the expression and organization of cytoplasmic plaque proteins of apical junctionsCytoplasmic plaque proteins of apical junctions
Vasileva Ekaterina, Sluysmans Sophie, Bochaton-Piallat Marie-Luce, Citi Sandra (2017), Cell-specific diversity in the expression and organization of cytoplasmic plaque proteins of apical junctionsCytoplasmic plaque proteins of apical junctions, in Annals of the New York Academy of Sciences, 1405(1), 160-176.

Collaboration

Group / person Country
Types of collaboration
Prof. M. Grigorian, Neuro-Oncology Group, University of Copenhagen Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. BR Kwak, Dpt of Pathology and Immunology, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr B. Masri, I2MC, Université Toulouse III, CHU Rangueil, Toulouse France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr H. Hao, Dpt of Surgical Pathology, Hyogo College of Medicine, Hyogo Japan (Asia)
- Publication
Prof. S. Hugues, Dpt of Pathology and Immunology, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
3rd joint European Society for Microcirculation and European Vascular Biology Organisation (ESM-EVBO) meeting Poster Role of apelin in vascular smooth muscle cell phenotypic transition: a proatherogenic factor for atherosclerosis 15.04.2019 Maastricht, Netherlands Bochaton-Piallat Marie-Luce; Cardoso dos Santos Luis Miguel;
3rd joint European Society for Microcirculation and European Vascular Biology Organisation (ESM-EVBO) meeting Talk given at a conference Smooth muscle cell plasticity in atherosclerosis. Role of S100A4 15.04.2019 Maastricht, Netherlands Bochaton-Piallat Marie-Luce;
Second Cardiovascular Research Meeting Poster S100A4: a key player in plaque stabilization? 14.03.2019 Fribourg, Switzerland Bochaton-Piallat Marie-Luce; Sakic Antonija;
Second Cardiovascular Research Meeting Talk given at a conference Role of smooth muscle cells in atherosclerosis: a matter of intracellular S100A4? 14.03.2019 Fribourg, Switzerland Cardoso dos Santos Luis Miguel; Bochaton-Piallat Marie-Luce;
Life Sciences Switzerland (LS2) Poster S100A4: a key player in plaque stabilization? 14.02.2019 Zürich, Switzerland Sakic Antonija; Bochaton-Piallat Marie-Luce;
Seminar, Ludwig-Maximilians-University (LMU), invited by Prof. Sabine Steffens. Individual talk Smooth muscle cell plasticity in atherosclerosis. 28.11.2018 Munich, Germany Bochaton-Piallat Marie-Luce;
Eurothrombosis 2018 Talk given at a conference Smooth muscle cell plasticity in vascular remodeling 04.10.2018 Barcelona, Spain Bochaton-Piallat Marie-Luce;
International Vascular Biology Meeting Poster S100A4: a key player in plaque stabilization? 03.06.2018 Helsinki, Finland Bochaton-Piallat Marie-Luce; Sakic Antonija;
Towards standardisation of studies onto human and animal intracranial aneurysm wall vulnerability / Workshop Talk given at a conference Recent advances in smooth muscle cell phenotype 24.05.2018 Geneva, Switzerland Bochaton-Piallat Marie-Luce;
Frontiers in CardioVascular Biology Meeting Poster S100A4 and PDGF-BB induce smooth muscle cell phenotypic activation: it also takes two to waltz 20.04.2018 Vienna, Austria Bochaton-Piallat Marie-Luce; Sakic Antonija;
Printemps de la Cardiologie Talk given at a conference Transition phenotypic des cellules musculaires lisses artérielles 04.04.2018 Montpellier, France Bochaton-Piallat Marie-Luce;
First Cardiovascular Research Meeting Talk given at a conference S100A4: a key player in plaque stabilization? 15.03.2018 Fribourg, Switzerland Sakic Antonija; Bochaton-Piallat Marie-Luce;
Seminar, Physiopharmacology, University of Antwerp,invited by Prof. Guido de Meyer. Individual talk New insights in smooth muscle cell phenotypic transition. Implications in atherosclerosis. 28.11.2017 Antwerp, Belgium Bochaton-Piallat Marie-Luce;
ENABLE Poster Smooth muscle cell switch in atherosclerosis: a matter of intracellular S100A4? 15.11.2017 Barcelona, Spain Bochaton-Piallat Marie-Luce; Cardoso dos Santos Luis Miguel;
“Ask the expert” seminar for PhD students. University of Fribourg, invited by Prof. Curzio Rüegg. Individual talk Smooth muscle cells in pathophysiology of vascular disease 18.10.2017 Smooth muscle cells in pathophysiology of vascular disease., Switzerland Bochaton-Piallat Marie-Luce;
Seminar. Department of Medicine, University of Fribourg, invited by Prof. Curzio Rüegg. Individual talk New insights in smooth muscle cell phenotypic transition. Implications in atherosclerosis. 18.10.2017 Fribourg, Switzerland Bochaton-Piallat Marie-Luce;
Colloque de Chirurgie Cardiaque, HUG, Geneva, invited by Prof. Christoph Huber Individual talk La cellule musculaire lisse de la plaque d’athérome: amie et ennemie! 16.10.2017 Geneva, Switzerland Bochaton-Piallat Marie-Luce;
European Society of Cardiology 2017 Congress Poster . Extracellular S100A4 and PDGF-BB act in synergy to induce smooth muscle cell transition and activation. Implications in atherosclerosis. 26.08.2017 Barcelona, Spain Bochaton-Piallat Marie-Luce; Sakic Antonija;
2nd joint European Society for Microcirculation and European Vascular Biology Organisation (ESM-EVBO) meeting Talk given at a conference Extracellular S100A4 and PDGF-BB promote a pro-inflammatory-like smooth muscle cell phenotype: implications in atherosclerosis 29.05.2017 Geneva, Switzerland Sakic Antonija; Bochaton-Piallat Marie-Luce;
Printemps de la Cardiologie Poster Nuclear targeting of apelin promotes smooth muscle cell phenotypic transition. Implications in atherosclerosis 06.04.2017 Nantes, France Bochaton-Piallat Marie-Luce; Chaabane Chiraz;
International Neurovascular Exploratory Workshop Talk given at a conference Smooth muscle cell and myofibroblast mediated vessel wall remodelling. 15.02.2017 Zürich, Switzerland Bochaton-Piallat Marie-Luce;
CardioVascular and Metabolic Research Meeting Talk given at a conference Extracellular S100A4 and PDGF-BB act in synergy to induce smooth muscle cell transition and activation. Implications in atherosclerosis. 19.01.2017 Fribourg, Switzerland Sakic Antonija; Bochaton-Piallat Marie-Luce;
International Vascular Biology Meeting Poster Extracellular S100A4 and PDGF-BB act in synergy to induce smooth muscle cell transition and activation. Implications in atherosclerosis. 30.10.2016 Boston, United States of America Sakic Antonija; Bochaton-Piallat Marie-Luce;
Cardiovascular program @ Karolinska Institutet / Annual Retreat 2016 Talk given at a conference New insights in smooth muscle cell phenotypic transition. Implications in atherosclerosis. 06.10.2016 Stockholm, Sweden Bochaton-Piallat Marie-Luce;
Autumn Meeting 2016 of the British Atherosclerosis Society Talk given at a conference Phenotypic transformation of smooth muscle cells 15.09.2016 Cambridge, Great Britain and Northern Ireland Bochaton-Piallat Marie-Luce;
Frontiers in CardioVascular Biology Meeting Poster Extracellular S100A4 is a key player of smooth muscle cell phenotypic transition: implications in atherosclerosis 08.07.2016 Florence, Italy Bochaton-Piallat Marie-Luce; Sakic Antonija;


Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Diabète et obésité au coeur de la recherche 2018 Western Switzerland 2018
Talks/events/exhibitions Diabète et obésité au coeur de la recherche 2017 Western Switzerland 2017
Talks/events/exhibitions Diabète et obésité au coeur de la recherche 2016 Western Switzerland 2016

Awards

Title Year
Best poster Second Cardiovascular Research Meeting, as member of the Scientific Committee of the Intersection Cardiovascular Biology, a section of Life Sciences Switzerland (LS2) and of the Swiss Society of Cardiology. March 14-15, 2019, Fribourg, Switzerland S100A4: a key player in plaque stabilization? 2019

Associated projects

Number Title Start Funding scheme
146790 Hétérogénéité des cellules musculaires lisses artérielles: implications dans l'athérosclérose et la resténose 01.04.2013 Project funding

Abstract

During atherosclerosis and restenosis, smooth muscle cells (SMCs) are known to accumulate into the intima and to switch from a contractile to a synthetic phenotype. In our model, we isolated two distinct SMC populations, spindle-shaped (S-) and rhomboid (R-) SMCs from the porcine coronary artery; the R-phenotype represents the synthetic phenotype. We further identified S100A4 as a marker of R-SMCs in vitro and of intimal SMCs in both pigs and humans. Recently we have shown that the extracellular form of S100A4 is essential for the establishment of the R-phenotype and acts, to some extent, through the receptor for advanced glycation end products (RAGE). Remarkably, S-SMCs treated with S100A4-rich conditioned medium (CM, collected from S100A4-transfected SMCs) acquire pro-inflammatory properties. In the frame of this grant, we will continue our studies on the role of S100A4 in porcine SMC phenotypic transition and atherosclerotic plaque formation.Aim 1. We have preliminary shown that multimeric recombinant S100A4 induces a transition from S- to R-phenotype. We will confirm that the multimeric recombinant S100A4 is exclusively responsible for this phenotypic transition and whether it recapitulates the pro-inflammatory properties observed after treatment of S-SMCs with S100A4-rich CM. The SMC phenotype will be characterized using SMC differentiation marker expression, proliferation, apoptosis, and migration assays. The pro-inflammatory profile of SMCs will be characterized by matrix metalloproteinase (MMP) and their inhibitor (TIMP) expression. These results will be strengthen by treating S-SMCs with S100A4-rich CM containing neutralizing S100A4 antibody. To decipher the signaling pathways induced by the multimeric recombinant S100A4, we will first explore the possible implication of RAGE. Based on a microarray assay data comparing S-SMCs treated with CM containing or not extracellular S100A4 and bio-informatics analysis, we will investigate the role of the lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) and Toll-like receptor-4 (TLR4) in SMC phenotypic transition. Codependence between RAGE/LOX-1 and RAGE/TLR4 will be also explored. The unexpected upregulation of granulocyte macrophage-colony stimulating factors (GM-CSF) gene, detected by microarray assay, provides new perspectives on the possible activation of monocytes by SMCs. We will examine whether extracellular S100A4-treated SMCs yield GM-CSF secretion and further induce monocyte activation. Finally, we will perform a cytokine array to identify additional factor(s) present in S100A4-rich CM, possibly involved in the S- to R-phenotypic transition.Aim 2. We will investigate whether altered S100A4 expression is causally related to the formation of restenotic and atherosclerotic lesions. For this purpose we will perform balloon catheter injury in carotid arteries (a model of restenosis) of S100A4-/-ApoE-/- mice as well as of ApoE-/- mice simultaneously treated with a neutralizing S100A4 antibody. In addition S100A4-/-ApoE-/- mice, fed with a high-cholesterol diet, will be studied for atherosclerotic plaque development. The size and composition of the lesions will be further analyzed.Aim 3. We have preliminarily observed that apelin, a small peptide hitherto poorly studied in SMCs, is involved in SMC phenotypic transition and we will hence study its relationship with intra and extracellular S100A4. We have observed a nuclear expression of apelin in R-SMCs. Transfection of a plasmid containing nuclear-targeting apelin in S-SMCs (devoid of apelin) induces a phenotypic transition toward a R-phenotype, which is associated with increased expression of S100A4. We will confirm these unexpected results by thoroughly characterizing the SMC phenotypic transition induced by nuclear apelin overexpression and to clearly define whether apelin acts upstream or downstream of S100A4. In parallel, we will explore the effects of secreted apelin in SMC phenotypic transition. Taken together, our results suggest that a better understanding of S100A4 expression, release and regulation in SMCs will help to shed light on the mechanisms of SMC accumulation in the intima. The ultimate aim of our work is the development of tools to influence the evolution of atherosclerotic and restenotic lesions.
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