PARCC Director
Team Leader
TEAM LEADERS : Jean-Sébastien Silvestre and Jean-Sébastien Hulot
Mail : jean-sebastien.silvestre@inserm.fr / jean-sebastien.hulot@inserm.fr
PHONE :+33 1 53 98 79 66 (JS Silvestre) / +33 1 56 09 20 17 (JS Hulot)
LOCATION : Lab 216 (Group JS Silvestre) & Lab 362-369 (Group JS Hulot) & Lab 174 (Group P Menasché)
DOCTORAL SCHOOL : ED 562 – BIO SCIENCE PARIS CITE – Université PARIS CITE
The team is based on the complementary expertise contributed by a group (Jean-Sébastien Silvestre) experienced in deciphering the signaling pathways involved in post-ischemic tissue remodeling, a group (Jean-Sébastien Hulot) with an internationally recognized expertise in understanding the molecular and cellular mechanisms involved in cardiac muscle repair during heart failure; and a group (Philippe Menasché) with a long–standing experience in the preclinical, translational and clinical aspects of stem cell research.
The team therefore constitutes an ideal platform of expertise and technical know-how, extending from the basic features of cardiac injury, cardiomyocyte regeneration and contractility as well as tissue remodeling and stiffness to the clinical applications of regenerative and reparative therapies for patients with cardiac diseases, including heart failure.
Namely, our current objectives are :
– To understand the contribution of immune cells in the development of different forms of heart failure
– To describe the cascade of molecular and cellular events leading to a stiffer heart
– To develop and test innovative therapeutic approaches to promote regeneration and repair of the heart
Currently, the team has three major scientific aims: a) deciphering the mechanisms of cardiac repair, b) deciphering the mechanisms leading to the stiffening of cardiac muscle and c) developing innovative therapies comprising cell and non-cell-based approaches for patients with cardiac diseases. We have a specific interest in cardioimmunology and cardiometabolism. In particular, we have:
i) decrypted the importance of the interaction between different cellular components of innate and adaptive immunity and cardiac homeostasis including cardiac regeneration and remodeling (Loyer X et al, Circ Res, 2018; Zlatanova I et al, Circulation, 2019; Santos-Zas I et al, Nat Commun, 2021; Gomez I et al, Int J Mol Sci, 2022; Sun Y et al, J Am Coll Cardiol, 2022).
ii) demonstrated that activation of cardiac stromal cells promote a pro-fibrotic program and thus identified novel therapeutic targets and biomarkers related to the fibrotic remodeling of the heart (Bouvet M et al., Sci Rep 2020, Sayed A. Sci Rep 2022, Masurkar N et al, Circulation 2023, Delacroix C et al. BioXriv 2022). We have developed innovative in vitro assays based on human iPSC-derived cardiomyocytes in order to better characterize some key functions (i.e. relaxation phase) that are best observed in the human heart and poorly recapitulated in animals. These platforms helped us to identify novel mechanisms and miRNA modulating the mechano-sensing machinery of cardiomyocytes (Vermersch E el al. JCI Insight, 2024; Seguret M et al., eLife 2024). These innovative tools open new avenues to explore cardiomyocytes as seen in humans and has generated multiple international interactions (with success to a ANR/DKG grant in 2022). Last, the team has developed novel imaging tools to assess large and small arteries stiffness, as well as cardiac tissue stiffness in humans (PACIFIC research project ongoing).
iii) developed cellular and acellular-based therapeutic approaches for patients with cardiac diseases. After the successful completion of our phase I trial testing cardiac progenitors derived from human embryonic stem cells embedded in a patch (Menasché P et al, J Am Coll Cardiol, 2018), the recognition of the predominant role of paracrine signaling has led to shift towards an a-cellular therapy based on the exclusive use of the secretome (of the same pluripotent stem cell cardiac derivatives) to further streamlining the clinical translatability of this myocardial repair strategy (El Harane N et al, Eur Heart J, 2018; Lima Correa B et al, Cardiovasc Res, 2021; Lima Correa B et al, Theranostics 2021; Pezzana C et al, Biomaterials, 2022).
The current strategic research axes of the team are :
Axis #1: The understanding of the molecular and cellular mechanisms involved in the inter and intra-organ pathogenic dialogue in cardiac diseases. We speculate that cardiac resident macrophages (CRM) establishing time-dependent residence in the perivascular niche acquire unchallenged reparative function in the cardiac tissue. We will characterize the perivascular identity of CRM in the cardiac tissue and unravel the environmental cues involved in this niche-dependent functional programming. We also hypothesize that efferocytosis favors the activation of the regulated secretion pathways allowing CRM to immediately adjust their phenotype and cytokine secretion to promote inflammation resolution and initiate reparative processes (Project funded by ANR-22-CE14-0008; ANR-21-CE14-0073-01). Furthermore, we speculate that extracellular vesicles (EVs) are decisive components of the common body language as EVs may employ an apoptotic mimicry strategy to subjugate CRM efferocytic function, playing a fundamental role in CRM-based organ quorum sensing
Axis #2: The understanding of the molecular and cellular mechanisms leading to myocardial stiffness. An increased stiffening of the myocardium has been constantly reported in patients with heart failure, suggesting that approaches to limit this progressive remodeling can improve cardiac performance and limit the transition to heart failure after myocardial injury. We will especially focus on two key processes involved in myocardial stiffness that are 1/ the abnormal remodeling of the extra-cellular matrix (i.e. increased fibrosis), (Project funded by eRa4Health Cardinnov ID-Preserved) and 2/ changes in the internal mechano-energetic properties of cardiac myocytes (i.e. increased resistance to stretch amd metabolic deficiency) (Project funded by ANR-22-CE14-0025; ANR-22-CE94-0034).
Axis #3: The development of innovative therapeutic modalities for cardiac diseases including regenerative and gene editing therapies. We have developed models of cardiac regeneration in mice (Zlatanova I et al, Circulation, 2019; Lima-Correa B et al, Theranostics, 2021) and obtained a grant from the European Union on this theme, whose European coordinator is P. Menasché (REGeRNA, Horizon-RIA 101057318, 2022). We have therefore framed a project aimed at developing a synthetic mRNA able to trigger a time-controlled induction of endogenous (quiescent) cardiomyocyte proliferation in the context of heart failure with loss of contractile function. We are also part of another EU-funded project (CellBeat) aimed at improving the maturation of iPSC-derived cardiomyocytes with a particular focus on the mitigation of engraftment arrhythmias. Finally, we continue our studies of CAR-T cells against a fibrosis-associated fibrosis (FAP) in a Duchenne Muscular Dystrophy (DMD) model and, upon the succesful completion of proof-of-concept experiments with ex-vivo anti-FAP CAR-T manufacturing, we are now exploring, in the context of an ANR-funded project, the possibility of in vivo CAR generation by a mRNA delivered in targeted LNP, both in DMD and systemic sclerosis models.
Following our prior involvement in the development of gene therapies for heart failure (Hulot JS et al. Eur J Heart Fail 2017), we are developing a novel CRISPR/Cas9-based gene editing therapy for LMNA cardiomyopathy (Project funded ANR19-CE17-0013-02). We have designed, tested and developed a genome editing correction package on iPSCells from patients carrying the LMNA pH222P (associated with the Emery Dreyfuss myopathy dystrophy, a highly debilitating monogenic disease with severe cardiomyopathy at age 20).
PARCC Director
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2026 – Fondation de France. Decoding cardiac resident macrophage dysfunction in insulin resistance and postischemic cardiac remodeling. (WB-2025-58624) Principal Investigator: Dr Stéphane Camus.
2025 – Emergence Recherche 2024 – IdEx Université de Paris. Prolifération des macrophages résidents cardiaques induite par l’efférocytose dans la réparation cardiaque après infarctus du myocarde. Principal Investigator: Dr Stéphane Camus
2025 Agence Nationale de la Recherche. Cardiomyocyte-derived extracellular vesicles and inter-organ dialogue after myocardial infarction (ANR-25-CE14). Principal Investigator. X Loyer.
2024 ERA4HEALTH – European Union – CARDINOV – Immunotherapy targeting marginal zone B lymphocytes to promote cardiac repair after acute myocardial infarction. Principal Investigator JS Silvestre.
2022 Agence Nationale de la Recherche. Deciphering HEArt-liVEr communication in nonalcoholic fatty liver disease (ANR-22-CE14-0002). Partner Dr JS Silvestre.
2022 Agence Nationale de la Recherche – JCJC – Molecular mechanisms controlling cytokine secretion during macrophage-mediated cardiac repair (ANR-22-CE14-0008). Principal investigator Dr S Camus.
2022 Horizon H2020 – European Union. Cardiac regeneration by mRNA-triggered proliferation of cardiomyocytes (REGeRNA, Horizon-RIA 101057318). Coordinator : Pr P Menasché.
2021 Deutsch DFG/Agence Nationale de la Recherche. Tissue experienced resident macrophages of the perivascular niche in myocardial infarction (ANR-21-CE14-0073-01). Principal investigator Dr JS Silvestre.
2021 Agence Nationale de la Recherche. Cardiac vectoring of extracellular vesicles by modification of their glycosylation – Exoglyc. (ANR-21-CE18-0003). Principal investigator Pr P Menasché.
2021 French Society of Cardiology. Hepatic steatosis and cardiac ischemic pathology (FFC-2021). Principal investigator Dr JS Silvestre.
2021 Fondation de France. Exploring the role of the cardio-splenic axis after myocardial infarction in diabetes. (FDF 00121054) Co-principal investigator Dr JS Silvestre.
2020 Émergence en Recherche 2020 – IdEx Université de Paris. Deciphering HEArt-liVEr communication in nonalcohoLic fatty liver disease. (Idex/EK/RR 2020-274). Co-principal investigator Dr JS Silvestre.
2020 Fondation de France. The GPR50 receptor in the adipose tissue-heart dialogue: role in post-ischemic remodeling of diabetic and obese myocardium (FDF 00107035). Co-principal investigator Dr A Levoye.
2020 EQUIPE LABELLISEE PAR LA FRM Patient-specific human induced pluripotent stem cells as a cellular platform to detect and predict anti-cancer drug-induced cardiac arrhythmias
2019 Ministère des solidarité et de la santé. Programme Hospitalier de Recherche Clinique National. Traitement des cardiomyopathies dilatées non ischémiques par infusions intraveineuses du sécrétome enrichi en vésicules extracellulaires de cellules progénitrices cardiovasculaires. (SECRET-HF, PHRC-19-0330). Principal investigator Pr P Menasché.
2019 French Society of Cardiology. Macrophages and Heart Failure with preserved Ejection Fraction. (FFC-2019). 10/2019-10/2021. Principal investigator Dr JS Silvestre.
2019 Fondation de France. Vesicular trafficking of cytokines in cardiac macrophages: role in the pathological remodelling of the diabetic myocardium. (FDF 00096283). Principal investigator Dr JS Silvestre.
2019 ANR CORRECT-LMNA Gene editing therapeutics for LMNA cardiomyopathy JS Hulot Partner
2019 Leducq Foundation Translatlantic Networks of Excellence Towards precision medicine with human iPSCs for cardiac channelopathies coordinated by Prs Joseph Wu (Stanford, USA) and Peter Schwartz (Milano, IT) JS Hulot Network member
2018 Agence Nationale de la Recherche. Treatment of severe heart failure with extracellular vesicles from cardiovascular progenitors – Exogel. (ANR-17-CE18-0003). Principal investigator Pr P Menasché.
2018 ANR PRC PACIFIC project Pw1+ stromal cells in cardiac fibrosis JS Hulot PI
2018 ANRT – CIFRE Modeling cardiac relaxation using human iPSC-based engineered cardiac tissues JS Hulot PI
2017 ANR PRC NAD-Heart NAD+ precursor for metabolic therapy of heart failure JS Hulot partner
2017 ANR PRC CAPTOR Controling fate-determination of adipose-tissue derived progenitors to improve obesity-related metabolic disorders D Sassoon Partner
2017 Era-CVD CLARIFY Communicaition between cardiomyocytes, cardiac stem cells and innate immune cells in failing hearts JS Hulot Partner
2016 Fondation pour la recherche médicale – Team Award. Extracellular membrane vesicles derived from cardiovascular progenitors: therapeutic potential in heart failure (DEQ20160334910). Principal investigator Dr JS Silvestre.
2016 LABEX Revive Cellules souches et médecine régénérative D Sassoon Partner
2016 H2020 CVENT Risk assessment of plaque rupture and future cardiovascular events by multi-spectral photoacoustic imaging P Boutouyrie Partner
2015 H2020, CARDIS Early Stage Cardiovascular disease detection with integrated silicon photonics P Boutouyrie Partner
Clément Delacroix, Alexandra Achab Ali, Paul Alayrac, Marine Gandon-Renard, Aïcha Ben Zemzem, Charlène Jouve, Feriel Hamidou, Morgane Aubert, David Sassoon, Jean-Sébastien Silvestre, Clément Cochain, Stéphane Camus, Jean-Sébastien Hulot. Inhibition of integrin alpha V reduces inflammation and the transition to heart failure after pressure overload. Biochemical Pharmacology. 2025. Volume 242, Part 4. December 2025, 117393.
Coly PM, Chatterjee S, Mezine F, Jekmek CE, Devue C, Nipoti T, Mazlan S, Corona ML, Dingli F, Loew D, van Niel G, Loyer X, Boulanger CM. Low fluid shear stress stimulates the uptake of noxious endothelial extracellular vesicles via MCAM and PECAM-1 cell adhesion molecules. J Extracell Vesicles. 2024 Oct;13(10):e12414. doi: 10.1002/jev2.12414.
Hulot JS, Janiak P, Boutinaud P, Boutouyrie P, Chézalviel-Guilbert F, Christophe JJ, Cohen A, Damy T, Djadi-Prat J, Firat H, Hervé PY, Isnard R, Jondeau G, Mousseaux E, Pernot M, Prot P, Tyl B, Soulat G, Logeart D; PACIFIC consortium. Rationale and design of the PACIFIC-PRESERVED (PhenomApping, ClassiFication and Innovation for Cardiac dysfunction in patients with heart failure and PRESERVED left ventricular ejection fraction) study. Arch Cardiovasc Dis. 2024 May;117(5):332-342.
Al Sayed ZR, Pereira C, Le Borgne R, Viaris de Lesegno C, Jouve C, Pénard E, Mallet A, Masurkar N, Loussouarn G, Verbavatz JM, Lamaze C, Trégouët DA, Hulot JS. CAVIN-1 mediated hERG dynamics: a novel mechanism underlying the interindividual variability in drug-induced long QT. Circulation. 2024 Apr 29. doi: 10.1161/CIRCULATIONAHA.123.063917. Online ahead of print.
Vermersch E, Neuvendel S, Jouve C, Ruiz-Velasco A, Pereira C, Seguret M, Cattin-Messaoudi ME, Lotfi S, Dorval T, Berson P, Hulot JS. Hsa-miRNA-548v controls the viscoelastic properties of human cardiomyocytes and improve their relaxation rates. JCI Insight. 2024:e161356. doi: 10.1172/jci.insight.161356
Masurkar N, Bouvet M, Logeart D, Claude O, Roux M, Delacroix C, Bergerot D, Mercadier JJ, Sirol M, Gellen B, Livrozet M, Fayol A, Robidel E, Trégouët DA, Marazzi G, Sassoon D, Valente M, Hulot JS. The novel cardiokine GDF3 predicts adverse fibrotic remodeling post-myocardial infarction. Circulation 2023, 147:498-511
Lecoeur E, Domenge O, Fayol A, Jannot AS, Hulot JS. Epidemiology of heart failure in young adults in France. Eur Heart J 2023; 44:383-392
Seguret M, Davidson P, Robben S, Jouve C, Pereira C, Cerveau C, Le Berre M, Rodrigues Ribeiro R, Hulot JS. A versatile high-throughput assay based on 3D ring-shaped cardiac tissues generated from human induced pluripotent stem cell derived cardiomyocytes. Elife. 2024 Apr 5;12:RP87739. doi: 10.7554/eLife.87739
Pezzana C, Cras A, Simelière F, Guesdon R, Desgres M, Correa BL, Peuffier A, Bellamy V, Gouarderes S, Alberdi A, Perier MC, Pidial L, Agnely F, Bochot A, Hagège A, Silvestre JS, Menasché P. Biomaterial-embedded extracellular vesicles improve recovery of the dysfunctional myocardium. Biomaterials. 2022 Dec;291:121877.
Sun Y, Pinto C, Camus S, Duval V, Alayrac P, Zlatanova I, Loyer X, Vilar J, Lemitre M, Levoye A, Nus M, Ait-Oufella H, Mallat Z, Silvestre JS. Splenic Marginal Zone B Lymphocytes Regulate Cardiac Remodeling After Acute Myocardial Infarction in Mice.J Am Coll Cardiol. 2022 Feb 22;79(7):632-647.
Lima Correa B, El Harane N, Desgres M, Perotto M, Alayrac P, Guillas C, Pidial L, Bellamy V, Baron E, Autret G, Kamaleswaran K, Pezzana C, Perier MC, Vilar J, Alberdi A, Brisson A, Renault N, Gnecchi M, Silvestre JS, Menasché P. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts. Theranostics. 2021 Nov 2;11(20):10114-10124.
Fayol A, Wack M, Livrozet M, Carves JB, Domengé O, Vermersch E, Mirabel M, Karras A, Le Guen J, Blanchard A, Azizi M, Amar L, Bories MC, Mousseaux E, Carette C, Puymirat E, Hagège A, Jannot AS, Hulot JS. Aetiological classification and prognosis in patients with heart failure with preserved ejection fraction. ESC Heart Fail. 2021 Nov 29. doi: 10.1002/ehf2.13717.
Lima Correa B, El Harane N, Gomez I, Rachid Hocine H, Vilar J, Desgres M, Bellamy V, Keirththana K, Guillas C, Perotto M, Pidial L, Alayrac P, Tran T, Tan S, Hamada T, Charron D, Brisson A, Renault NK, Al-Daccak R, Menasché P, Silvestre JS. Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts. Cardiovasc Res. 2021 Jan 1;117(1):292-307.
Zlatanova I, Pinto C, Bonnin P, Mathieu JRR, Bakker W, Vilar J, Lemitre M, Voehringer D, Vaulont S, Peyssonnaux C, Silvestre JS. Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury. Circulation. 2019 Mar 19;139(12):1530-1547.
El Harane N, Kervadec A, Bellamy V, Pidial L, Neametalla HJ, Perier MC, Lima Correa B, Thiébault L, Cagnard N, Duché A, Brunaud C, Lemitre M, Gauthier J, Bourdillon AT, Renault MP, Hovhannisyan Y, Paiva S, Colas AR, Agbulut O, Hagège A, Silvestre JS, Menasché P, Renault NKE. Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. Eur Heart J. 2018 May 21;39(20):1835-1847.
Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Parouchev A, Cacciapuoti I, Al-Daccak R, Benhamouda N, Blons H, Agbulut O, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Charron D, Tartour E, Tachdjian G, Desnos M, Larghero J. Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction. J Am Coll Cardiol. 2018 Jan 30;71(4):429-438.
Yaniz-Galende E, Roux M, Nadaud S, Mougenot N, Bouvet M, Claude O, Lebreton G, Blanc C, Pinet F, Atassi F, Perret C, Dierick F, Dussaud S, Leprince P, Tregouet DA, Marazzi G, Sasoon D, Hulot JS. Fibrogenic potential of PW1/Peg3 expressing cardiac stem cells. J Am Coll Cardiol 2017;70:728-741
Hulot JS, Salem JE, Redheuil A, Collet JP, Varnous S, Jourdain P, Logeart D, Gandjbakhch E, Bernard C, Hatem SN, Isnard R, Cluzel P, Le Feuvre C, Leprince P, Hammoudi N, Lemoine F, Klatzman D, Vicaut E, Komajda M, Montalescot G, Lompre AM, Hajjar RJ on behalf of the AGENT-HF investigators. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodeling in patients with advanced systolic heart failure : Results from the AGENT-HF randomized phase 2 trial. European Journal of Heart Failure 2017 Nov;19(11):1534-1541
Ngkelo A, Richart A, Kirk JA, Bonnin P, Vilar J, Lemitre M, Marck P, Branchereau M, Le Gall S, Renault N, Guerin C, Ranek MJ, Kervadec A, Danelli L, Gautier G, Blank U, Launay P, Camerer E, Bruneval P, Menasche P, Heymes C, Luche E, Casteilla L, Cousin B, Rodewald HR, Kass DA, Silvestre JS. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction. J Exp Med. 2016. Jun 27;213(7):1353-74.
Howangyin KY, Zlatanova I, Pinto C, Ngkelo A, Cochain C, Rouanet M, Vilar J, Lemitre M, Stockmann C, Fleischmann BK, Mallat Z, Silvestre JS. Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Co-Ordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor. Circulation. 2016 Mar 1;133(9):826-39.
Kervadec A, Bellamy V, El Harane N, Arakélian L, Vanneaux V, Cacciapuoti I, Nemetalla H, Périer MC, Toeg HD, Richart A, Lemitre M, Yin M, Loyer X, Larghero J, Hagège A, Ruel M, Boulanger CM, Silvestre JS, Menasché P, Renault NK. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J Heart Lung Transplant. 2016 Jun;35(6):795-807.
Bernard L, Oh JG, Cacheux M, Lee A, Nonnenmacher M, Matasic D, Kohlbrenner E, Kho CW, Pavoine C, Hajjar RJ, Hulot JS. Cardiac Stim1 silencing impairs adaptive hypertrophy and promotes heart failure through inactivation of mTORC2/Akt signaling. Circulation, 2016, 133:1458-71
