physiopathology of development

Congenital heart diseases (CHD) are the most frequent congenital diseases. GWAS  and exome sequencing performed for the last decade revealed mutations in coding sequence in only a minority of CHD patients. Rather a high proportion of hits in epigenetic modifiers was found. Thus, the team physiopathology of cardiac development focuses its research on epigenetic regulation of cell fate determination during cardiac embryonic development. We are specifically focused on Tetralogy of Fallot and valve development and diseases, as they represent altogether 50% of cardiac congenital defects. These pathologies either lead to heart failure at the adulthood or become prominent in the aging population, respectively. Our research is also dedicated to better design strategies of cell therapy of heart failure for repaired tetralogy of Fallot, a complex cardiac congenital disease, for which reparation of the septal defect at birth has consequences on adult right ventricular function. To more specifically address such a broad biological question, we carry out different projects using patient specific iPS cell lines and mouse models of diseases:

  1. The Cornelia de Lange syndrome:  what are the epigenetic mechanisms underlying this cohesinopathy? What is the role of cohesin complex in cardiac cell fate decision? Thomas Moore-Morris and Fanny Boulet in collaboration with Valérie Cormier-Daire (Imagine Institute , Paris)
  2. Cell fate determination during cardiac valvulogenesis: a clonal analysis combined with a single cell-sequencing approaches: from development to diseases Batoul Fahrat
  3. The laminopathy at the origin of a cardiomyopathy: a congenital disease with an epigenetic origin: postdoc to be recruited in collaboration with Gisèle Bonne Institute of Myology (Institut de myologie, Paris)
  4. The role of epigenetics in vitamin D deficiency and CHD: Eva Siepelt in collaboration with Jean-Francois Landrier (Nort Univ AMU)
  5. Cardiac Regeneration in a pig model of cardiac congenital disease : Virginie Lambert  in collaboration with the pediatric cardiology service La timone Hospital ( Service médico-chirurgical de cardiologie pédiatrique et congénitale - Hôpital de la Timone) and CERIMED (CERIMED)

The head of the team Michel Puceat is an INSERM director of research. He has signed more than 110 publications. He has acquired a background of cardiac biochemistry and physiology as well as cardiac developmental biology.

Seipelt, EM.  et al. 2020

Prenatal maternal vitamin D deficiency sex-dependently programs adipose tissue metabolism and energy homeostasis in offspring.

In utero environment is crucial to ensure normal development of the fetus and to program metabolic health throughout the life. Beside macronutrients, the role of micronutrients, including vitamin D,...
FASEB J - issue: - volume: in press - pages: .

Stefanovic, S.  et al. 2020

Hox-dependent coordination of mouse cardiac progenitor cell patterning and differentiation

Perturbation of addition of second heart field (SHF) cardiac progenitor cells to the poles of the heart tube results in congenital heart defects (CHD). The transcriptional programs and upstream...
eLife - issue: - volume: 9 - pages: e55124.

Fontana, F.  et al. 2020

Antagonistic Activities of Vegfr3/Flt4 and Notch1b Fine-tune Mechanosensitive Signaling during Zebrafish Cardiac Valvulogenesis.

The formation of cardiac valves depends on mechanical forces exerted by blood flow. Endocardial cells lining the interior of the heart are sensitive to these stimuli and respond by rearranging into...
Cell Rep - issue: 2 - volume: 32 - pages: 107883.

Suffee, N.  et al. 2020

Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy.

Rationale: Fibro-fatty infiltration of subepicardial layers of the atrial wall has been shown to contribute to the substrate of atrial fibrillation. Objective: Here, we examined if the epicardium...
Circ Res - issue: 10 - volume: 126 - pages: 1330-1342.

Wünnemann, F.  et al. 2020

Loss of ADAMTS19 causes progressive non-syndromic heart valve disease.

Valvular heart disease is observed in approximately 2% of the general population1. Although the initial observation is often localized (for example, to the aortic or mitral valve), disease...
Nat Genet - issue: 1 - volume: 52 - pages: 40-47.

Piche, J.  et al. 2019

Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TPF-beta Signaling and Epigenomics

BACKGROUND & AIMS: A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic...
Cell Mol Gastroenterol Hepatol - issue: 2 - volume: 7 - pages: 411-431.

Puceat, M.  et al. 2019

The primary eyelash at the heart of the pathogenesis of the mitral valve prolapse

Med Sci - issue: 11 - volume: 35 - pages: 836-838.

Piche, J.  et al. 2019

The expanding phenotypes of cohesinopathies: one ring to rule them all!

Preservation and development of life depend on the adequate segregation of sister chromatids during mitosis and meiosis. This process is ensured by the cohesin multi-subunit complex. Mutations in this...
Cell Cycle - issue: 21 - volume: 18 - pages: 2828-2848.

Neri, T.  et al. 2019

Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis

Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by...
Nat Comm - issue: 1 - volume: 10 - pages: 1929.

Moore-Morris, T.  et al. 2018

Role of Epigenetics in Cardiac Development and Congenital Diseases

The heart is the first organ to be functional in the fetus. Heart formation is a complex morphogenetic process regulated by both genetic and epigenetic mechanisms. Congenital heart diseases (CHD) are...
Physiol Rev - issue: 4 - volume: 98 - pages: 2453-2475.

Blin, G.  et al. 2018

Geometrical confinement controls the asymmetric patterning of brachyury in cultures of pluripotent cells

Diffusible signals are known to orchestrate patterning during embryogenesis, yet diffusion is sensitive to noise. The fact that embryogenesis is remarkably robust suggests that additional layers of...
Development - issue: 18 - volume: 145 - pages: pii: dev166025.

Chatzifrangkeskou, M.  et al. 2018

Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation

Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene (LMNA cardiomyopathy). The mechanism of...
Hum Mol Genet - issue: 17 - volume: 27 - pages: 3060-3078.

Moore-Morris, T.  et al. 2018

Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages

RATIONALE: Myocardial infarction is a major cause of adult mortality worldwide. The origin(s) of cardiac fibroblasts that constitute the postinfarct scar remain controversial, in particular the...
Circ Res - issue: 4 - volume: 122 - pages: 583-590.

Suffee, N.  et al. 2017

Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria

The abundance of epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), the most frequent cardiac arrhythmia. However, both the origin and the factors involved in EAT expansion...
Proc Natl Acad Sci - issue: 5 - volume: 114 - pages: E771-E780.

Rampersad, SN.  et al. 2016

Adaptive phenotypic modulation of human arterial endothelial cells to fluid shear stress-encoded signals: modulation by phosphodiesterase 4D-VE-cadherin signalling

Although cAMP-signalling regulates numerous functions of vascular endothelial cells (VECs), including their ability to impact vascular resistance in response to changes in blood flow dynamics, few of...
Cell. Signal. - issue: 7 - volume: 28 - pages: 741-748.

Rampersad, SN.  et al. 2016

EPAC1 promotes adaptive responses in human arterial endothelial cells subjected to low levels of laminar fluid shear stress: Implications in flow-related endothelial dysfunction

Blood flow-associated fluid shear stress (FSS) dynamically regulates the endothelium's ability to control arterial structure and function. While arterial endothelial cells (AEC) subjected to high...
Cell. Signal. - issue: 6 - volume: 28 - pages: 606-619.

Smith, PM.  et al. 2016

Leptin influences the excitability of area postrema neurons

The area postrema (AP) is a circumventricular organ with important roles in central autonomic regulation. This medullary structure has been shown to express the leptin receptor and has been suggested...
Am. J. Physiol.-Regul. Integr. Comp. Physiol. - issue: 5 - volume: 310 - pages: R440-R448.

Durst, R.  et al. 2015

Mutations in DCHS1 cause mitral valve prolapse

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals(1-3). It can manifest as mitral regurgitation and is the leading indication for mitral valve...
Nature - issue: 7567 - volume: 525 - pages: 109-+.

Leschik, J.  et al. 2015

A View of Bivalent Epigenetic Marks in Two Human Embryonic Stem Cell Lines Reveals a Different Cardiogenic Potential

Human embryonic stem (HUES) cells are derived from early individual embryos with unique genetic printing. However, how their epigenetic status might affect their potential to differentiate toward...
Stem Cells Dev. - issue: 3 - volume: 24 - pages: 384-392.

Ahles, A.  et al. 2015

Interhelical Interaction and Receptor Phosphorylation Regulate the Activation Kinetics of Different Human beta(1)-Adrenoceptor Variants

G protein-coupled receptors represent the largest class of drug targets, but genetic variation within G protein-coupled receptors leads to variable drug responses and, thereby, compromises their...
J. Biol. Chem. - issue: 3 - volume: 290 - pages: 1760-1769.

Hamdi, H.  et al. 2014

Long-Term Functional Benefits of Epicardial Patches as Cell Carriers

Both enzymatic dissociation of cells prior to needle-based injections and poor vascularization of myocardial infarct areas are two important contributors to cell death and impede the efficacy of...
Cell Transplant. - issue: 1 - volume: 23 - pages: 87-96.

Richart, A.  et al. 2014

MicroRNA-21 Coordinates Human Multipotent Cardiovascular Progenitors Therapeutic Potential

Published clinical trials in patients with ischemic diseases show limited benefit of adult stem cell-based therapy, likely due to their restricted plasticity and commitment toward vascular cell...
Stem Cells - issue: 11 - volume: 32 - pages: 2908-2922.

Sussman, MA.  et al. 2014

Response to Letter Regarding Article, "Embryonic Stem Cell-Derived Cardiac Myocytes Are Not Ready for Human Trials"

Circ.Res. - issue: 10 - volume: 115 - pages: E30-E31.

Moore-Morris, T.  et al. 2014

Targeting cardiac fibroblasts: The pressure is on

Cell Cycle - issue: 17 - volume: 13 - pages: 2647-2648.

Anderson, ME.  et al. 2014

Embryonic Stem Cell-Derived Cardiac Myocytes Are Not Ready for Human Trials

Circ.Res. - issue: 3 - volume: 115 - pages: 335-338.

Maurice, DH.  et al. 2014

Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals

The cyclic nucleotide second messengers cAMP and cGMP each affect virtually all cellular processes. Although these hydrophilic small molecules readily diffuse throughout cells, it is remarkable that...
Biochem. Soc. Trans. - issue: - volume: 42 - pages: 250-256.

Hiriart, E.  et al. 2014

Cell Labeling and Injection in Developing Embryonic Mouse Hearts

Testing the fate of embryonic or pluripotent stem cell-derivatives in in vitro protocols has led to controversial outcomes that do not necessarily reflect their in vivo potential. Preferably, these...
J. Vis. Exp. - issue: 86 - volume: - pages: e51356.

Maurice, DH.  et al. 2014

Cyclic nucleotide phosphodiesterases (PDEs): coincidence detectors acting to spatially and temporally integrate cyclic nucleotide and non-cyclic nucleotide signals

The cyclic nucleotide second messengers cAMP and cGMP each affect virtually all cellular processes. Although these hydrophilic small molecules readily diffuse throughout cells, it is remarkable that...
Biochem. Soc. Trans. - issue: - volume: 42 - pages: 250-256.

Ahles, A.  et al. 2014

The Arg389Gly polymorphism determines structure and activation kinetics of the human beta(1)-adrenergic receptor

Naunyn-Schmiedebergs Arch. Pharmacol. - issue: - volume: 387 - pages: S24-S24.

Puceat, M.  et al. 2013

Could a pluripotent stem cell give rise to a high yield of a single cell lineage: a myocardial cell?

Curr. Opin. Genet. Dev. - issue: 4 - volume: 23 - pages: 498-499.

Catelain, C.  et al. 2013

Myoblasts and Embryonic Stem Cells Differentially Engraft in a Mouse Model of Genetic Dilated Cardiomyopathy

The functional and architectural benefits of embryonic stem cells (ESC) and myoblasts (Mb) transplantations into infarcted myocardium have been investigated extensively. Whereas ESC repopulated...
Mol. Ther. - issue: 5 - volume: 21 - pages: 1064-1075.

Puceat, M.  et al. 2013

Embryological origin of the endocardium and derived valve progenitor cells: From developmental biology to stem cell-based valve repair

The cardiac valves are targets of both congenital and acquired diseases. The formation of valves during embryogenesis (i.e., valvulogenesis) originates from endocardial cells lining the myocardium....
Biochim. Biophys. Acta-Mol. Cell Res. - issue: 4 - volume: 1833 - pages: 917-922.

Ahles, A.  et al. 2013

Phosphorylation-dependent receptor memory of the human beta(1)-adrenergic receptor

Naunyn-Schmiedebergs Arch. Pharmacol. - issue: - volume: 386 - pages: S3-S3.

Van Vliet, P.  et al. 2012

Early cardiac development: a view from stem cells to embryos

From the 1920s, early cardiac development has been studied in chick and, later, in mouse embryos in order to understand the first cell fate decisions that drive specification and determination of the...
Cardiovasc. Res. - issue: 3 - volume: 96 - pages: 352-362.

Zhai, K.  et al. 2012

beta-Adrenergic cAMP Signals Are Predominantly Regulated by Phosphodiesterase Type 4 in Cultured Adult Rat Aortic Smooth Muscle Cells

Background: We investigated the role of cyclic nucleotide phosphodiesterases (PDEs) in the spatiotemporal control of intracellular cAMP concentrations in rat aortic smooth muscle cells (RASMCs)....
PLoS One - issue: 10 - volume: 7 - pages: e47826.

Calderon, D.  et al. 2012

Immune response to human embryonic stem cell-derived cardiac progenitors and adipose-derived stromal cells

Transplantation of allogeneic human embryonic stem cell-derived cardiac progenitors triggers an immune response. We assessed whether this response could be modulated by the concomitant use of...
J. Cell. Mol. Med. - issue: 7 - volume: 16 - pages: 1544-1552.

Boon, R.  et al. 2012

A Day in the Life of a Young Investigator

Circulation - issue: 25 - volume: 125 - pages: F145-F150.

Ahles, A.  et al. 2012

The Gly389Arg polymorphism determines the activation kinetics of the human beta(1)-adrenergic receptor

Naunyn-Schmiedebergs Arch. Pharmacol. - issue: - volume: 385 - pages: 4-4.

Goebel, P.  et al. 2012

Identification of novel targets of beta-adrenergic signaling through phosphoproteomics of the heart in vivo

Naunyn-Schmiedebergs Arch. Pharmacol. - issue: - volume: 385 - pages: 29-30.

Paris, M.  et al. 2012

Regulation of skin aging and heart development by TAp63

Since the discovery of the TP63 gene in 1998, many studies have demonstrated that Delta Np63, a p63 isoform of the p53 gene family, is involved in multiple functions during skin development and in...
Cell Death Differ. - issue: 2 - volume: 19 - pages: 186-193.