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1. In vitro differentiation of W8B2+ human cardiac stem cells: gene expression of ionic channels and spontaneous calcium activity

Author

Oualid Ayad, Zeina R. Al Sayed, Stéphane Sebille, Christophe Magaud, Charles-Albert Chapotte-Baldacci, Christophe Jayle, Jean-François Faivre, Nathalie Gaborit, Aurélien Chatelier, and Patrick Bois

Subjects
W8B2+ human cardiac stem cell, Cardiac differentiation, Calcium activity, Oscillations, Ion channels, GCaMP, Cytology, QH573-671
Abstract

Abstract Background Human cardiac stem cells expressing the W8B2 marker (W8B2+ CSCs) were recently identified and proposed as a new model of multipotent CSCs capable of differentiating into smooth muscle cells, endothelial cells and immature myocytes. Nevertheless, no characterization of ion channel or calcium activity during the differentiation of these stem cells has been reported. Methods The objectives of this study were thus to analyze (using the TaqMan Low-Density Array technique) the gene profile of W8B2+ CSCs pertaining to the regulation of ion channels, transporters and other players involved in the calcium homeostasis of these cells. We also analyzed spontaneous calcium activity (via the GCaMP calcium probe) during the in vitro differentiation of W8B2+ CSCs into cardiac myocytes. Results Our results show an entirely different electrophysiological genomic profile between W8B2+ CSCs before and after differentiation. Some specific nodal genes, such as Tbx3, HCN, ICaT, L, KV, and NCX, are overexpressed after this differentiation. In addition, we reveal spontaneous calcium activity or a calcium clock whose kinetics change during the differentiation process. A pharmacological study carried out on differentiated W8B2+ CSCs showed that the NCX exchanger and IP3 stores play a fundamental role in the generation of these calcium oscillations. Conclusions Taken together, the present results provide important information on ion channel expression and intrinsic calcium dynamics during the differentiation process of stem cells expressing the W8B2 marker.

Published
2020
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2. Generation of three human induced pluripotent stem cell lines with IRX5 knockout and knockin genetic editions using CRISPR-Cas9 system

Author

Robin Canac, Amandine Caillaud, Bastien Cimarosti, Aurore Girardeau, Hanan Hamamy, Bruno Reversade, Carine Bonnard, Zeina R. Al Sayed, Laurent David, Jeremie Poschmann, Patricia Lemarchand, Guillaume Lamirault, and Nathalie Gaborit

Subjects
Biology (General), QH301-705.5
Abstract

Studies on animal models have shown that Irx5 is an important regulator of cardiac development and that it regulates ventricular electrical repolarization gradient in the adult heart. Mutations in IRX5 have also been linked in humans to cardiac conduction defects. In order to fully characterize the role of IRX5 during cardiac development and in cardiomyocyte function, we generated three genetically-modified human induced pluripotent stem cell lines: two knockout lines (heterozygous and homozygous) and a knockin HA-tagged line (homozygous).

Published
2022
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3. A consistent arrhythmogenic trait in Brugada syndrome cellular phenotype

Author

Zeina R. Al Sayed, Mariam Jouni, Jean‐Baptiste Gourraud, Nadjet Belbachir, Julien Barc, Aurore Girardeau, Virginie Forest, Aude Derevier, Anne Gaignerie, Caroline Chariau, Bastien Cimarosti, Robin Canac, Pierre Olchesqui, Eric Charpentier, Jean‐Jacques Schott, Richard Redon, Isabelle Baró, Vincent Probst, Flavien Charpentier, Gildas Loussouarn, Kazem Zibara, Guillaume Lamirault, Patricia Lemarchand, and Nathalie Gaborit

Subjects
Medicine (General), R5-920
Published
2021
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4. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

Bastien Cimarosti, Guillaume Lamirault, Hanan Hamamy, Nathalie Gaborit, Céline Marionneau, Flavien Charpentier, Gildas Loussouarn, Laurent David, Kazem Zibara, Nicolas Jacob, Virginie Forest, Mariam Jouni, Caroline Chariau, Carine Bonnard, Hülya Kayserili, Bruno Reversade, Anne Gaignerie, Jean-Baptiste Gourraud, Robin Canac, Zeina R Al Sayed, Patricia Lemarchand, Aurore Girardeau, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Reversade, Bruno, Al Sayed, Zeina R, Canac, Robin, Cimarosti, Bastien, Bonnard, Carine, Gourraud, Jean-Baptiste, Hamamy, Hanan, Girardeau, Aurore, Jouni, Mariam, Jacob, Nicolas, Gaignerie, Anne, Chariau, Caroline, David, Laurent, Forest, Virginie, Marionneau, Céline, Charpentier, Flavien, Loussouarn, Gildas, Lamirault, Guillaume, Zibara, Kazem, Lemarchand, Patricia, Gaborit, Nathalie, School of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Agency for science, technology and research [Singapore] (A*STAR), Department of Genetic Medicine and Development [Geneva], Université de Genève (UNIGE), Koç University, Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), National University of Singapore (NUS), University of Amsterdam [Amsterdam] (UvA), Laboratory of Stem Cells [Lebanese, Beirut] (ER045-PRASE), Lebanese University [Beirut] (LU), This work was funded by grants from The National Research Agency [HEART iPS ANR-15-CE14-0019-01], and La Fédération Française de Cardiologie. Nathalie Gaborit was laureate of fellowships from Fondation Lefoulon-Delalande and International Incoming Fellowship FP7-PEOPLE-2012-IIF [PIIF-GA-2012-331436]. Zeina R. Al Sayed is supported by Eiffel scholarship program of Excellence (Campus France), by Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie., ACS - Heart failure & arrhythmias, ARD - Amsterdam Reproduction and Development, Unité de recherche de l'institut du thorax (ITX-lab), and Université de Genève = University of Geneva (UNIGE)

Subjects
conduction, IRX5 mutations, Physiology, Transcription factor complex, Connexin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030204 cardiovascular system & hematology, Biology, arrhythmia, Ventricular action potential, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), transcription factors, Cardiac conduction, Transcription factor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, GATA4, Sodium channel, Depolarization, Human-induced pluripotent stem cells, Cell biology, human induced pluripotent stem cells, cardiovascular system, IRX5, Cardiology and Cardiovascular Medicine, Hamamy syndrome
Abstract

Aims: several inherited arrhythmic diseases have been linked to single gene mutations in cardiac ion channels and interacting proteins. However, the mechanisms underlying most arrhythmias, are thought to involve altered regulation of the expression of multiple effectors. In this study, we aimed to examine the role of a transcription factor (TF) belonging to the Iroquois homeobox family, IRX5, in cardiac electrical function. Methods and results: using human cardiac tissues, transcriptomic correlative analyses between IRX5 and genes involved in cardiac electrical activity showed that in human ventricular compartment, IRX5 expression strongly correlated to the expression of major actors of cardiac conduction, including the sodium channel, Nav1.5, and Connexin 40 (Cx40). We then generated human-induced pluripotent stem cells (hiPSCs) derived from two Hamamy syndrome-affected patients carrying distinct homozygous loss-of-function mutations in IRX5 gene. Cardiomyocytes derived from these hiPSCs showed impaired cardiac gene expression programme, including misregulation in the control of Nav1.5 and Cx40 expression. In accordance with the prolonged QRS interval observed in Hamamy syndrome patients, a slower ventricular action potential depolarization due to sodium current reduction was observed on electrophysiological analyses performed on patient-derived cardiomyocytes, confirming the functional role of IRX5 in electrical conduction. Finally, a cardiac TF complex was newly identified, composed by IRX5 and GATA4, in which IRX5 potentiated GATA4-induction of SCN5A expression. Conclusion: altogether, this work unveils a key role for IRX5 in the regulation of human ventricular depolarization and cardiac electrical conduction, providing therefore new insights into our understanding of cardiac diseases., National Research Agency; European Union (EU); Horizon 2020; Marie Curie Actions International Incoming Fellowship FP7-PEOPLE-2012-IIF; La Fédération Française de Cardiologie; Fondation LefoulonDelalande; Eiffel Scholarship Programme of Excellence (Campus France), Doctoral School of Science and Technology-Lebanese University and The Fondation Genavie

Published
2020

5. RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome

Author

Zeina R Al Sayed, Sabine Pattier, Hongchao Guo, Floriane Simonet, Solena Le Scouarnec, Emmanuelle Génin, Laurent David, Flavien Charpentier, Jean-Baptiste Gourraud, Caroline Chariau, Anne Gaignerie, Haodi Wu, Vincent Probst, Jean-François Deleuze, Stéphanie Bonnaud, Carol Scott, Florian Dilasser, Jean-Jacques Schott, Gervaise Loirand, Joseph C. Wu, Christian Dina, Isabelle Baró, Aurore Girardeau, Christophe Guilluy, Richard Redon, Vincent Sauzeau, Nathalie Gaborit, Sophie Burel, Matilde Karakachoff, Nadjet Belbachir, Laurence Jesel, Céline Marionneau, Vincent Portero, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic and Cellular Engineering in Immunology and Regenerative Medicine (Team 2 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Le Bihan, Sylvie

Subjects
RAD GTPase, 030204 cardiovascular system & hematology, medicine.disease_cause, Afterdepolarization, 03 medical and health sciences, 0302 clinical medicine, Basic Science, Medicine, Missense mutation, Brugada syndrome, Induced pluripotent stem cell, Endocardium, 030304 developmental biology, 0303 health sciences, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, L-type calcium current, Actin cytoskeleton, medicine.disease, Cell biology, Electrophysiology, Induced pluripotent stem cells, Sodium current, Cardiology and Cardiovascular Medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Aims The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias. Despite considerable efforts, its genetic basis and cellular mechanisms remain largely unknown. The objective of this study was to identify a new susceptibility gene for BrS through familial investigation. Methods and results Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3/186 unrelated index cases. We detected higher levels of RRAD transcripts in subepicardium than in subendocardium in human heart, and in the right ventricle outflow tract compared to the other cardiac compartments in mice. The p.R211H variant was then subjected to electrophysiological and structural investigations in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Cardiomyocytes derived from induced pluripotent stem cells from two affected family members exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and less focal adhesions, compared with intra-familial control iPSC-CMs Insertion of p.R211H-RRAD variant in control iPSCs by genome editing confirmed these results. In addition, iPSC-CMs from affected patients exhibited a decreased L-type Ca2+ current amplitude. Conclusion This study identified a potential new BrS-susceptibility gene, RRAD. Cardiomyocytes derived from induced pluripotent stem cells expressing RRAD variant recapitulated single-cell electrophysiological features of BrS, including altered Na+ current, as well as cytoskeleton disturbances.

Published
2019

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