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1. In vitro and in vivo models define a molecular signature reference for human embryonic notochordal cells

Author

Warin, Julie, Vedrenne, Nicolas, Tam, Vivian, Zhu, Mengxia, Yin, Danqing, Lin, Xinyi, Guidoux-D’halluin, Bluwen, Humeau, Antoine, Roseiro, Luce, Paillat, Lily, Chédeville, Claire, Chariau, Caroline, Riemers, Frank, Templin, Markus, Guicheux, Jérôme, Tryfonidou, Marianna A., Ho, Joshua W.K., David, Laurent, Chan, Danny, and Camus, Anne

Published
2024
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2. In vitro and in vivo models define a molecular signature reference for human embryonic notochordal cells

Author

Chirurgie, CS_Locomotion, Locomotion - Surgery (CA), Warin, Julie, Vedrenne, Nicolas, Tam, Vivian, Zhu, Mengxia, Yin, Danqing, Lin, Xinyi, Guidoux-D'halluin, Bluwen, Humeau, Antoine, Roseiro, Luce, Paillat, Lily, Chédeville, Claire, Chariau, Caroline, Riemers, Frank, Templin, Markus, Guicheux, Jérôme, Tryfonidou, Marianna A., Ho, Joshua W.K., David, Laurent, Chan, Danny, Camus, Anne, Chirurgie, CS_Locomotion, Locomotion - Surgery (CA), Warin, Julie, Vedrenne, Nicolas, Tam, Vivian, Zhu, Mengxia, Yin, Danqing, Lin, Xinyi, Guidoux-D'halluin, Bluwen, Humeau, Antoine, Roseiro, Luce, Paillat, Lily, Chédeville, Claire, Chariau, Caroline, Riemers, Frank, Templin, Markus, Guicheux, Jérôme, Tryfonidou, Marianna A., Ho, Joshua W.K., David, Laurent, Chan, Danny, and Camus, Anne

Published
2024

4. A dominant vimentin variant causes a rare syndrome with premature aging

Author

Cogné, Benjamin, Bouameur, Jamal-Eddine, Hayot, Gaëlle, Latypova, Xenia, Pattabiraman, Sundararaghavan, Caillaud, Amandine, Si-Tayeb, Karim, Besnard, Thomas, Küry, Sébastien, Chariau, Caroline, Gaignerie, Anne, David, Laurent, Bordure, Philippe, Kaganovich, Daniel, Bézieau, Stéphane, Golzio, Christelle, Magin, Thomas M., and Isidor, Bertrand

Published
2020
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5. Characterization of genetic variants in the EGLN1/PHD2 gene identified in a European collection of patients with erythrocytosis

Author

Delamare, Marine, primary, Le Roy, Amandine, additional, Pacault, Mathilde, additional, Schmitt, Loïc, additional, Garrec, Céline, additional, Maaziz, Nada, additional, Myllykoski, Matti, additional, Rimbert, Antoine, additional, Karaghiannis, Valéna, additional, Aral, Bernard, additional, Catherwood, Mark, additional, Airaud, Fabrice, additional, Mansour-Hendili, Lamisse, additional, Hoogewijs, David, additional, Peroni, Edoardo, additional, Idriss, Salam, additional, Lesieur, Valentine, additional, Caillaud, Amandine, additional, Si-Tayeb, Karim, additional, Chariau, Caroline, additional, Gaignerie, Anne, additional, Rab, Minke, additional, Haferlach, Torsten, additional, Meggendorfer, Manja, additional, Bézieau, Stéphane, additional, Benetti, Andrea, additional, Casadevall, Nicole, additional, Hirsch, Pierre, additional, Rose, Christian, additional, Wemeau, Mathieu, additional, Galacteros, Frédéric, additional, Cassinat, Bruno, additional, Bellosillo, Beatriz, additional, Bento, Celeste, additional, Van Wijk, Richard, additional, Petrides, Petro E., additional, Randi, Maria Luigia, additional, McMullin, Mary Frances, additional, Koivunen, Peppi, additional, Girodon, François, additional, Gardie, Betty, additional, and Consortium, ECYT, additional

Published
2023
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6. Integration of in Vitro and in Vivo Models Defines a Molecular Signature Reference for Human Embryonic Notochordal Cells

Author

Warin, Julie, primary, Vedrenne, Nicolas, additional, Tam, Vivian, additional, Zhu, Mengxia, additional, Yin, Danqing, additional, Lin, Xinyi, additional, Guidoux-D’halluin, Bluwen, additional, Humeau, Antoine, additional, Roseiro, Luce, additional, Paillat, Lily, additional, Chédeville, Claire, additional, Chariau, Caroline, additional, Riemers, Frank, additional, Templin, Markus, additional, Guicheux, Jérôme, additional, Tryfonidou, Marianna A., additional, Ho, Joshua W. K., additional, David, Laurent, additional, Chan, Danny, additional, and Camus, Anne, additional

Published
2023
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8. Generation of human induced pluripotent stem cell lines from four unrelated healthy control donors carrying European genetic background

Author

Girardeau, Aurore, primary, Atticus, Diane, additional, Canac, Robin, additional, Cimarosti, Bastien, additional, Caillaud, Amandine, additional, Chariau, Caroline, additional, Simonet, Floriane, additional, Cariou, Bertrand, additional, Charpentier, Flavien, additional, Gourraud, Jean-Baptiste, additional, Probst, Vincent, additional, Belbachir, Nadjet, additional, Jesel, Laurence, additional, Lemarchand, Patricia, additional, Barc, Julien, additional, Redon, Richard, additional, Gaborit, Nathalie, additional, and Lamirault, Guillaume, additional

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

Author

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

Published
2021
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10. Induction of Human Trophoblast Stem Cells from Somatic Cells and Pluripotent Stem Cells

Author

Castel, Gaël, Meistermann, Dimitri, Bretin, Betty, Firmin, Julie, Blin, Justine, Loubersac, Sophie, Bruneau, Alexandre, Chevolleau, Simon, Kilens, Stéphanie, Chariau, Caroline, Gaignerie, Anne, Francheteau, Quentin, Kagawa, Harunobu, Charpentier, Eric, Flippe, Léa, François--Campion, Valentin, Haider, Sandra, Dietrich, Bianca, Knöfler, Martin, Arima, Takahiro, Bourdon, Jérémie, Rivron, Nicolas, Masson, Damien, Fournier, Thierry, Okae, Hiroaki, Fréour, Thomas, David, Laurent, 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), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire des Sciences du Numérique de Nantes (LS2N), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), 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), Austrian Academy of Sciences (OeAW), Medizinische Universität Wien = Medical University of Vienna, Tohoku University [Sendai], and The Enteric Nervous System in gut and brain disorders [U1235] (TENS)

Subjects
Pluripotent Stem Cells, human induced trophoblast stem cells, induced pluripotent stem cells, [SDV]Life Sciences [q-bio], naive pluripotent stem cells, Cell Differentiation, somatic cell reprogramming, Trophoblasts, cell fate conversion, [SDV] Life Sciences [q-bio], human placenta, Pregnancy, embryonic structures, Humans, OSKM, Female, extended pluripotent stem cells, trophoblast stem cells, human peri-implantation embryo, reproductive and urinary physiology
Abstract

International audience; Human trophoblast stem cells (hTSCs) derived from blastocysts and first-trimester cytotrophoblasts offer an unprecedented opportunity to study the placenta. However, access to human embryos and first-trimester placentas is limited, thus preventing the establishment of hTSCs from diverse genetic backgrounds associated with placental disorders. Here, we show that hTSCs can be generated from numerous genetic backgrounds using post-natal cells via two alternative methods: (1) somatic cell reprogramming of adult fibroblasts with OCT4, SOX2, KLF4, MYC (OSKM) and (2) cell fate conversion of naive and extended pluripotent stem cells. The resulting induced/converted hTSCs recapitulated hallmarks of hTSCs including long-term self-renewal, expression of specific transcription factors, transcriptomic signature, and the potential to differentiate into syncytiotrophoblast and extravillous trophoblast cells. We also clarified the developmental stage of hTSCs and show that these cells resemble day 8 cytotrophoblasts. Altogether, hTSC lines of diverse genetic origins open the possibility to model both placental development and diseases in a dish.

Published
2020

11. NOTO Transcription Factor Directs Human Induced Pluripotent Stem Cell-Derived Mesendoderm Progenitors to a Notochordal Fate

Author

Colombier, Pauline, Halgand, Boris, Chédeville, Claire, Chariau, Caroline, François-Campion, Valentin, Kilens, Stephanie, Vedrenne, Nicolas, Clouet, Johann, David, Laurent, Guicheux, Jérome, Camus, Anne, Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-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 Odontologie, Université de Nantes (UN), 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), Université de Nantes (UN)-Université de Nantes (UN), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and CAMUS, ANNE

Subjects
animal structures, Induced Pluripotent Stem Cells, mesendoderm progenitors, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], stem cell therapy, Article, Mesoderm, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, signalling, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, directed differentiation, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, intervertebral disc regeneration, Cell Differentiation, notochord, human induced pluripotent stem cells, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, lcsh:Biology (General), [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, embryonic structures, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Transcription Factors
Abstract

The founder cells of the Nucleus pulposus, the centre of the intervertebral disc, originate in the embryonic notochord. After birth, mature notochordal cells (NC) are identified as key regulators of disc homeostasis. Better understanding of their biology has great potential in delaying the onset of disc degeneration or as a regenerative-cell source for disc repair. Using human pluripotent stem cells, we developed a two-step method to generate a stable NC-like population with a distinct molecular signature. Time-course analysis of lineage-specific markers shows that WNT pathway activation and transfection of the notochord-related transcription factor NOTO are sucient to induce high levels of mesendoderm progenitors and favour their commitment toward the notochordal lineage instead of paraxial and lateral mesodermal or endodermal lineages. This study results in the identification of NOTO-regulated genes including some that are found expressed in human healthy disc tissue and highlights NOTO function in coordinating the gene network to human notochord di erentiation.

Published
2020

12. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

School of Medicine, 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, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945); Reversade, Bruno, and 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

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.

Published
2020

13. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

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, 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, and School of Medicine

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

14. Generation of human induced trophoblast stem cells

Author

Castel, Gaël, primary, Meistermann, Dimitri, additional, Bretin, Betty, additional, Firmin, Julie, additional, Blin, Justine, additional, Loubersac, Sophie, additional, Bruneau, Alexandre, additional, Chevolleau, Simon, additional, Kilens, Stephanie, additional, Chariau, Caroline, additional, Gaignerie, Anne, additional, Francheteau, Quentin, additional, Kagawa, Harunobu, additional, Charpentier, Eric, additional, Flippe, Léa, additional, Francois - - Campion, Valentin, additional, Haider, Sandra, additional, Dietrich, Bianca, additional, Knöfler, Martin, additional, Arima, Takahiro, additional, Bourdon, Jérémie, additional, Rivron, Nicolas, additional, Masson, Damien, additional, Fournier, Thierry, additional, Okae, Hiroaki, additional, Freour, Thomas, additional, and David, Laurent, additional

Published
2020
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15. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction

Author

Al Sayed, Zeina R, primary, Canac, Robin, additional, Cimarosti, Bastien, additional, Bonnard, Carine, additional, Gourraud, Jean-Baptiste, additional, Hamamy, Hanan, additional, Kayserili, Hulya, additional, Girardeau, Aurore, additional, Jouni, Mariam, additional, Jacob, Nicolas, additional, Gaignerie, Anne, additional, Chariau, Caroline, additional, David, Laurent, additional, Forest, Virginie, additional, Marionneau, Céline, additional, Charpentier, Flavien, additional, Loussouarn, Gildas, additional, Lamirault, Guillaume, additional, Reversade, Bruno, additional, Zibara, Kazem, additional, Lemarchand, Patricia, additional, and Gaborit, Nathalie, additional

Published
2020
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16. TET3 controls the expression of the H3K27me3 demethylase Kdm6b during neural commitment

Author

Montibus, Bertille, primary, Cercy, Jil, additional, Bouschet, Tristan, additional, Charras, Amandine, additional, Maupetit-Méhouas, Stéphanie, additional, Nury, David, additional, Gonthier-Guéret, Céline, additional, Chauveau, Sabine, additional, Allegre, Nicolas, additional, Chariau, Caroline, additional, Hong, Charles C., additional, Vaillant, Isabelle, additional, Marques, C. Joana, additional, Court, Franck, additional, and Arnaud, Philippe, additional

Published
2020
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17. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction.

Author

Sayed, Zeina R Al, Canac, Robin, Cimarosti, Bastien, Bonnard, Carine, Gourraud, Jean-Baptiste, Hamamy, Hanan, Kayserili, Hulya, Girardeau, Aurore, Jouni, Mariam, Jacob, Nicolas, Gaignerie, Anne, Chariau, Caroline, David, Laurent, Forest, Virginie, Marionneau, Céline, Charpentier, Flavien, Loussouarn, Gildas, Lamirault, Guillaume, Reversade, Bruno, and Zibara, Kazem

Subjects
BRUGADA syndrome, TRANSCRIPTION factors, PLURIPOTENT stem cells, SODIUM channels, ION channels, GENETIC mutation
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. [ABSTRACT FROM AUTHOR]

Published
2021
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18. RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome

Author

Belbachir, Nadjet, primary, Portero, Vincent, additional, Al Sayed, Zeina R, additional, Gourraud, Jean-Baptiste, additional, Dilasser, Florian, additional, Jesel, Laurence, additional, Guo, Hongchao, additional, Wu, Haodi, additional, Gaborit, Nathalie, additional, Guilluy, Christophe, additional, Girardeau, Aurore, additional, Bonnaud, Stephanie, additional, Simonet, Floriane, additional, Karakachoff, Matilde, additional, Pattier, Sabine, additional, Scott, Carol, additional, Burel, Sophie, additional, Marionneau, Céline, additional, Chariau, Caroline, additional, Gaignerie, Anne, additional, David, Laurent, additional, Genin, Emmanuelle, additional, Deleuze, Jean-François, additional, Dina, Christian, additional, Sauzeau, Vincent, additional, Loirand, Gervaise, additional, Baró, Isabelle, additional, Schott, Jean-Jacques, additional, Probst, Vincent, additional, Wu, Joseph C, additional, Redon, Richard, additional, Charpentier, Flavien, additional, and Le Scouarnec, Solena, additional

Published
2019
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19. Parallel derivation of isogenic human primed and naive induced pluripotent stem cells.

Author

Kilens, Stéphanie, Meistermann, Dimitri, Moreno, Diego, Chariau, Caroline, Gaignerie, Anne, Reignier, Arnaud, Lelièvre, Yohann, Casanova, Miguel, Vallot, Céline, Nedellec, Steven, Flippe, Léa, Firmin, Julie, Song, Juan, Charpentier, Eric, Lammers, Jenna, Donnart, Audrey, Marec, Nadège, Deb, Wallid, Bihouée, Audrey, and Le Caignec, Cédric

Subjects
PLURIPOTENT stem cells, INDUCED pluripotent stem cells, HUMAN biology, REGENERATION (Biology), DEVELOPMENTAL biology, SOMATIC cells
Abstract

Induced pluripotent stem cells (iPSCs) have considerably impacted human developmental biology and regenerative medicine, notably because they circumvent the use of cells of embryonic origin and offer the potential to generate patient-specific pluripotent stem cells. However, conventional reprogramming protocols produce developmentally advanced, or primed, human iPSCs (hiPSCs), restricting their use to post-implantation human development modeling. Hence, there is a need for hiPSCs resembling preimplantation naive epiblast. Here, we develop a method to generate naive hiPSCs directly from somatic cells, using OKMS overexpression and specific culture conditions, further enabling parallel generation of their isogenic primed counterparts. We benchmark naive hiPSCs against human preimplantation epiblast and reveal remarkable concordance in their transcriptome, dependency on mitochondrial respiration and X-chromosome status. Collectively, our results are essential for the understanding of pluripotency regulation throughout preimplantation development and generate new opportunities for disease modeling and regenerative medicine. [ABSTRACT FROM AUTHOR]

Published
2018
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20. 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

21. Human model of IRX5 mutations reveals key role for this transcription factor in ventricular conduction.

Author

Al Sayed ZR, Canac R, Cimarosti B, Bonnard C, Gourraud JB, Hamamy H, Kayserili H, Girardeau A, Jouni M, Jacob N, Gaignerie A, Chariau C, David L, Forest V, Marionneau C, Charpentier F, Loussouarn G, Lamirault G, Reversade B, Zibara K, Lemarchand P, and Gaborit N

Subjects
Animals, Arrhythmias, Cardiac metabolism, Arrhythmias, Cardiac physiopathology, Bone Diseases metabolism, Bone Diseases physiopathology, Cells, Cultured, Connexins genetics, Connexins metabolism, GATA4 Transcription Factor genetics, GATA4 Transcription Factor metabolism, Heart Rate, Homeodomain Proteins metabolism, Humans, Hypertelorism metabolism, Hypertelorism physiopathology, Intellectual Disability metabolism, Intellectual Disability physiopathology, Male, Mice, Inbred C57BL, Myopia metabolism, Myopia physiopathology, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism, Transcription Factors metabolism, Transcriptome, Gap Junction alpha-5 Protein, Mice, Action Potentials, Arrhythmias, Cardiac genetics, Bone Diseases genetics, Heart Ventricles metabolism, Homeodomain Proteins genetics, Hypertelorism genetics, Induced Pluripotent Stem Cells metabolism, Intellectual Disability genetics, Loss of Function Mutation, Myocytes, Cardiac metabolism, Myopia genetics, Transcription Factors genetics
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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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22. Induction of Human Trophoblast Stem Cells from Somatic Cells and Pluripotent Stem Cells.

Author

Castel G, Meistermann D, Bretin B, Firmin J, Blin J, Loubersac S, Bruneau A, Chevolleau S, Kilens S, Chariau C, Gaignerie A, Francheteau Q, Kagawa H, Charpentier E, Flippe L, François-Campion V, Haider S, Dietrich B, Knöfler M, Arima T, Bourdon J, Rivron N, Masson D, Fournier T, Okae H, Fréour T, and David L

Subjects
Cell Differentiation, Female, Humans, Pregnancy, Pluripotent Stem Cells metabolism, Trophoblasts metabolism
Abstract

Human trophoblast stem cells (hTSCs) derived from blastocysts and first-trimester cytotrophoblasts offer an unprecedented opportunity to study the placenta. However, access to human embryos and first-trimester placentas is limited, thus preventing the establishment of hTSCs from diverse genetic backgrounds associated with placental disorders. Here, we show that hTSCs can be generated from numerous genetic backgrounds using post-natal cells via two alternative methods: (1) somatic cell reprogramming of adult fibroblasts with OCT4, SOX2, KLF4, MYC (OSKM) and (2) cell fate conversion of naive and extended pluripotent stem cells. The resulting induced/converted hTSCs recapitulated hallmarks of hTSCs including long-term self-renewal, expression of specific transcription factors, transcriptomic signature, and the potential to differentiate into syncytiotrophoblast and extravillous trophoblast cells. We also clarified the developmental stage of hTSCs and show that these cells resemble day 8 cytotrophoblasts. Altogether, hTSC lines of diverse genetic origins open the possibility to model both placental development and diseases in a dish., Competing Interests: Declaration of Interests D.M. is supported by FINOX forward grant initiative. G.C. and L.D. have a provisional patent filled on the generation of hiTSCs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
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23. NOTO Transcription Factor Directs Human Induced Pluripotent Stem Cell-Derived Mesendoderm Progenitors to a Notochordal Fate.

Author

Colombier P, Halgand B, Chédeville C, Chariau C, François-Campion V, Kilens S, Vedrenne N, Clouet J, David L, Guicheux J, and Camus A

Subjects
Cell Differentiation physiology, Humans, Induced Pluripotent Stem Cells cytology, Mesoderm cytology, Notochord cytology, Induced Pluripotent Stem Cells metabolism, Mesoderm metabolism, Notochord metabolism, Transcription Factors metabolism
Abstract

The founder cells of the Nucleus pulposus, the centre of the intervertebral disc, originate in the embryonic notochord. After birth, mature notochordal cells (NC) are identified as key regulators of disc homeostasis. Better understanding of their biology has great potential in delaying the onset of disc degeneration or as a regenerative-cell source for disc repair. Using human pluripotent stem cells, we developed a two-step method to generate a stable NC-like population with a distinct molecular signature. Time-course analysis of lineage-specific markers shows that WNT pathway activation and transfection of the notochord-related transcription factor NOTO are sufficient to induce high levels of mesendoderm progenitors and favour their commitment toward the notochordal lineage instead of paraxial and lateral mesodermal or endodermal lineages. This study results in the identification of NOTO-regulated genes including some that are found expressed in human healthy disc tissue and highlights NOTO function in coordinating the gene network to human notochord differentiation.

Published
2020
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