Contributors: Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM); Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon; Marseille medical genetics - Centre de génétique médicale de Marseille (MMG); Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM); University of California San Diego (UC San Diego); University of California (UC); Medical University of South Carolina Charleston (MUSC); Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI); Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); Mayo Clinic Rochester; Keck Graduate Institute Claremont, Californie (KGI); Massachusetts General Hospital Boston; Centro Nacional de Investigaciones Cardiovasculares Carlos III Madrid, Spain (CNIC); Instituto de Salud Carlos III Madrid (ISCIII); Division of Cardiovascular Diseases; Mayo Clinic College of Medicine; Skaggs School of Pharmacy and Pharmaceutical Sciences San Diego; University of California (UC)-University of California (UC); Department of Medicine Univ California San Diego (MED - UC San Diego); School of Medicine Univ California San Diego (UC San Diego); University of California (UC)-University of California (UC)-University of California San Diego (UC San Diego); Department of Pharmacology La Jolla, CA, USA; Part of this work in South Carolina University was conducted in a facility constructed with support from the National Institutes of Health, Grant Number C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Other funding sources: National Heart Lung and Blood Institute: RO1-HL33756 (R.R.M.), COBRE P20RR016434–07 (R.R.M., R.A.N.), P20RR016434–09S1 (R.R.M. and R.A.N.); American Heart Association: 11SDG5270006 (R.A.N.); National Science Foundation: EPS-0902795 (R.R.M. and R.A.N.); American Heart Association: 10SDG2630130 (A.C.Z.), NIH: P01HD032573 (A.C.Z.), NIH: U54 HL108460 (A.C.Z), NCATS: UL1TR000100 (A.C.Z.); EH was supported by a fellowship of the Ministere de la recherche et de l’éducation in France.TM-M was supported by a fellowship from the Fondation Foulon Delalande and the Leducq Foundation. P.v.V. was sponsored by a UC San Diego Cardiovascular Scholarship Award and a Postdoctoral Fellowship from the California Institute for Regenerative Medicine (CIRM) Interdisciplinary Stem Cell Training Program II. S.M.E. was funded by a grant from the National Heart, Lung, and Blood Institute (HL-117649). A.T. is supported by the National Heart, Lung, and Blood Institute (R01-HL134664).; We are grateful to the UCSD Neuroscience Microscopy Shared Facility (supported by a grant P30 NS047101) for access to the Spinning disk microscope, to Jeff Smith and Dr Joan Heller Brown (UCSD, dept of Pharmacology, UCSD) for kindly allowing us to use their microinjection set up, and to Daniel Stockolm (Genethon, Evry, France) for access to the cell imaging facility. We are also thankful to Dr Valérie Balme and colleagues at HALIODX (Marseille) for helpful discussions and skilful single-cell-seq experiments. We thank the Leducq Fondation for supporting Tui Neri, and funding this research under the framework of the MITRAL network and for generously awarding us for the equipment of our cell imaging facility in the frame of their program “Equipement de Recherche et Plateformes Technologiques” (ERPT to M.P.), the Genopole at Evry and the Fondation de la recherche Medicale (grant DEQ20100318280) for supporting the laboratory of Michel Puceat.; ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011)
نبذة مختصرة : International audience ; Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.
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