title: Efficient Generation of Cardiac Purkinje Cells from ESCs by Activating cAMP Signaling.
abstract: Dysfunction of the specialized cardiac conduction system (CCS) is associated with life-threatening arrhythmias. Strategies to derive CCS cells, including rare Purkinje cells (PCs), would facilitate models for mechanistic studies and drug discovery and also provide new cellular materials for regenerative therapies. A high-throughput chemical screen using CCS:lacz and Contactin2:egfp (Cntn2:egfp) reporter embryonic stem cell (ESC) lines was used to discover a small molecule, sodium nitroprusside (SN), that efficiently promotes the generation of cardiac cells that express gene profiles and generate action potentials of PC-like cells. Imaging and mechanistic studies suggest that SN promotes the generation of PCs from cardiac progenitors initially expressing cardiac myosin heavy chain and that it does so by activating cyclic AMP signaling. These findings provide a strategy to derive scalable PCs, along with insight into the ontogeny of CCS development.
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Su-Yi
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Maass
authors.affiliation: Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.affiliation: Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: glenn.fishman@nyumc.org.
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: shc2034@med.cornell.edu.
authors.forename: Shuibing
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: tre2003@med.cornell.edu.
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D002392:Catechin / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D019301:Oleic Acid / Q000494:pharmacology; D010641:Phenotype; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects
chemical_list: D009599:Nitroprusside; D019301:Oleic Acid; D002392:Catechin; D000242:Cyclic AMP; D018995:Myosin Heavy Chains