title: Programming and isolation of highly pure physiologically and pharmacologically functional sinus-nodal bodies from pluripotent stem cells.
abstract: Therapeutic approaches for "sick sinus syndrome" rely on electrical pacemakers, which lack hormone responsiveness and bear hazards such as infection and battery failure. These issues may be overcome via "biological pacemakers" derived from pluripotent stem cells (PSCs). Here, we show that forward programming of PSCs with the nodal cell inducer TBX3 plus an additional Myh6-promoter-based antibiotic selection leads to cardiomyocyte aggregates consisting of >80% physiologically and pharmacologically functional pacemaker cells. These induced sinoatrial bodies (iSABs) exhibited highly increased beating rates (300-400 bpm), coming close to those found in mouse hearts, and were able to robustly pace myocardium ex vivo. Our study introduces iSABs as highly pure, functional nodal tissue that is derived from PSCs and may be important for future cell therapies and drug testing in vitro.
authors.affiliation: Referenz und Translationszentrum für Kardiale Stammzelltherapie (RTC) der Universität Rostock, 18057 Rostock, Germany.
authors.forename: Julia Jeannine
authors.initials: JJ
authors.lastname: Jung
authors.affiliation: Universitätsklinik für Innere Medizin III, Kardiologie und Angiologie, 6020 Innsbruck, Austria ; Walter Brendel Centre, LMU Munich, 81377 Munich, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Husse
authors.affiliation: Referenz und Translationszentrum für Kardiale Stammzelltherapie (RTC) der Universität Rostock, 18057 Rostock, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rimmbach
authors.affiliation: Gene Center Munich, LMU Munich, 81377 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der FAU Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Stieber
authors.affiliation: Referenz und Translationszentrum für Kardiale Stammzelltherapie (RTC) der Universität Rostock, 18057 Rostock, Germany.
authors.forename: Gustav
authors.initials: G
authors.lastname: Steinhoff
authors.affiliation: Walter Brendel Centre, LMU Munich, 81377 Munich, Germany ; German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
authors.affiliation: Universitätsklinik für Innere Medizin III, Kardiologie und Angiologie, 6020 Innsbruck, Austria.
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
authors.affiliation: Referenz und Translationszentrum für Kardiale Stammzelltherapie (RTC) der Universität Rostock, 18057 Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: David
mesh_terms: D000818:Animals; D001683:Biological Clocks; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D018920:Coculture Techniques; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D012804:Sick Sinus Syndrome / Q000378:metabolism / Q000473:pathology / Q000662:veterinary; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C584019:Myh6 protein, mouse; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D018995:Myosin Heavy Chains; D002118:Calcium