title: cKit+ cardiac progenitors of neural crest origin.
abstract: The degree to which cKit-expressing progenitors generate cardiomyocytes in the heart is controversial. Genetic fate-mapping studies suggest minimal contribution; however, whether or not minimal contribution reflects minimal cardiomyogenic capacity is unclear because the embryonic origin and role in cardiogenesis of these progenitors remain elusive. Using high-resolution genetic fate-mapping approaches with cKit(CreERT2/+) and Wnt1::Flpe mouse lines, we show that cKit delineates cardiac neural crest progenitors (CNC(kit)). CNC(kit) possess full cardiomyogenic capacity and contribute to all CNC derivatives, including cardiac conduction system cells. Furthermore, by modeling cardiogenesis in cKit(CreERT2)-induced pluripotent stem cells, we show that, paradoxically, the cardiogenic fate of CNC(kit) is regulated by bone morphogenetic protein antagonism, a signaling pathway activated transiently during establishment of the cardiac crescent, and extinguished from the heart before CNC invasion. Together, these findings elucidate the origin of cKit(+) cardiac progenitors and suggest that a nonpermissive cardiac milieu, rather than minimal cardiomyogenic capacity, controls the degree of CNC(kit) contribution to myocardium.
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136;
authors.forename: Konstantinos E
authors.initials: KE
authors.lastname: Hatzistergos
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136;
authors.forename: Lauro M
authors.initials: LM
authors.lastname: Takeuchi
authors.affiliation: Department of Internal Medicine, Mediziniche Klinik und Policlinik Der Technischen Universitat Munchen, Munich 81675, Germany;
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: Department of Internal Medicine, Mediziniche Klinik und Policlinik Der Technischen Universitat Munchen, Munich 81675, Germany;
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115;
authors.forename: Susan M
authors.initials: SM
authors.lastname: Dymecki
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115;
authors.forename: Jia Jia
authors.initials: JJ
authors.lastname: Mai
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136;
authors.forename: Ian A
authors.initials: IA
authors.lastname: White
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136;
authors.forename: Wayne
authors.initials: W
authors.lastname: Balkan
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136; Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, Miami, FL 33136;
authors.forename: Rosemeire M
authors.initials: RM
authors.lastname: Kanashiro-Takeuchi
authors.affiliation: Department of Pathology and Medicine, University of Miami School of Medicine and Veterans Affairs Medical Center, Miami, FL 33125 jhare@miami.edu andrew.schally@va.gov.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.affiliation: Interdisciplinary Stem Cell Institute, Leonard M. Miller School of Medicine, Miami, FL 33136; jhare@miami.edu andrew.schally@va.gov.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D019485:Bone Morphogenetic Proteins; D019009:Proto-Oncogene Proteins c-kit
keywords: BMP signalling; cardiac neural crest; cardiac stem cells; cardiomyogenesis