title: Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells.
abstract: BACKGROUND
  Embryonic and fetal myocardial growth is characterized by a dramatic increase in myocyte number, but whether the expansion of the myocyte compartment is dictated by activation and commitment of resident cardiac stem cells (CSCs), division of immature myocytes or both is currently unknown.
  
  
  OBJECTIVE
  In this study, we tested whether prenatal cardiac development is controlled by activation and differentiation of CSCs and whether division of c-kit-positive CSCs in the mouse heart is triggered by spontaneous Ca(2+) oscillations.
  
  
  RESULTS
  We report that embryonic-fetal c-kit-positive CSCs are self-renewing, clonogenic and multipotent in vitro and in vivo. The growth and commitment of c-kit-positive CSCs is responsible for the generation of the myocyte progeny of the developing heart. The close correspondence between values computed by mathematical modeling and direct measurements of myocyte number at E9, E14, E19 and 1 day after birth strongly suggests that the organogenesis of the embryonic heart is dependent on a hierarchical model of cell differentiation regulated by resident CSCs. The growth promoting effects of c-kit-positive CSCs are triggered by spontaneous oscillations in intracellular Ca(2+), mediated by IP3 receptor activation, which condition asymmetrical stem cell division and myocyte lineage specification.
  
  
  CONCLUSIONS
  Myocyte formation derived from CSC differentiation is the major determinant of cardiac growth during development. Division of c-kit-positive CSCs in the mouse is promoted by spontaneous Ca(2+) spikes, which dictate the pattern of stem cell replication and the generation of a myocyte progeny at all phases of prenatal life and up to one day after birth.
authors.affiliation: Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: João
authors.initials: J
authors.lastname: Ferreira-Martins
authors.forename: Barbara
authors.initials: B
authors.lastname: Ogórek
authors.forename: Donato
authors.initials: D
authors.lastname: Cappetta
authors.forename: Alex
authors.initials: A
authors.lastname: Matsuda
authors.forename: Sergio
authors.initials: S
authors.lastname: Signore
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Amario
authors.forename: James
authors.initials: J
authors.lastname: Kostyla
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steadman
authors.forename: Noriko
authors.initials: N
authors.lastname: Ide-Iwata
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Grazia
authors.initials: G
authors.lastname: Iaffaldano
authors.forename: Sergio
authors.initials: S
authors.lastname: Ottolenghi
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D046149:Embryo Culture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006321:Heart / Q000196:embryology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology*; D038081:Organogenesis / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D019009:Proto-Oncogene Proteins c-kit; D002118:Calcium