title: A Nodal-to-TGFβ cascade exerts biphasic control over cardiopoiesis.
abstract: BACKGROUND
  The transforming growth factor-β (TGFβ) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGFβ family proteins for myocardial remodeling and regeneration.
  
  
  OBJECTIVE
  To determine the function(s) of TGFβ family members during stem cell cardiogenesis.
  
  
  RESULTS
  Murine embryonic stem cells were engineered with a constitutively active human type I Nodal receptor (caACVR1b) to mimic activation by Nodal and found to secrete a paracrine signal that promotes cardiogenesis. Transcriptome and gain- and loss-of-function studies identified the factor as TGFβ2. Both Nodal and TGFβ induced early cardiogenic progenitors in embryonic stem cell cultures at day 0 to 2 of differentiation. However, Nodal expression declines by day 4 due to feedback inhibition, whereas TGFβ persists. At later stages (days 4-6), TGFβ suppresses the formation of cardiomyocytes from multipotent Kdr(+) progenitors while promoting the differentiation of vascular smooth muscle and endothelial cells.
  
  
  CONCLUSIONS
  Nodal induces TGFβ, and both stimulate the formation of multipotent cardiovascular Kdr(+) progenitors. TGFβ, however, becomes uniquely responsible for controlling subsequent lineage segregation by stimulating vascular smooth muscle and endothelial lineages and simultaneously blocking cardiomyocyte differentiation.
authors.affiliation: Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Cai
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guzzo
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.forename: Erik
authors.initials: E
authors.lastname: Willems
authors.forename: Herman
authors.initials: H
authors.lastname: Davidovics
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D004815:Epidermal Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D055457:Nodal Protein / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; C489450:Tdgf1 protein, mouse; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor