title: Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling.
abstract: The anterior heart field (AHF), which contributes to the outflow tract and right ventricle of the heart, is defined in part by expression of the LIM homeobox transcription factor Isl-1. The importance of Isl-1-positive cells in cardiac development and homeostasis is underscored by the finding that these cells are required for cardiac development and act as cardiac stem/progenitor cells within the postnatal heart. However, the molecular pathways regulating these cells' expansion and differentiation are poorly understood. We show that Isl-1-positive AHF progenitor cells in mice were responsive to Wnt/beta-catenin signaling, and these responsive cells contributed to the outflow tract and right ventricle of the heart. Loss of Wnt/beta-catenin signaling in the AHF caused defective outflow tract and right ventricular development with a decrease in Isl-1-positive progenitors and loss of FGF signaling. Conversely, Wnt gain of function in these cells led to expansion of Isl-1-positive progenitors with a concomitant increase in FGF signaling through activation of a specific set of FGF ligands including FGF3, FGF10, FGF16, and FGF20. These data reveal what we believe to be a novel Wnt-FGF signaling axis required for expansion of Isl-1-positive AHF progenitors and suggest future therapies to increase the number and function of these cells for cardiac regeneration.
authors.affiliation: Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Ethan David
authors.initials: ED
authors.lastname: Cohen
authors.forename: Zhishan
authors.initials: Z
authors.lastname: Wang
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Epstein
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D006321:Heart / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005346:Fibroblast Growth Factors; D005819:Genetic Markers; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C498766:Hand2 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1