title: Fibrosis of the Neonatal Mouse Heart After Cryoinjury Is Accompanied by Wnt Signaling Activation and Epicardial-to-Mesenchymal Transition.
abstract: BACKGROUND
  The adult mammalian heart responds to cardiac injury by formation of persistent fibrotic scar that eventually leads to heart failure. In contrast, the neonatal mammalian heart reacts to injury by the development of transient fibrotic tissue that is eventually replaced by regenerated cardiomyocytes. How fibrosis occurs in the neonatal mammalian heart remains unknown. To start elucidating the molecular underpinnings of neonatal cardiac fibrosis, we investigated Wnt signaling in the neonatal heart after cryoinjury.
  
  
  RESULTS
  Using expression of the Wnt target gene Axin2 as an indicator of Wnt/β-catenin signaling activation, we discovered that epicardial cells in the ventricles are responsive to Wnt in the uninjured neonatal heart. Lineage-tracing studies of these Wnt-responsive epicardial cells showed that they undergo epithelial-to-mesenchymal transition and infiltrate into the subepicardial space and exhibit fibroblast phenotypes after injury. In addition, we showed that-similar to adult ischemic injury-neonatal cryoinjury results in activation of Wnt signaling in cardiac fibroblasts near injured areas. Furthermore, through in situ hybridization of all 19 Wnt ligands in injured neonatal hearts, we observed upregulation of Wnt ligands (Wnt2b, Wnt5a, and Wnt9a) that had not been implicated in the adult cardiac injury response.
  
  
  CONCLUSIONS
  These results demonstrate that cryoinjury in neonatal heart leads to the formation of fibrotic tissue that involves Wnt-responsive epicardial cells undergoing epithelial-to-mesenchymal transition to give rise to fibroblasts and activation of Wnt signaling in resident cardiac fibroblasts.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Makiko
authors.initials: M
authors.lastname: Mizutani
authors.affiliation: Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA Howard Hughes Medical Institute, Stanford University, Stanford, CA rnusse@stanford.edu.
authors.forename: Roeland
authors.initials: R
authors.lastname: Nusse
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D019070:Cell Lineage; D003080:Cold Temperature; D003452:Cryosurgery; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental; D006335:Heart Injuries / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D010496:Pericardium / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C492031:Wnt2b protein, mouse; C438615:Wnt5a protein, mouse; C486388:Wnt9a protein, mouse
keywords: Wnt signaling; fibrosis; neonatal heart injury