title: Genetic lineage tracing defines myofibroblast origin and function in the injured heart.
abstract: Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo. Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin(+) myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21(+) tissue-resident fibroblasts.
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Onur
authors.initials: O
authors.lastname: Kanisicak
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Hadi
authors.initials: H
authors.lastname: Khalil
authors.affiliation: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors.forename: Malina J
authors.initials: MJ
authors.lastname: Ivey
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Karch
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Maliken
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Correll
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Brody
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Suh-Chin
authors.initials: SC
authors.lastname: J Lin
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Aronow
authors.affiliation: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tallquist
authors.affiliation: Department of Pediatrics and Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.|Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019426:Integrases; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000378:metabolism*; D013629:Tamoxifen
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D019426:Integrases; D013629:Tamoxifen; C082838:Postn protein, mouse; C112923:Tcf21 protein, mouse; C045073:Cre recombinase