title: Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration.
abstract: Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tien
authors.initials: T
authors.lastname: Peng
authors.affiliation: Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Frank
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Kadzik
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morley
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Komal S
authors.initials: KS
authors.lastname: Rathi
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D053823:Hedgehog Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D008168:Lung / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D019899:Paracrine Communication; D012038:Regeneration; D014945:Wound Healing
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse