title: Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm.
abstract: Development of the mammalian lung is predicated on cross-communications between two highly interactive tissues, the endodermally derived epithelium and the mesodermally derived pulmonary mesenchyme. While much attention has been paid for the lung epithelium, the pulmonary mesenchyme, partly due to lack of specific tractable markers remains under-investigated. The lung mesenchyme is derived from the lateral plate mesoderm and is the principal recipient of Hedgehog (Hh) signaling, a morphogenetic network that regulates multiple aspects of embryonic development. Using the Hh-responsive Gli1-cre(ERT2) mouse line, we identified the mesodermal targets of Hh signaling at various time points during embryonic and postnatal lung development. Cell lineage analysis showed these cells serve as progenitors to contribute to multiple lineages of mesodermally derived differentiated cell types that include parenchymal or interstitial myofibroblasts, peribronchial and perivascular smooth muscle as well as rare populations of cells within the mesothelium. Most importantly, Gli1-cre(ERT2) identified the progenitors of secondary crest myofibroblasts, a hitherto intractable cell type that plays a key role in alveolar formation, a vital process about which little is currently known. Transcriptome analysis of Hh-targeted progenitor cells transitioning from the pseudoglandular to the saccular phase of lung development revealed important modulations of key signaling pathways. Among these, there was significant downregulation of canonical WNT signaling. Ectopic stabilization of β-catenin via inactivation of Apc by Gli1-cre(ERT2) expanded the Hh-targeted progenitor pools, which caused the formation of fibroblastic masses within the lung parenchyma. The Gli1-cre(ERT2) mouse line represents a novel tool in the analysis of mesenchymal cell biology and alveolar formation during lung development.
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, Los Angeles County+University of Southern California Medical Center and Childrens Hospital Los Angeles.
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xing
authors.forename: Chang-Yo
authors.initials: CY
authors.lastname: Yang
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
authors.forename: Stijn
authors.initials: S
authors.lastname: De Langhe
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D008168:Lung / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
keywords: ACTA2; Apc; Gli1; Lung; PDGFRa; Secondary crest myofibroblast; Shh