title: Lung epithelial tip progenitors integrate glucocorticoid- and STAT3-mediated signals to control progeny fate.
abstract: Insufficient alveolar gas exchange capacity is a major contributor to lung disease. During lung development, a population of distal epithelial progenitors first produce bronchiolar-fated and subsequently alveolar-fated progeny. The mechanisms controlling this bronchiolar-to-alveolar developmental transition remain largely unknown. We developed a novel grafting assay to test if lung epithelial progenitors are intrinsically programmed or if alveolar cell identity is determined by environmental factors. These experiments revealed that embryonic lung epithelial identity is extrinsically determined. We show that both glucocorticoid and STAT3 signalling can control the timing of alveolar initiation, but that neither pathway is absolutely required for alveolar fate specification; rather, glucocorticoid receptor and STAT3 work in parallel to promote alveolar differentiation. Thus, developmental acquisition of lung alveolar fate is a robust process controlled by at least two independent extrinsic signalling inputs. Further elucidation of these pathways might provide therapeutic opportunities for restoring alveolar capacity.
authors: Wellcome Trust/CRUK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Usua
authors: U
authors: Laresgoiti
authors: Wellcome Trust/CRUK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Marko Z
authors: 0000-0001-6304-6848
authors: MZ
authors: Nikolić
authors: Wellcome Trust/CRUK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Chandrika
authors: C
authors: Rao
authors: Wellcome Trust/CRUK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.
authors: Jane L
authors: JL
authors: Brady
authors: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors: Rachel V
authors: RV
authors: Richardson
authors: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors: Emma J
authors: EJ
authors: Batchen
authors: Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors: Karen E
authors: KE
authors: Chapman
authors: Wellcome Trust/CRUK Gurdon Institute, Wellcome Trust/MRC Stem Cell Institute, Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK e.rawlins@gurdon.cam.ac.uk.
authors: Emma L
authors: 0000-0001-7426-3792
authors: EL
authors: Rawlins
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D056809:Alveolar Epithelial Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D050796:STAT3 Transcription Factor; D015735:Mifepristone
keywords: Glucocorticoid; Human; Lung development; Mouse; STAT3