title: Origin and characterization of alpha smooth muscle actin-positive cells during murine lung development.
abstract: ACTA2 expression identifies pulmonary airway and vascular smooth muscle cells (SMCs) as well as alveolar myofibroblasts (MYF). Mesenchymal progenitors expressing fibroblast growth factor 10 (Fgf10), Wilms tumor 1 (Wt1), or glioma-associated oncogene 1 (Gli1) contribute to SMC formation from early stages of lung development. However, their respective contribution and specificity to the SMC and/or alveolar MYF lineages remain controversial. In addition, the contribution of mesenchymal cells undergoing active WNT signaling remains unknown. Using Fgf10CreERT2, Wt1CreERT2, Gli1CreERT2, and Axin2CreERT2inducible driver lines in combination with a tdTomatofloxreporter line, the respective differentiation of each pool of labeled progenitor cells along the SMC and alveolar MYF lineages was quantified. The results revealed that while FGF10+and WT1+cells show a minor contribution to the SMC lineage, GLI1+and AXIN2+cells significantly contribute to both the SMC and alveolar MYF lineages, but with limited specificity. Lineage tracing using the Acta2-CreERT2 transgenic line showed that ACTA2+cells labeled at embryonic day (E)11.5 do not expand significantly to give rise to new SMCs at E18.5. However, ACTA2+cells labeled at E15.5 give rise to the majority (85%-97%) of the SMCs in the lung at E18.5 as well as alveolar MYF progenitors in the lung parenchyma. Fluorescence-activated cell sorting-based isolation of different subpopulations of ACTA2+lineage-traced cells followed by gene arrays, identified transcriptomic signatures for alveolar MYF progenitors versus airway and vascular SMCs at E18.5. Our results establish a new transcriptional landscape for further experiments addressing the function of signaling pathways in the formation of different subpopulations of ACTA2+cells. Stem Cells 2017;35:1566-1578.
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Moiseenko
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Vahid
authors.initials: V
authors.lastname: Kheirollahi
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Chao
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Negah
authors.initials: N
authors.lastname: Ahmadvand
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Quantius
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Bad Nauheim, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ahlbrecht
authors.affiliation: Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Bad Nauheim, Germany.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.affiliation: Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Rizvanov
authors.affiliation: Department of Pediatrics, Division of Newborn Medicine, University of Southern California, Childrens Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Elie
authors.initials: E
authors.lastname: El Agha
authors.affiliation: Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Giessen and Marburg Lung Center (UGMLC), Justus Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
authors.forename: Saverio
authors.identifier: 0000-0002-1164-3795
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D019070:Cell Lineage; D002469:Cell Separation; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000196:embryology; D051379:Mice; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology; D015398:Signal Transduction / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D051526:Fibroblast Growth Factor 10; C498520:Gli1 protein, mouse; D000071676:Zinc Finger Protein GLI1
keywords: Alveolar myofibroblast; Lineage tracing; Lung; Lung development; Smooth muscle cell