title: ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling.
abstract: Genesis of myofibroblasts is obligatory for the development of pathology in many adult lung diseases. Adult lung tissue contains a population of perivascular ABCG2(pos) mesenchymal stem cells (MSC) that are precursors of myofibroblasts and distinct from NG2 pericytes. We hypothesized that these MSC participate in deleterious remodeling associated with pulmonary fibrosis (PF) and associated hypertension (PH). To test this hypothesis, resident lung MSC were quantified in lung samples from control subjects and PF patients. ABCG2(pos) cell numbers were decreased in human PF and interstitial lung disease compared with control samples. Genetic labeling of lung MSC in mice enabled determination of terminal lineage and localization of ABCG2 cells following intratracheal administration of bleomycin to elicit fibrotic lung injury. Fourteen days following bleomycin injury enhanced green fluorescent protein (eGFP)-labeled lung MSC-derived cells were increased in number and localized to interstitial areas of fibrotic and microvessel remodeling. Finally, gene expression analysis was evaluated to define the response of MSC to bleomycin injury in vivo using ABCG2(pos) MSC isolated during the inflammatory phase postinjury and in vitro bleomycin or transforming growth factor-β1 (TGF-β1)-treated cells. MSC responded to bleomycin treatment in vivo with a profibrotic gene program that was not recapitulated in vitro with bleomycin treatment. However, TGF-β1 treatment induced the appearance of a profibrotic myofibroblast phenotype in vitro. Additionally, when exposed to the profibrotic stimulus, TGF-β1, ABCG2, and NG2 pericytes demonstrated distinct responses. Our data highlight ABCG2(pos) lung MSC as a novel cell population that contributes to detrimental myofibroblast-mediated remodeling during PF.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Shennea
authors.initials: S
authors.lastname: Marriott
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennesse;
authors.forename: Rubin S
authors.initials: RS
authors.lastname: Baskir
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Christa
authors.initials: C
authors.lastname: Gaskill
authors.affiliation: Pulmonary Vascular Research Institute Kochi and AnalyzeDat Consulting Services, Kerala, India;
authors.forename: Swapna
authors.initials: S
authors.lastname: Menon
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Carrier
authors.affiliation: Vanderbilt Ingram Cancer Center, Electron Microscopy-Cell Imaging Shared Resource, Vanderbilt University, Nashville, Tennessee;
authors.forename: Janice
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Megha
authors.initials: M
authors.lastname: Talati
authors.affiliation: Cancer Center Flow Cytometry Shared Resource, University of Colorado, Aurora, Colorado.
authors.forename: Karen
authors.initials: K
authors.lastname: Helm
authors.affiliation: Department of Pathology and Laboratory Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee;
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Alford
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kropski
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: James
authors.initials: J
authors.lastname: Loyd
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Lisa
authors.initials: L
authors.lastname: Wheeler
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee;
authors.forename: Joyce
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee;
authors.forename: Eric
authors.initials: E
authors.lastname: Austin
authors.affiliation: Department of Pediatrics or Medicine, Pulmonary and Critical Care Medicine, Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado; and.
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse;
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyrick
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse; Vanderbilt Pulmonary Circulation Center, Vanderbilt University, Nashville, Tennessee;
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.affiliation: Department of Pediatrics or Medicine, Pulmonary and Critical Care Medicine, Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado, Aurora, Colorado; and.
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennesse; Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Pulmonary Circulation Center, Vanderbilt University, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennesse; Susan.M.Majka@Vanderbilt.Edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Majka
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D058628:Myofibroblasts / Q000502:physiology; D009363:Neoplasm Proteins / Q000378:metabolism*; D020286:Pericytes / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: ABCG2; fibrosis; lung MSC; myofibroblast; pericyte