title: Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis.
abstract: Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for regeneration, humans with age-related chronic diseases, such as cancer and fibrosis, show evidence of a recapitulation of developmental gene programs. We have previously identified a resident population of mesenchymal stromal cells (MSCs) in the terminal airways-alveoli by bronchoalveolar lavage (BAL) of human adult lungs. In this study, we characterized MSCs from BAL of patients with stable and progressive idiopathic pulmonary fibrosis (IPF), defined as <5% and ≥10% decline, respectively, in forced vital capacity over the preceding 6-month period. Gene expression profiles of MSCs from IPF subjects with progressive disease were enriched for genes regulating lung development. Most notably, genes regulating early tissue patterning and branching morphogenesis were differentially regulated. Network interactive modeling of a set of these genes indicated central roles for TGF-β and SHH signaling. Importantly, fibroblast growth factor-10 (FGF-10) was markedly suppressed in IPF subjects with progressive disease, and both TGF-β1 and SHH signaling were identified as critical mediators of this effect in MSCs. These findings support the concept of developmental gene re-activation in IPF, and FGF-10 deficiency as a potentially critical factor in disease progression.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Diptiman
authors.initials: D
authors.lastname: Chanda
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kurundkar
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Sunad
authors.initials: S
authors.lastname: Rangarajan
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Locy
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Bernard
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Nirmal S
authors.initials: NS
authors.lastname: Sharma
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Logsdon
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Heflin Center for Genomic Science, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Crossman
authors.affiliation: Division of Pulmonary and Critical Care Medicine Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.affiliation: Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Stijn
authors.initials: S
authors.lastname: De Langhe
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
mesh_terms: D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D065150:Cellular Reprogramming; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D050437:Genes, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology*; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051526:Fibroblast Growth Factor 10; D053823:Hedgehog Proteins; D016212:Transforming Growth Factor beta