Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis

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 progr...

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Veröffentlicht in:Scientific reports Jg. 6; H. 1; S. 37445
Hauptverfasser: Chanda, Diptiman, Kurundkar, Ashish, Rangarajan, Sunad, Locy, Morgan, Bernard, Karen, Sharma, Nirmal S., Logsdon, Naomi J., Liu, Hui, Crossman, David K., Horowitz, Jeffrey C., De Langhe, Stijn, Thannickal, Victor J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 21.11.2016
Nature Publishing Group
Schlagworte:
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14/63
38/77
631/532/7
631/553/2711
692/699/1785/3193
82/1
82/29
82/51
Age
Alveoli
Bronchoalveolar Lavage Fluid - cytology
Bronchus
Cancer
Cellular Reprogramming
Disease
Disease Progression
Down-Regulation - genetics
Fibroblast growth factor 10
Fibroblast Growth Factor 10 - metabolism
Fibrosis
Gene expression
Gene Expression Profiling
Gene Regulatory Networks
Genes, Developmental
Hedgehog Proteins - metabolism
Humanities and Social Sciences
Humans
Idiopathic Pulmonary Fibrosis - genetics
Idiopathic Pulmonary Fibrosis - pathology
Immunohistochemistry
Lung - pathology
Lung diseases
Mesenchymal stem cells
Mesenchymal Stem Cells - metabolism
Mesenchymal Stem Cells - pathology
Mesenchyme
Morphogenesis
multidisciplinary
Pattern formation
Pulmonary fibrosis
Reproducibility of Results
Science
Signal Transduction - genetics
Species diversity
Stromal cells
Transforming Growth Factor beta - metabolism
Transforming growth factor-b1
Up-Regulation - genetics
ISSN:2045-2322, 2045-2322
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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.
AbstractList 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.
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.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.
ArticleNumber 37445
Author Crossman, David K.
Bernard, Karen
Kurundkar, Ashish
Rangarajan, Sunad
Logsdon, Naomi J.
Locy, Morgan
De Langhe, Stijn
Sharma, Nirmal S.
Liu, Hui
Horowitz, Jeffrey C.
Chanda, Diptiman
Thannickal, Victor J.
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  fullname: Chanda, Diptiman
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  givenname: Ashish
  surname: Kurundkar
  fullname: Kurundkar, Ashish
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  givenname: Sunad
  surname: Rangarajan
  fullname: Rangarajan, Sunad
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  givenname: Morgan
  surname: Locy
  fullname: Locy, Morgan
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  surname: Bernard
  fullname: Bernard, Karen
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  givenname: Naomi J.
  surname: Logsdon
  fullname: Logsdon, Naomi J.
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  givenname: Hui
  surname: Liu
  fullname: Liu, Hui
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
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  givenname: David K.
  surname: Crossman
  fullname: Crossman, David K.
  organization: Department of Genetics, Heflin Center for Genomic Science, University of Alabama at Birmingham
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  givenname: Jeffrey C.
  surname: Horowitz
  fullname: Horowitz, Jeffrey C.
  organization: Division of Pulmonary and Critical Care Medicine Department of Internal Medicine, University of Michigan
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  surname: De Langhe
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  givenname: Victor J.
  surname: Thannickal
  fullname: Thannickal, Victor J.
  organization: Division of Pulmonary, Department of Medicine, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27869174$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright The Author(s) 2016
Copyright Nature Publishing Group Nov 2016
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Snippet Cellular plasticity and de-differentiation are hallmarks of tissue/organ regenerative capacity in diverse species. Despite a more restricted capacity for...
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SubjectTerms 13/106
14/63
38/77
631/532/7
631/553/2711
692/699/1785/3193
82/1
82/29
82/51
Age
Alveoli
Bronchoalveolar Lavage Fluid - cytology
Bronchus
Cancer
Cellular Reprogramming
Disease
Disease Progression
Down-Regulation - genetics
Fibroblast growth factor 10
Fibroblast Growth Factor 10 - metabolism
Fibrosis
Gene expression
Gene Expression Profiling
Gene Regulatory Networks
Genes, Developmental
Hedgehog Proteins - metabolism
Humanities and Social Sciences
Humans
Idiopathic Pulmonary Fibrosis - genetics
Idiopathic Pulmonary Fibrosis - pathology
Immunohistochemistry
Lung - pathology
Lung diseases
Mesenchymal stem cells
Mesenchymal Stem Cells - metabolism
Mesenchymal Stem Cells - pathology
Mesenchyme
Morphogenesis
multidisciplinary
Pattern formation
Pulmonary fibrosis
Reproducibility of Results
Science
Signal Transduction - genetics
Species diversity
Stromal cells
Transforming Growth Factor beta - metabolism
Transforming growth factor-b1
Up-Regulation - genetics
Title Developmental Reprogramming in Mesenchymal Stromal Cells of Human Subjects with Idiopathic Pulmonary Fibrosis
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