Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis
Hong Xia, … , Peter B. Bitterman, Craig A. Henke
Hong Xia, … , Peter B. Bitterman, Craig A. Henke
Published May 22, 2017
Citation Information: J Clin Invest. 2017;127(7):2586-2597. https://doi.org/10.1172/JCI90832.
View: Text | PDF
Research Article Pulmonology

Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis

  • Text
  • PDF
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a prevalence of 1 million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli and leads to death by asphyxiation. We previously discovered that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs) that serve as a cell of origin for disease-mediating myofibroblasts. In a prior genomewide transcriptional analysis, we found that IPF MPCs displayed increased expression of S100 calcium-binding A4 (S100A4), a protein linked to cancer cell proliferation and invasiveness. Here, we have examined whether S100A4 mediates MPC fibrogenicity. Ex vivo analysis revealed that IPF MPCs had increased levels of nuclear S100A4, which interacts with L-isoaspartyl methyltransferase to promote p53 degradation and MPC self-renewal. In vivo, injection of human IPF MPCs converted a self-limited bleomycin-induced mouse model of lung fibrosis to a model of persistent fibrosis in an S100A4-dependent manner. S100A4 gain of function was sufficient to confer fibrotic properties to non-IPF MPCs. In IPF tissue, fibroblastic foci contained cells expressing Ki67 and the MPC markers SSEA4 and S100A4. The expression colocalized in an interface region between myofibroblasts in the focus core and normal alveolar structures, defining this region as an active fibrotic front. Our findings indicate that IPF MPCs are intrinsically fibrogenic and that S100A4 confers MPCs with fibrogenicity.

Authors

Hong Xia, Adam Gilbertsen, Jeremy Herrera, Emilian Racila, Karen Smith, Mark Peterson, Timothy Griffin, Alexey Benyumov, Libang Yang, Peter B. Bitterman, Craig A. Henke

×

Figure 1

IPF MPCs display increased S100A4, which localizes to the nucleus.

Options: View larger image (or click on image) Download as PowerPoint
IPF MPCs display increased S100A4, which localizes to the nucleus.
(A) G...
(A) Genome-wide RNA sequencing data. Shown is the heatmap for S100A4 gene expression in IPF and control MPCs derived from 3 IPF patients and 3 control patients based on our previously published data (14). Colors represent per gene Z score (expression difference normalized for standard deviation). (B) Validation testing for S100A4 mRNA expression in IPF and control MPCs. Shown are relative expression levels of each mRNA by qPCR. Data shown represents the mean mRNA levels in IPF MPCs derived from 3 cell lines. (C) Immunocytochemical analysis illustrating S100A4 location in IPF and control colony-forming MPCs (red, S100A4; blue, DAPI; n = 3). Scale bar: 5 μm. (D) Western blot analysis of S100A4 expression in nuclear (N) and cytoplasmic (C) fractions of IPF and control MPCs. Lamin A/C and GAPDH were used as loading controls. Data are expressed as mean ± SEM. P value in B was determined by 2-tailed Student’s t test.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts