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

The Journal of Clinical Investigation
Hong XiaCraig A Henke

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 be...Continue Reading

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Citations

May 2, 2018·American Journal of Respiratory Cell and Molecular Biology·Peter Bitterman
Apr 11, 2018·American Journal of Respiratory and Critical Care Medicine·Milena S EspindolaCory M Hogaboam
Mar 27, 2018·American Journal of Respiratory and Critical Care Medicine·Jeremy HerreraPeter B Bitterman
Oct 10, 2019·Respirology : Official Journal of the Asian Pacific Society of Respirology·Norimichi AkiyamaTakafumi Suda
Oct 8, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Carlo MümmlerMelanie Königshoff
Sep 2, 2017·American Journal of Physiology. Lung Cellular and Molecular Physiology·Libang YangCraig A Henke
Apr 21, 2020·Journal of Cellular and Molecular Medicine·Zhenzhen LiZhihai Qin
Jan 3, 2018·The Journal of Clinical Investigation·Jeremy HerreraPeter B Bitterman
Feb 12, 2020·Nature Medicine·Ashley M LaughneyJoan Massagué
Aug 8, 2020·EMBO Molecular Medicine·Rajesh K KasamSatish K Madala
Nov 18, 2020·International Journal of Molecular Sciences·Veronika SimkoJaromir Pastorek
Jan 14, 2021·Seminars in Arthritis and Rheumatism·B WuM Kapoor
Mar 16, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Hong XiaCraig A Henke
Jul 3, 2021·International Journal of Molecular Sciences·Tanyalak ParimonChangfu Yao

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Datasets Mentioned

BETA
GSE97038

Methods Mentioned

BETA
immunoprecipitation
ubiquitination
PCR
xenograft
FCS
flow cytometry

Software Mentioned

Peaks Studio
LightCycler

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