A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis

Libang Yang, Hong Xia, Karen Smith, Adam Gilbertsen, Daniel Beisang, Jonathan Kuo, Peter B. Bitterman, Craig A. Henke

Research output: Contribution to journalArticlepeer-review

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease. We previously identified fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of patients with IPF who serve as drivers of progressive fibrosis. Recent single-cell RNA sequencing work revealed that IPF MPCs with the highest transcriptomic network entropy differ the most from control MPCs and that increased CD44 was a marker of these IPF MPCs. We hypothesize that IPF MPCs with high CD44 (CD44hi) expression will display enhanced fibrogenicity. We demonstrate that CD44-expressing MPCs are present at the periphery of the IPF fibroblastic focus, placing them in regions of active fibrogenesis. In a humanized mouse xenograft model, CD44hi IPF MPCs are more fibrogenic than CD44lo IPF MPCs, and knockdown of CD44 diminishes their fibrogenicity. CD44hi IPF MPCs display increased expression of pluripotency markers and enhanced self-renewal compared with CD44lo IPF MPCs, properties potentiated by IL-8. The mechanism involves the accumulation of CD44 within the nucleus, where it associates with the chromatin modulator protein Brahma-related gene 1 (Brg1) and the zinc finger E-box binding homeobox 1 (Zeb1) transcription factor. This CD44/Brg1/Zeb1 nuclear protein complex targets the Sox2 gene, promoting its upregulation and self-renewal. Our data implicate CD44 interaction with the epigenetic modulator protein Brg1 in conveying IPF MPCs with cell-autonomous fibrogenicity.

Original languageEnglish (US)
Article numbere144652
JournalJCI Insight
Volume6
Issue number9
DOIs
StatePublished - May 10 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants R01 HL125227 to CAH; F32 HL145988 to D.B and R01 HL125236 to PBB and funds provided by the O’Brien and Witowski families.

Funding Information:
We would like to acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598, BIONET (the University of Minnesota Tissue procurement service) and the University of Minnesota Imaging Center. We also acknowledge the Center for Mass Spectrometry and Proteomics. This work was supported by National Institutes of Health grants R01 HL125227 to CAH; F32 HL145988 to D.B and R01 HL125236 to PBB and funds provided by the O?Brien and Witowski families.

Funding Information:
We would like to acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598, BIONET (the University of Minnesota Tissue procurement service) and the University of Minnesota Imaging Center. We also acknowledge the Center for Mass Spectrometry and Proteomics.

Publisher Copyright:
© 2021, Yang et al.

PubMed: MeSH publication types

  • Journal Article

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