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ResearchIn-Press PreviewPulmonology Open Access | 10.1172/jci.insight.144652

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

Libang Yang,1 Hong Xia,1 Karen A. Smith,1 Adam Gilbertsen,1 Daniel Beisang,2 Jonathan Kuo,1 Peter B. Bitterman,1 and Craig A. Henke1

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Yang, L. in: PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Xia, H. in: PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Smith, K. in: PubMed | Google Scholar |

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Gilbertsen, A. in: PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Beisang, D. in: PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Kuo, J. in: PubMed | Google Scholar

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Bitterman, P. in: PubMed | Google Scholar |

1Department of Medicine, University of Minnesota, Minneapolis, United States of America

2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America

Find articles by Henke, C. in: PubMed | Google Scholar

Published April 6, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.144652.
Copyright © 2021, Yang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 6, 2021 - Version history
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Abstract

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease. We previously identified fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients that serve as an obligatory driver 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 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 knock-down of CD44 diminishes their fibrogenicity. CD44hi IPF MPCs display increased expression of pluripotency markers and self-renewal compared to 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 BRG1 and the Zeb1 transcription factor. This CD44/BRG1/Zeb1 nuclear protein complex targets the Sox2 gene promoting its upregulation and self-renewal. Our data implicates CD44 interaction with the epigenetic modulator protein Brg1 in conveying IPF MPCs with cell-autonomous fibrogenicity.

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  • Version 1 (April 6, 2021): In-Press Preview
  • Version 2 (May 10, 2021): Electronic publication

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