ResearchIn-Press PreviewPulmonology
Open Access |
10.1172/jci.insight.144652
1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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Smith, K.
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1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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1Department of Medicine, University of Minnesota, Minneapolis, United States of America
2Department of Pediatrics, University of Minnesota, Minneapolis, United States of America
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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
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.