PU.1 controls fibroblast polarization and tissue fibrosis

Thomas Wohlfahrt, Simon Rauber, Steffen Uebe, Markus Luber, Alina Soare, Arif Ekici, Stefanie Weber, Alexandru Emil Matei, Chih Wei Chen, Christiane Maier, Emmanuel Karouzakis, Hans P. Kiener, Elena Pachera, Clara Dees, Christian Beyer, Christoph Daniel, Kolja Gelse, Andreas E. Kremer, Elisabeth Naschberger, Michael StürzlFalk Butter, Michael Sticherling, Susetta Finotto, Alexander Kreuter, Mark H. Kaplan, Astrid Jüngel, Steffen Gay, Stephen L. Nutt, David W. Boykin, Gregory M.K. Poon, Oliver Distler, Georg Schett, Jörg H.W. Distler, Andreas Ramming

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.

Original languageEnglish (US)
Pages (from-to)344-349
Number of pages6
JournalNature
Volume566
Issue number7744
DOIs
StatePublished - Feb 21 2019

ASJC Scopus subject areas

  • General

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    Wohlfahrt, T., Rauber, S., Uebe, S., Luber, M., Soare, A., Ekici, A., Weber, S., Matei, A. E., Chen, C. W., Maier, C., Karouzakis, E., Kiener, H. P., Pachera, E., Dees, C., Beyer, C., Daniel, C., Gelse, K., Kremer, A. E., Naschberger, E., ... Ramming, A. (2019). PU.1 controls fibroblast polarization and tissue fibrosis. Nature, 566(7744), 344-349. https://doi.org/10.1038/s41586-019-0896-x