Wilms’ tumor 1 impairs apoptotic clearance of fibroblasts in distal fibrotic lung lesions

Harshavardhana H. Ediga; Chanukya P. Vemulapalli; Vishwaraj Sontake; Pradeep K. Patel; Hikaru Miyazaki; Dimitry Popov; Martin B. Jensen; Anil G. Jegga; Steven K. Huang; Christoph Englert; Andreas Schedl; Nishant Gupta; Francis X. McCormack; Satish K. Madala

doi:10.1172/JCI188819

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

Find articles by Huang, S. in: PubMed | Google Scholar |

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

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

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

Find articles by Gupta, N. in: PubMed | Google Scholar |

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

Find articles by McCormack, F. in: PubMed | Google Scholar |

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinnati, Cincinnati, United States of America

²Gordian Biotechnology, San Francisco, United States of America

³Division of Biomedical Informatics, Cincinnati Children Hospital Medical Center, Cincinnati, United States of America

⁴Division of Pulmonary and Critical Care Medicine, Department of Internal Me, University of Michigan Medical School, Ann Arbor, United States of America

⁵Molecular Genetics Lab, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany

⁶Institute of Biology Valrose, University of Sophia-Antipolis, Nice, France

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Inte, University of Cincinanti, Cincinnati, United States of America

Find articles by Madala, S. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI188819.
Copyright © 2025, Ediga 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 June 10, 2025 - Version history

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease characterized by impaired fibroblast clearance and excessive extracellular matrix (ECM) protein production. Wilms' Tumor 1 (WT1), a transcription factor, is selectively upregulated in IPF fibroblasts. However, the mechanisms by which WT1 contributes to fibroblast accumulation and ECM production remain unknown. Here, we investigated the heterogeneity of WT1-expressing mesenchymal cells using single-nucleus RNA sequencing of distal lung tissues from IPF patients and control donors. WT1 was selectively upregulated in a subset of IPF fibroblasts that co-expressed several pro-survival and ECM genes. The results of both loss-of-function and gain-of-function studies are consistent with a role for WT1 as a positive regulator of pro-survival genes to impair apoptotic clearance and promote ECM production. Fibroblast-specific overexpression of WT1 augmented fibroproliferation, myofibroblast accumulation, and ECM production during bleomycin-induced pulmonary fibrosis in young and aged mice. Together, these findings suggest that targeting WT1 is a promising strategy for attenuating fibroblast expansion and ECM production during fibrogenesis.

Wilms’ tumor 1 impairs apoptotic clearance of fibroblasts in distal fibrotic lung lesions

Harshavardhana H. Ediga,¹ Chanukya P. Vemulapalli,¹ Vishwaraj Sontake,² Pradeep K. Patel,¹ Hikaru Miyazaki,² Dimitry Popov,² Martin B. Jensen,² Anil G. Jegga,³ Steven K. Huang,⁴ Christoph Englert,⁵ Andreas Schedl,⁶ Nishant Gupta,¹ Francis X. McCormack,¹ and Satish K. Madala⁷

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Wilms’ tumor 1 impairs apoptotic clearance of fibroblasts in distal fibrotic lung lesions

Harshavardhana H. Ediga,1 Chanukya P. Vemulapalli,1 Vishwaraj Sontake,2 Pradeep K. Patel,1 Hikaru Miyazaki,2 Dimitry Popov,2 Martin B. Jensen,2 Anil G. Jegga,3 Steven K. Huang,4 Christoph Englert,5 Andreas Schedl,6 Nishant Gupta,1 Francis X. McCormack,1 and Satish K. Madala7

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Harshavardhana H. Ediga,¹ Chanukya P. Vemulapalli,¹ Vishwaraj Sontake,² Pradeep K. Patel,¹ Hikaru Miyazaki,² Dimitry Popov,² Martin B. Jensen,² Anil G. Jegga,³ Steven K. Huang,⁴ Christoph Englert,⁵ Andreas Schedl,⁶ Nishant Gupta,¹ Francis X. McCormack,¹ and Satish K. Madala⁷