J Clin Invest. 2025 Jun 10:e188819. doi: 10.1172/JCI188819

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

Harshavardhana H Ediga¹, Chanukya P Vemulapalli¹, Vishwaraj Sontake², Pradeep K Patel¹, Hikaru Miyazaki², Dimitry Popov², Martin B Jensen², Anil G Jegga³, Steven K Huang⁴, Christoph Englert⁵, Andreas Schedl⁶, Nishant Gupta¹, Francis X McCormack¹, Satish K Madala⁷

Affiliations
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.

Abstract

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.

DOI: 10.1172/JCI188819