# Non-Canonical Wnt11 Signaling Regulates Pulmonary Fibrosis via Fibroblast and Alveolar Epithelial Type II Cell Crosstalk

## TL;DR

This study shows that non-canonical Wnt11 signaling contributes to lung fibrosis by promoting myofibroblast differentiation through interactions with epithelial cells.

## Contribution

The study identifies a novel regulatory role of non-canonical Wnt11 signaling in pulmonary fibrosis via fibroblast-epithelial cell communication.

## Key findings

- Non-canonical Wnt pathway components are upregulated in bleomycin-induced pulmonary fibrosis.
- Wnt11 depletion in mouse lung fibroblasts reduces lung fibrosis.
- TGFβ increases Wnt11 transcription via Smad3 binding in human lung fibroblasts.

## Abstract

The reactivation of Wnt signaling pathways plays an important role in driving myofibroblast differentiation in fibrotic diseases; however, the mechanism is not clearly understood. In this study, we investigate the role of non-canonical Wnt11 signaling in human lung fibroblasts and its contributions to myofibroblast differentiation. Our results show that components of the non-canonical Wnt pathway are upregulated in bleomycin-induced pulmonary fibrosis and that in vivo depletion of Wnt11 in mouse lung fibroblasts significantly reduces lung fibrosis. Furthermore, co-culture studies using fibroblasts and alveolar type II epithelial cells (AECII) revealed a Wnt11-mediated mechanism that promotes myofibroblast differentiation. Finally, we demonstrate that in human lung fibroblasts, TGFβ can increases Wnt11 transcription by regulating Smad3 binding to the Wnt11 promoter and by modulating Wnt11 promoter activity. Together, these findings identify non-canonical Wnt11 as a regulator of myofibroblast differentiation and lung fibrosis.