# Microenvironmental niches dictate divergent fibroblast fates in reversible versus progressive lung fibrosis

## TL;DR

This study shows how different lung environments shape fibroblast behavior, leading to either reversible or progressive lung fibrosis.

## Contribution

The paper identifies disease-specific microenvironmental niches that determine fibroblast fate in different lung diseases.

## Key findings

- OP shows GC-responsive niches with apoptosis-prone fibroblasts, suggesting reversibility.
- IPF features glucocorticoid-resistant myofibroblasts and strong matrix activity, indicating progressive fibrosis.
- CTD-ILD is marked by macrophage-rich niches and multinucleated giant cells, showing immune-driven fibrosis.

## Abstract

Fibroblast behaviour is a key determinant of outcomes in interstitial lung diseases (ILDs), yet mechanisms governing the switch between reversible repair and progressive fibrosis remain unclear. How disease-specific cellular niches shape fibroblast fate across ILD phenotypes has not been compared in situ.

We profiled peripheral lung tissues from controls, organising pneumonia (OP), connective tissue disease–associated ILD (CTD-ILD), and idiopathic pulmonary fibrosis (IPF) using High-Definition Visium spatial transcriptomics. A matched single-cell RNA-seq atlas was integrated via robust cell-type deconvolution to map cellular neighbourhoods. Differential expression and pathway activity were validated by immunofluorescence. Predicted ligand–receptor mechanisms and fibroblast responses were tested in vitro under glucocorticoid (GC), TGF-β1, and B-cell/MIF perturbations with receptor blockade.

Disease-specific niches were tightly coupled to fibroblast states. OP exhibited B-cell–AT2–myofibroblast–enriched niches with high GC responsiveness and apoptosis. IPF was dominated by bronchiolised epithelium, alongside myofibroblasts exhibiting glucocorticoid resistance and strong matrix programmes. CTD-ILD exhibited macrophage-rich niches with multinucleated giant cells. In vitro, GC induced NR3C1-mediated apoptosis in fibroblasts, whereas TGF-β1 drove a senescent, GC-resistant phenotype. IgD + B-cell-derived MIF enhanced fibroblast migration via CD74, an effect blunted by TGF-β1. Thus, niche composition dictates fibroblast fate, distinguishing GC-sensitive resolution from apoptosis-resistant fibrosis.

A GC-sensitive, apoptosis-prone myofibroblast niche in OP may underpin reversibility, whereas CTD-ILD and IPF follow distinct trajectories driven by immune dysregulation and epithelial–stromal maladaptation. These spatial microenvironmental signatures nominate therapeutic targets and may inform precision therapy for fibrotic lung disease.

The 10.13039/501100001809National Natural Science Foundation of China (82172109 to L.X., 82570001 to H.C.), the 10.13039/501100002855Ministry of Science and Technology of the People's Republic of China (2023YFC3502605, 2024YFA1108906) (H.C.), the 10.13039/501100006606Natural Science Foundation of Tianjin, China (25JCZDJC01260) (H.C.); the Key Laboratory of Medical Rescue Key Technology and Equipment, 10.13039/100020763Ministry of Emergency Management (Open Fund Project No. YJBKFKT202410).