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Regulating the cell shift of endothelial cell-like myofibroblasts in pulmonary fibrosis
Xiuju Wu1,2, Daoqin Zhang3,2, Xiaojing Qiao1
1Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Abstract:
Pulmonary fibrosis is a common and severe fibrotic lung disease with high morbidity and mortality. Recent studies have reported a large number of unwanted myofibroblasts appearing in pulmonary fibrosis, and shown that the sustained activation of myofibroblasts is essential for unremitting interstitial fibrogenesis. However, the origin of these myofibroblasts remains poorly understood. Here, we create new mouse models of pulmonary fibrosis and identify a previously unknown population of endothelial cell (EC)-like myofibroblasts in normal lung tissue. We show that these EC-like myofibroblasts significantly contribute myofibroblasts to pulmonary fibrosis, which is confirmed by single-cell RNA sequencing of human pulmonary fibrosis. Using the transcriptional profiles, we identified a small molecule that redirects the differentiation of EC-like myofibroblasts and reduces pulmonary fibrosis in our mouse models. Our study reveals the mechanistic underpinnings of the differentiation of EC-like myofibroblasts in pulmonary fibrosis and may provide new strategies for therapeutic interventions.
Insights
Researchers discovered a new source of myofibroblasts in pulmonary fibrosis originating from endothelial cells (EC). A novel small molecule therapy targeting these EC-like myofibroblasts effectively reduced fibrosis in mouse models, offering new therapeutic avenues.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Fibrotic Diseases
Background:
- Pulmonary fibrosis is a severe lung disease characterized by high mortality.
- Sustained myofibroblast activation drives interstitial fibrogenesis in pulmonary fibrosis.
- The origin of the increased myofibroblasts in pulmonary fibrosis is not well understood.
Purpose of the Study:
- To investigate the origin of myofibroblasts in pulmonary fibrosis.
- To identify novel therapeutic targets for pulmonary fibrosis.
Main Methods:
- Development of novel mouse models for pulmonary fibrosis.
- Single-cell RNA sequencing of human pulmonary fibrosis samples.
- Identification and testing of a small molecule inhibitor.
Main Results:
- A previously unrecognized population of endothelial cell (EC)-like myofibroblasts was identified in normal lung tissue.
- These EC-like myofibroblasts were confirmed to contribute significantly to pulmonary fibrosis in both mouse models and human samples.
- A small molecule was identified that redirects EC-like myofibroblast differentiation and ameliorates pulmonary fibrosis in mice.
Conclusions:
- Endothelial cells are a significant source of myofibroblasts in pulmonary fibrosis.
- Targeting EC-like myofibroblast differentiation presents a promising therapeutic strategy for pulmonary fibrosis.
- This study elucidates the mechanistic basis of EC-like myofibroblast differentiation in fibrotic lung disease.
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