Author
Listed:
- Yinshan Fang
(Columbia University Irving Medical Center)
- Sanny S. W. Chung
(Columbia University Irving Medical Center)
- Le Xu
(University of California San Diego)
- Chenyi Xue
(Columbia University Irving Medical Center)
- Xue Liu
(Cedars-Sinai Medical Center)
- Dianhua Jiang
(Cedars-Sinai Medical Center)
- Rongbo Li
(University of California San Diego)
- Yohei Korogi
(University of California San Diego)
- Ke Yuan
(Boston Children’s Hospital and Harvard Medical School)
- Anjali Saqi
(Columbia University Irving Medical Center)
- Hanina Hibshoosh
(Columbia University Irving Medical Center)
- Yuefeng Huang
(Columbia University)
- Chyuan-Sheng Lin
(Columbia University)
- Tatsuya Tsukui
(University of California San Francisco)
- Dean Sheppard
(University of California San Francisco)
- Xin Sun
(University of California San Diego)
- Jianwen Que
(Columbia University Irving Medical Center)
Abstract
A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix1–3. Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR+ fibroblasts that arise during alveologenesis include SCUBE2+ alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1+POSTN+ pathological fibroblasts. Genetic ablation of POSTN+ pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with LeprcreERT2 or Scube2creERT2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR+ cells that include SCUBE2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.
Suggested Citation
Yinshan Fang & Sanny S. W. Chung & Le Xu & Chenyi Xue & Xue Liu & Dianhua Jiang & Rongbo Li & Yohei Korogi & Ke Yuan & Anjali Saqi & Hanina Hibshoosh & Yuefeng Huang & Chyuan-Sheng Lin & Tatsuya Tsuku, 2025.
"RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition,"
Nature, Nature, vol. 640(8057), pages 221-230, April.
Handle:
RePEc:nat:nature:v:640:y:2025:i:8057:d:10.1038_s41586-024-08542-2
DOI: 10.1038/s41586-024-08542-2
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