PEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis.
Yan GengLin LiJie YanKevin LiuAizhen YangLin ZhangYingzhi ShenHan GaoXuefeng WuImre NothYong HuangJunling LiuXuemei FanPublished in: Nature communications (2022)
Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1 -/- fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.
Keyphrases
- pulmonary fibrosis
- extracellular matrix
- rna seq
- single cell
- systemic sclerosis
- interstitial lung disease
- idiopathic pulmonary fibrosis
- respiratory failure
- high glucose
- stem cells
- multiple sclerosis
- drug induced
- bone marrow
- pulmonary hypertension
- rheumatoid arthritis
- type diabetes
- diabetic rats
- signaling pathway
- insulin resistance
- metabolic syndrome
- mouse model
- binding protein
- endothelial cells
- amino acid
- mesenchymal stem cells
- cell therapy
- wild type