Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.

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Publication Year:
2026
Authors:
Changfu Yao, Milena Espinola, Xue Liu, Yizhi Wang, Marilia Zuttion, Virinchi Kuchibhotla, Xuexi Zhang, Larissa Langhi Prata, Silvia Cho, Zackery Ortega, Emily Braghramian, Kimberly Merene, Ying Wang, Susan Jackman, Antonina Caudill, Fatima Contreras, Jiurong Liang, Dianhua Jiang, Paul W Noble, Cory M Hogaboam, Barry R Stripp, Cecilia Lopez-Martinez, Sina A Gharib, Amara Seng, Nunzio Bottini, William C Parks, Peter Chen, Tanyalak Parimon
PubMed ID:
41889838
Funding Grants:
Public Summary:
Idiopathic pulmonary fibrosis (IPF) is a severe, age-related lung disease where the lungs become heavily scarred and lose their ability to breathe. Normally, a specific group of lung cells—called AT2 cells—act like built-in repair mechanics that fix and rebuild the lungs when they get damaged. However, in IPF, these repair cells prematurely age, stop working, and start contributing to the scarring instead of fixing it. To find out why this happens, researchers looked at a specific surface protein called syndecan-1. They discovered that levels of this protein spike dramatically in the repair cells of older mice and human patients with lung fibrosis. By running lab tests and genetic studies, they found that too much syndecan-1 essentially forces the lung's repair cells to "retire" early (a process called senescence), stripping away their ability to multiply, heal, or produce the vital fluids that keep the lungs pliable. The good news is that when researchers genetically removed this protein in mice, the repair cells stayed healthy and were able to successfully fix the lung tissue after an injury. This suggests that creating a drug to block syndecan-1 could stop this destructive aging process in lung cells, offering a promising new way to treat or even reverse deadly lung scarring.
Scientific Abstract:
Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive, and fatal interstitial lung disease for which effective therapies remain limited. Alveolar type 2 (AT2) epithelial cells serve as facultative stem cells essential for alveolar repair; however, AT2 cell senescence disrupts epithelial regeneration and contributes to fibrotic remodeling in IPF. Syndecan-1 is a transmembrane heparan sulfate proteoglycan predominantly expressed by lung epithelial cells, but its role in AT2 dysfunction during fibrosis is poorly defined. Here, we demonstrate that syndecan-1 is robustly upregulated in AT2 cells in IPF and other fibrotic lung diseases, as well as in murine bleomycin-induced lung fibrosis. Syndecan-1 expression was further enhanced with aging and associated with increased fibrotic burden in aged mice. Using integrated human transcriptomic analyses, mouse genetic models, and epithelial cell-based systems, we show that excess syndecan-1 promotes cell-autonomous epithelial senescence and impairs AT2 progenitor function. Elevated syndecan-1 reduced AT2 renewal capacity, disrupted differentiation, and diminished surfactant protein C level, whereas genetic loss of syndecan-1 attenuated senescence and preserved epithelial function following injury. Together, these findings identify syndecan-1 as a critical epithelial regulator of AT2 senescence and maladaptive repair in pulmonary fibrosis and support targeting syndecan-1-driven epithelial dysfunction as a potential therapeutic strategy.