Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles
Tanyalak Parimon, Changfu Yao, David M. Habiel, Lingyin Ge, Stephanie A. Bora, Rena Brauer, Christopher M. Evans, Ting Xie, Felix Alonso-Valenteen, Lali K. Medina-Kauwe, Dianhua Jiang, Paul W. Noble, Cory M. Hogaboam, Nan Deng, Olivier Burgy, Travis J. Antes, Melanie Königshoff, Barry R. Stripp, Sina A. Gharib, Peter Chen
Tanyalak Parimon, Changfu Yao, David M. Habiel, Lingyin Ge, Stephanie A. Bora, Rena Brauer, Christopher M. Evans, Ting Xie, Felix Alonso-Valenteen, Lali K. Medina-Kauwe, Dianhua Jiang, Paul W. Noble, Cory M. Hogaboam, Nan Deng, Olivier Burgy, Travis J. Antes, Melanie Königshoff, Barry R. Stripp, Sina A. Gharib, Peter Chen
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Research Article Pulmonology

Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease. A maladaptive epithelium due to chronic injury is a prominent feature and contributor to pathogenic cellular communication in IPF. Recent data highlight the concept of a “reprogrammed” lung epithelium as critical in the development of lung fibrosis. Extracellular vesicles (EVs) are potent mediators of cellular crosstalk, and recent evidence supports their role in lung pathologies, such as IPF. Here, we demonstrate that syndecan-1 is overexpressed by the epithelium in the lungs of patients with IPF and in murine models after bleomycin injury. Moreover, we find that syndecan-1 is a profibrotic signal that alters alveolar type II cell phenotypes by augmenting TGF-β and Wnt signaling among other profibrotic pathways. Importantly, we demonstrate that syndecan-1 controls the packaging of several antifibrotic microRNAs into EVs that have broad effects over several fibrogenic signaling networks as a mechanism of regulating epithelial plasticity and pulmonary fibrosis. Collectively, our work reveals new insight into how EVs orchestrate cellular signals that promote lung fibrosis and demonstrate the importance of syndecan-1 in coordinating these programs.

Authors

Tanyalak Parimon, Changfu Yao, David M. Habiel, Lingyin Ge, Stephanie A. Bora, Rena Brauer, Christopher M. Evans, Ting Xie, Felix Alonso-Valenteen, Lali K. Medina-Kauwe, Dianhua Jiang, Paul W. Noble, Cory M. Hogaboam, Nan Deng, Olivier Burgy, Travis J. Antes, Melanie Königshoff, Barry R. Stripp, Sina A. Gharib, Peter Chen

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Figure 5

Syndecan-1 alters EV cargo to promote reprogramming of epithelial cells.

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Syndecan-1 alters EV cargo to promote reprogramming of epithelial cells....
MLE-12 cells were treated with fibrotic EVs isolated from WT and Sdc1–/– mice lungs injured with bleomycin. Cells were subsequently processed for RNA-Seq. (A) Heatmap of differentially expressed genes between MLE-12 cells treated with fibrotic EVs from bleomycin-injured WT and Sdc1–/– mice. (B) KEGG pathway analysis of differentially expressed genes in WT and Sdc1–/– fibrotic EV–treated cells. Bars indicate the number of genes in the pathway, and color indicates FDR level (only highly significant pathways with FDR < 0.0001 are presented). Furthermore, KEGG pathway analysis was performed for differentially expressed genes in ATII cells using a published data set from an scRNA-Seq evaluation of IPF versus control lungs (48). The hashed filling pattern indicates the identical KEGG pathway identified between analysis of the 2 scRNA-Seq data sets (EV-treated lung epithelial cells and ATII cells from patients with IPF). Please refer to Supplemental Table 3 for the complete KEGG analysis and gene lists. (C) Volcano plot of the FDR level versus magnitude of differentially expressed genes in WT and Sdc1–/– fibrotic EV–treated cells. Highly significant genes (FDR > 0.0001) pertinent to lung fibrosis were identified and notated in the graph and color-coded into groups consistent with their effect.