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 6

Syndecan-1 controls packaging of antifibrotic miRNAs into EVs.

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Syndecan-1 controls packaging of antifibrotic miRNAs into EVs. WT and Sd...
WT and Sdc1–/– mice were injured with bleomycin (0.75 unit/kg) and sacrificed 21 days after injury. Fibrotic EVs were collected from the airspaces, and miRNAs were isolated for RNA-Seq. (A) Analysis of the miRNA levels within fibrotic EVs from bleomycin-injured WT and Sdc1–/– mice identified significant differences in 5 miRNAs. (B) Predicted miR-34b-5p binding site in the Muc5b 3′ UTR region was identified with http://www.microrna.org/microrna/home.do (C) Muc5b dot blot of MLE-12 cells transfected with control and miR-34b-5p mimics. (D) Luciferase activity of HEK cells transfected with a reporter plasmid containing a chimeric firefly luciferase with the Muc5b 3′ UTR and either a control or miR-34b-5p. *P < 0.05; Fluc/Rluc (firefly luciferase/renilla luciferase). (E) Predicted miR-144-3p binding site in the Tgfbr1 3′ UTR region was identified with http://www.microrna.org/microrna/home.do (F) Tgfbr1 immunoblot of MLE-12 cells transfected with the control or miR-144-3p mimics. (G) Luciferase activity of HEK cells transfected with a reporter plasmid containing a chimeric firefly luciferase with the Tgfbr1 3′ UTR and either a control or miR-144-3p. *P < 0.05. (H) TGF-β signaling regulatory network of experimentally identified targets of miR-34b-5p (blue), miR-503-5p (purple), miR-144-3p (brick red), and miR-142-3p (orange). These curated targets were experimentally validated either by UTR analysis (closed circle) or with pull-down methods (dotted circle). (I) Immunoblot for phosphorylated SMAD2 and SMAD2 using MLE-12 cells transfected with control or miR-144-3p mimics followed by TGF-β stimulation. (J) Wnt signaling regulatory network of experimentally identified targets (labeling identical to H). (K) Luciferase activity of HEK cells cotransfected with a TopFlash reporter plasmid and miRNAs as labeled. *P < 0.05; **P < 0.005; ***P < 0.0005 by 1-way ANOVA analysis.