Increased Extracellular Vesicles Mediate WNT5A Signaling in Idiopathic Pulmonary Fibrosis

Martín-Medina, Aina; Lehmann, Mareike; Burgy, Olivier; Hermann, Sarah; Baarsma, Hoeke A.; Wagner, Darcy E.; Santis, Martina M. De; Ciolek, Florian; Hofer, Thomas P.; Frankenberger, Marion; Aichler, Michaela; Lindner, Michael; Gesierich, Wolfgang; Güenther, Andreas; Walch, Axel; Coughlan, Christina; Wolters, Paul J.; Lee, Joyce; Behr, Jürgen; Königshoff, Mélanie

doi:10.1164/rccm.201708-1580oc

Cited by 145 publications

(148 citation statements)

References 46 publications

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“…However, the more plausible explanation is that fibrotic EVs also carry profibrotic factors. In support of this, we recently reported that fibrotic EVs isolated from IPF lungs carried functional WNT5A (34), but additional protein cargoes likely exist that drive fibrogenesis. Perhaps, other noncoding RNAs, such as long noncoding RNAs, may be present that antagonize antifibrotic miRNAs, resulting in a profibrotic state.…”

Section: Discussionmentioning

confidence: 65%

“…EVs isolated from fibrotic lungs promote lung fibrosis. Recent studies have found that EVs carry profibrotic mediators that have fibrogenic consequences in vitro (34)(35)(36)(37). However, no studies to date to our knowledge have determined the in vivo effects of EVs in lung fibrosis.…”

Section: Resultsmentioning

confidence: 99%

“…To this end, several studies reported EVs having a functional role in pulmonary diseases, such as acute lung injury, chronic obstructive pulmonary disease, and lung cancer (25)(26)(27)(28)(29)(30)(31). Only recently have studies begun unraveling the role that EVs play in mediating fibroproliferation (32)(33)(34)(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

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

Parimon¹,

Yao²,

Habiel³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Parimon¹,

Yao²,

Habiel³

et al. 2019

JCI Insight

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“…Extracellular vessicles act as major channels in cell‐cell communication and PD‐L1 on EVs has been shown to mediate immune evasion and inhibit T cell functions . Moreover, recent studies have demonstrated (i) that in IPF there is an increased number of EVs which contribute to pulmonary fibrosis pathogenesis; and (ii) fibroblast‐derived EVs induce an invasive phenotype in recipient fibroblasts . Since TGFβ induced expression of the checkpoint inhibitor PD‐L1 which acted in a cell‐dependent/autocrine manner (Figures ), we investigated whether the expressed PD‐L1 was secreted into EVs; and if so, could such PD‐L1 act as a paracrine mediator of immune suppression and/or fibroblast migration.…”

Section: Resultsmentioning

confidence: 99%

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

et al. 2019

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Transforming growth factor-beta (TGFβ) is an enigmatic protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGFβ is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in various malignancies, characterizing the pathways and players mediating its action is fundamental. In the current study, we found that TGFβ induces the expression of the immunoinhibitory molecule Programed death-ligand 1 (PD-L1) in human and murine fibroblasts in a Smad2/3-and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGFβ-dependent induction of extracellular matrix proteins, including collagen Iα1 (colIα1) and alpha-smooth muscle actin (α-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGFβ signaling, TGFβ stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases. K E Y W O R D Sfibroblast, checkpoint inhibitor, extracellular vesicles, signaling 2214 | KANG et Al. | 2223 KANG et Al. F I G U R E 6EVs from TGFβ treated fibroblasts inhibit T cell proliferation and cell migration. A, MRC5 cultures were treated in the absence(−) or presence (+) of TGFβ (10 ng/mL) for 3 days. Following the collection of the supernatant for EV isolation, the cells were lysed, and both were assessed for expression of PD-L1 or the EV-associated protein CD63 by Western blotting (representative of 3 independent experiments). B, EV particle size distribution was identified through nanoparticle tracking analysis and processed with NTA software (NanoSight). C, EVs were purified from MRC5 cells cultured in the absence (−) or presence (+) of TGFβ as in (A). Peripheral blood mononuclear cells (n = 5 volunteers) were then treated with anti-CD3 (+αCD3; 500 ng/mL) to activate T cell proliferation and incubated for 6 days with no EVs, EVs (10 μg/mL) isolated from cells ± TGFβ, or EVs isolated from cells ± TGFβ ± blocking antibody to PD-L1 (10 μg/mL Avelumab). The percent change in proliferation, measured by carboxyfluorescein diacetate succinimidyl ester (CFSE) content, compared to anti-CD3 treatment alone is shown. D, (Top 2 panels) Transwell invasion assays were performed in MRC5 cells treated in 0.1% FBS/DME alone (Con) or supplemented with 5 ng/mL TGFβ for 18 hours as described in Materials and Methods. (Bottom 3 panels) MRC5 cells were assessed as in the top panels except that the 0.1% FBS/DME contained EVs (10 μg/mL) isolated from MRC5 cells ± TGFβ or MRC5 cells which had been treated with siRNA to PD-L1 and then stimulated with TGFβ. E, Quantitation of transwell migration of cells treated in (D). Data reflect mean ±...

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“…23 The relevance of this finding has been proved in many models, such as pulmonary fibrosis or heart diseases. [24][25][26] Wnts may bind to lipoproteins that stabilize them as well. 19,27 Interestingly, macrophage-derived EVs carry Wnt proteins to ISCs in intestinal repair, 11 and we provide evidence that fibroblast-derived EVs transfer Wnt activity in the ISC niche in WT organoids as well.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

et al. 2019

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Extracellular vesicles (EV) are membrane-surrounded vesicles that represent a novel way of intercellular communication by carrying biologically important molecules in a concentrated and protected form. The intestinal epithelium is continuously renewed by a small proliferating intestinal stem cell (ISC) population, residing at the bottom of the intestinal crypts in a specific microenvironment, the stem cell niche. By using 3D mouse and human intestinal organoids, we show that intestinal fibroblast-derived EVs are involved in forming the ISC niche by transmitting Wnt and epidermal growth factor (EGF) activity. With a mouse model that expresses EGFP in the Lgr5+ ISCs, we prove that loss in ISC number in the absence of EGF is prevented by fibroblastderived EVs. Furthermore, we demonstrate that intestinal fibroblast-derived EVs carry EGF family members, such as amphiregulin. Mechanistically, blocking EV-bound amphiregulin inhibited the EV-induced survival of organoids. In contrast, EVs have no role in transporting R-Spondin, a critical niche factor amplifying Wnt signaling. Collectively, we prove the important role of fibroblast-derived EVs as a novel transmission mechanism of factors in the normal ISC niche. K E Y W O R D S amphiregulin, exosomes, extracellular vesicle, fibroblast, intestinal stem cell, Lgr5, organoid, Wnt

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Increased Extracellular Vesicles Mediate WNT5A Signaling in Idiopathic Pulmonary Fibrosis

Abstract: Increased EVs function as carriers for signaling mediators, such as WNT-5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis.

Cited by 145 publications

References 46 publications

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

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

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD‐L1 into extracellular vesicles

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

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