Bone marrow mesenchymal stem cells attenuate silica-induced pulmonary fibrosis via paracrine mechanisms

Li, Xiaoli; An, Guoliang; Liang, Dan; Zhu, Zhaohui; Lian, Ximeng; Niu, Piye; Guo, Caixia; Lin, Tian

doi:10.1016/j.toxlet.2017.02.016

Cited by 40 publications

(35 citation statements)

References 52 publications

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“…Paracrine secretion is a process during which vesicles, exosomes, and various cytokines are released by MSCs into the extracellular environment or in the medium (conditioned medium, CM) when they are cultured in vitro [ 11 ]. In support of this, a more recent study [ 12 ] found that BMSCs can improve pulmonary fibrosis induced by silica in vivo and in vitro, but more likely through a series of paracrine factors (HGF, KGF, BMP-7), rather than by a differentiation mechanism. These studies strengthen the hypothesis that BMSC or CM may be suitable for the treatment of pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 84%

“…Recently, much attention has been paid to stem cell therapy in experimental pulmonary fibrosis models [ 12 , 34 – 36 ]. However, most of these studies explored the anti-fibrotic effects of early transplantation [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…For idiopathic pulmonary fibrosis (IPF), it was proposed that a dysregulated communication between epithelial pulmonary components and mesenchymal after tissue injury is key to the irreversible process of fibrosis and tissue remodeling [ 14 , 15 ]. In addition, BMSC treatment has been identified to reduce the injury of alveolar epithelial cells in vivo and attenuate silica-induced pulmonary fibrosis [ 12 ]. Previous studies have also reported that CM from BMSCs can inhibit the EMT process [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow mesenchymal stromal cells attenuate silica-induced pulmonary fibrosis potentially by attenuating Wnt/β-catenin signaling in rats

et al. 2018

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BackgroundPulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis.MethodsSprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n = 6) which were normally fed, (2) silica model group (n = 6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n = 6) which received 1 mL BMSC suspension (2 × 106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n = 6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson’s trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting.ResultsSuccessful construction of a pulmonary fibrosis model was confirmed by H&E and Masson’s trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson’s trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and α-Smooth actin (α-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/β-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression.ConclusionsBMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/β-catenin signaling.ᅟᅟElectronic supplementary materialThe online version of this article (10.1186/s13287-018-1045-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bone marrow mesenchymal stromal cells attenuate silica-induced pulmonary fibrosis potentially by attenuating Wnt/β-catenin signaling in rats

et al. 2018

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“…Cellular viability of BMSCs was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT) assays as previously described [ 12 ]. BMSCs (5 × 10 3 cells/well) were seeded in 96-well plates, cultured for 24 h, then added with 0, 2.5, 5, or 10 μg/ml DiR buffer for 24 h, 48 h, and 72 h, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that BMSCs inhibited pulmonary fibrosis and protected damaged epithelial cells in a rat model of silica-induced pulmonary fibrosis [ 12 ]. Therefore, it was considered that BMSCs were able to engraft with high efficacy in the lung, make direct contact with the injured lung epithelium, and repair or restore the damaged tissue.…”

Section: Introductionmentioning

confidence: 99%

Targeted migration of bone marrow mesenchymal stem cells inhibits silica-induced pulmonary fibrosis in rats

Wang

et al. 2018

Stem Cell Res Ther

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BackgroundSilicosis is a common occupational disease, characterized by silicotic nodules and diffuse pulmonary fibrosis. We demonstrated an anti-fibrotic effect of bone marrow mesenchymal stem cells (BMSCs) in silica-induced lung fibrosis. In the present study, we sought to clarify the homing ability of BMSCs and the specific mechanisms for their effects.Methods and resultsThe biodistribution of BMSCs was identified by near-infrared fluorescence (NIRF) imaging in vivo and in vitro. The results showed that BMSCs labeled with NIR-DiR dyes targeted silica-injured lung tissue, wherein they reached a peak at 6 h post-injection and declined dramatically by day 3. Based on these findings, a second injection of BMSCs was administered 3 days after the first injection. The injected BMSCs migrated to the injured lungs, but did not undergo transformation into specific lung cell types. Interestingly, the injection of BMSC-conditioned medium (BMSCs-CM) significantly attenuated silica-induced pulmonary fibrosis. The collagen deposition and number of nodules were decreased in lung tissues of BMSCs-CM-treated rats. In parallel with these findings, the mRNA levels of collagen I, collagen III, and fibronectin, and the content of transforming growth factor (TGF)-β1 and hydroxyproline were decreased in the BMSCs-CM-treated group compared with the silica group. In addition, alveolar epithelial markers were upregulated by BMSCs-CM treatment.ConclusionsBMSCs migrated to injured areas of the lung after silica instillation and attenuated pulmonary fibrosis. The anti-fibrotic effects of BMSCs were mainly exerted in paracrine manner, rather than through their ability to undergo differentiation.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1083-y) contains supplementary material, which is available to authorized users.

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Amnion Epithelial Cell-Derived Exosomes Restrict Lung Injury and Enhance Endogenous Lung Repair

Tan

Lau

Leaw

et al. 2018

Stem Cells Translational Medicine

164

178

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Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation, severe scarring, and stem cell senescence. Stem cell‐based therapies modulate inflammatory and fibrogenic pathways by release of soluble factors. Stem cell‐derived extracellular vesicles should be explored as a potential therapy for IPF. Human amnion epithelial cell‐derived exosomes (hAEC Exo) were isolated and compared against human lung fibroblasts exosomes. hAEC Exo were assessed as a potential therapy for lung fibrosis. Exosomes were isolated and evaluated for their protein and miRNA cargo. Direct effects of hAEC Exo on immune cell function, including macrophage polarization, phagocytosis, neutrophil myeloperoxidase activity and T cell proliferation and uptake, were measured. Their impact on immune response, histological outcomes, and bronchioalveolar stem cell (BASC) response was assessed in vivo following bleomycin challenge in young and aged mice. hAEC Exo carry protein cargo enriched for MAPK signaling pathways, apoptotic and developmental biology pathways and miRNA enriched for PI3K‐Akt, Ras, Hippo, TGFβ, and focal adhesion pathways. hAEC Exo polarized and increased macrophage phagocytosis, reduced neutrophil myeloperoxidases, and suppressed T cell proliferation directly. Intranasal instillation of 10 μg hAEC Exo 1 day following bleomycin challenge reduced lung inflammation, while treatment at day 7 improved tissue‐to‐airspace ratio and reduced fibrosis. Administration of hAEC Exo coincided with the proliferation of BASC. These effects were reproducible in bleomycin‐challenged aged mice. The paracrine effects of hAECs can be largely attributed to their exosomes and exploitation of hAEC Exo as a therapy for IPF should be explored further. Stem Cells Translational Medicine 2018;7:180–196

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Bone marrow mesenchymal stem cells attenuate silica-induced pulmonary fibrosis via paracrine mechanisms

Cited by 40 publications

References 52 publications

Bone marrow mesenchymal stromal cells attenuate silica-induced pulmonary fibrosis potentially by attenuating Wnt/β-catenin signaling in rats

Bone marrow mesenchymal stromal cells attenuate silica-induced pulmonary fibrosis potentially by attenuating Wnt/β-catenin signaling in rats

Targeted migration of bone marrow mesenchymal stem cells inhibits silica-induced pulmonary fibrosis in rats

Amnion Epithelial Cell-Derived Exosomes Restrict Lung Injury and Enhance Endogenous Lung Repair

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