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首页> 外文期刊>Cell and Tissue Research >Mesenchymal stromal cells can repair radiation-induced pulmonary fibrosis via a DKK-1-mediated Wnt/beta-catenin pathway
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Mesenchymal stromal cells can repair radiation-induced pulmonary fibrosis via a DKK-1-mediated Wnt/beta-catenin pathway

机译：间充质基质细胞可以通过DKK-1介导的WNT /β-连环蛋白途径修复辐射诱导的肺纤维化

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摘要

Pulmonary injury occurring after thoracic radiotherapy is a main factor limiting the curative effect of radiotherapy. Robust activation of the Wnt signalling pathway induced by ionizing radiation stress plays a critical role in epithelial-mesenchymal transition (EMT) in irradiated type II alveolar epithelial cells and in the proliferation of pulmonary fibroblasts, which contributes to the formation of fibrotic lesions in irradiated lungs. The pathogenesis of radiation-induced pulmonary fibrosis could be restricted by systemic delivery of human adipose-derived mesenchymal stromal cells (Ad-MSCs), as evidenced by the inhibitory effects of Ad-MSCs on EMT in irradiated type II alveolar epithelial cells. The purpose of this study is to observe the effects of mesenchymal stromal cells (MSCs) on repairing fibrosis caused by radiation. We used western blotting and real-time PCR to observe the expression of DKK-1 in MSCs of different origins and passages. After the successful establishment of a radiation-induced lung injury model, we investigated the potency of the supernatant from stromal cells to reduce pro-fibrotic events, including EMT and fibroblast activation. To study the mechanism, we evaluated the levels of active beta-catenin, TCF4 and the target genes Snail, Twist and c-Myc. After the injection of Ad-MSCs into mice via the tail vein, proteins related to EMT, fibroblasts and Wnt/beta-catenin signalling were investigated. The TGF-beta and IL-10 protein concentrations in peripheral blood were measured by ELISA. Ad-MSC-derived supernatant effectively reversed the decrease in E-cadherin expression and inhibited the increase in vimentin expression induced by ionizing radiation in epithelial cells and suppressed the expression of alpha-SMA, a mediator of fibroblast proliferation. The canonical Wnt pathway may be activated by irradiation but the nuclear localization of active beta-catenin was reduced in the presence of the supernatant from Ad-MSCs. In addition, the expression of target genes involved in EMT was downregulated. Additionally, when DKK-1 in the supernatant was neutralized, all these effects were reversed. Changes in the levels of proteins related to EMT and fibroblast activation, as well as those of active beta-catenin and TCF4, were similar in vivo and in vitro. The serum level of the immunosuppressive factor IL-10 was increased after radiation and was further enhanced after Ad-MSC interference for one month. In conclusion, Ad-MSCs medium can contain DKK-1 and inhibit the induction of EMT via Wnt/beta-catenin signalling in vitro and in vivo.
机译：胸部放疗后发生的肺损伤是限制放疗疗效的主要因素。电离辐射应激诱导的Wnt信号通路的强烈激活在受照II型肺泡上皮细胞的上皮-间质转化（EMT）和肺成纤维细胞的增殖中起着关键作用，这有助于受照肺纤维化病变的形成。辐射诱导的肺纤维化的发病机制可通过全身输送人脂肪间充质干细胞（Ad-MSCs）来限制，Ad-MSCs对受照II型肺泡上皮细胞EMT的抑制作用证明了这一点。本研究的目的是观察间充质干细胞（MSCs）对辐射性纤维化的修复作用。我们采用western印迹和实时荧光定量PCR技术观察不同来源和传代的MSCs中DKK-1的表达。在成功建立放射性肺损伤模型后，我们研究了基质细胞上清液对减少促纤维化事件（包括EMT和成纤维细胞激活）的效力。为了研究其机制，我们评估了活性β连环蛋白、TCF4和靶基因Snail、Twist和c-Myc的水平。通过尾静脉向小鼠注射Ad-MSCs后，研究了与EMT、成纤维细胞和Wnt/β连环蛋白信号相关的蛋白质。采用ELISA法测定外周血TGF-β和IL-10蛋白浓度。Ad-MSC衍生上清液有效逆转上皮细胞中E-cadherin表达的降低，抑制电离辐射诱导的波形蛋白表达的增加，并抑制成纤维细胞增殖介质α-SMA的表达。典型的Wnt途径可能被辐射激活，但在Ad MSC上清液的存在下，活性β-连环蛋白的核定位降低。此外，参与EMT的靶基因表达下调。此外，当上清液中的DKK-1被中和时，所有这些作用都被逆转。在体内和体外，与EMT和成纤维细胞激活相关的蛋白质水平，以及活性β-连环蛋白和TCF4的水平变化相似。放射治疗后血清免疫抑制因子IL-10水平升高，Ad-MSC干扰1个月后进一步升高。综上所述，Ad-MSCs培养基可含有DKK-1，并在体外和体内通过Wnt/β-连环蛋白信号抑制EMT的诱导。

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