骨髓间充质干细胞中的Notch 2通过介导肺泡细胞分化减轻烟雾吸入诱导的肺损伤。
Notch 2 from bone marrow mesenchymal stem cells alleviates smoke inhalation-induced lung injury by mediating alveolar cell differentiation.
作者信息
Yin Cunping, Wang Xiaoyan, Tao Yanmei, Wu Xiaoqing, Li Yuan, Li Haiping, Liang Yuan
机构信息
Department of Vascular Surgery Department, 920th Hospital of PLA Joint Logistics Support Force, 212 Daguan Road, Kunming, Yunnan, China.
Department of Neurology, 920th Hospital of PLA Joint Logistics Support Force, 212 Daguan Road, Kunming, Yunnan, China.
出版信息
J Mol Histol. 2025 Mar 22;56(2):113. doi: 10.1007/s10735-025-10393-8.
BACKGROUND
Smoke inhalation-induced lung injury (SILI) is the major fatality in fire- and blast-related accidents. Bone marrow mesenchymal stem cells (BMSCs) have a potential therapeutic role in SILI through directional differentiation into AT1, AT2, and pulmonary vascular endothelial cells. The present study proposes to evaluate the effect of Notch 2 on the directional differentiation of BMSCs and to characterize its reparative role in a SILI model.
METHODS
pGMLV-SC5 RNAi and pcDNA 3.1 lentivirus exogenously regulate Notch 2 expression in rat-derived BMSCs and BMSCs were injected into the tail vein of the SILI rat model. H&E, Masson and TUNEL stains characterized pathological changes in rat lung tissue. ELISA, western blot, and RT-qPCR identified inflammatory factors (IL-1β, IL-6 and TNF-α), Notch 2 pathway- (Notch 2 and Hes1), lung fibrosis- (α-SMA and E-cadherin), AT1- (AQP5), and AT2- (SPC and SPD) associated markers.
RESULTS
pGMLV-SC5 RNAi or pcDNA 3.1 lentivirus could decrease or increase Notch 2 expression in BMSCs. In vivo imaging showed that BMSCs could be localized in the lungs of the SILI model at 24 h after model development. Treatment with BMSCs alleviated diffuse congestion, lung fibrosis, and alveolar cell apoptosis in lung tissues of the SILI model. Treatment of BMSCs decreased the levels of IL-1β, IL-6, TNF-α, and α-SMA and increased the expression of Notch 2, Hes1, E-cadherin, AQP5, SPC, and SPD in the SILI model. Overexpression of Notch 2 enhances the therapeutic effect of BMSCs on lung injury in the SILI model. Notably, overexpression of Notch 2 attenuated the BMSCs-induced upregulation of AQP5 expression and enhanced the BMSCs-induced upregulation of SPC and SPD expression.
CONCLUSION
Notch 2 contributes to lung injury repair in the SILI rat model by facilitating the differentiation of BMSCs to AT2. This study provides a new idea and target for the treatment of BMSCs for SILI.
背景
烟雾吸入性肺损伤（SILI）是火灾和爆炸相关事故中的主要致死原因。骨髓间充质干细胞（BMSCs）通过定向分化为1型肺泡上皮细胞（AT1）、2型肺泡上皮细胞（AT2）和肺血管内皮细胞，在SILI中具有潜在的治疗作用。本研究旨在评估Notch 2对BMSCs定向分化的影响，并表征其在SILI模型中的修复作用。
方法
采用pGMLV-SC5 RNAi和pcDNA 3.1慢病毒外源调控大鼠来源的BMSCs中Notch 2的表达，并将BMSCs注入SILI大鼠模型的尾静脉。苏木精-伊红（H&E）染色、Masson染色和TUNEL染色用于表征大鼠肺组织的病理变化。酶联免疫吸附测定（ELISA）、蛋白质免疫印迹法（western blot）和逆转录-定量聚合酶链反应（RT-qPCR）用于鉴定炎症因子（白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α）、Notch 2信号通路相关分子（Notch 2和Hes1）、肺纤维化相关分子（α-平滑肌肌动蛋白和E-钙黏蛋白）、AT1相关分子（水通道蛋白5）和AT2相关分子（表面活性蛋白C和表面活性蛋白D）。
结果
pGMLV-SC5 RNAi或pcDNA 3.1慢病毒可降低或增加BMSCs中Notch 2的表达。体内成像显示，在模型建立后24小时，BMSCs可定位于SILI模型的肺中。BMSCs治疗可减轻SILI模型肺组织中的弥漫性充血、肺纤维化和肺泡细胞凋亡。BMSCs治疗可降低SILI模型中白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α和α-平滑肌肌动蛋白的水平，并增加Notch 2、Hes1、E-钙黏蛋白、水通道蛋白5、表面活性蛋白C和表面活性蛋白D的表达。Notch 2的过表达增强了BMSCs对SILI模型肺损伤的治疗效果。值得注意的是，Notch 2的过表达减弱了BMSCs诱导的水通道蛋白5表达上调，并增强了BMSCs诱导的表面活性蛋白C和表面活性蛋白D表达上调。
结论
Notch 2通过促进BMSCs向AT2分化，有助于SILI大鼠模型的肺损伤修复。本研究为BMSCs治疗SILI提供了新的思路和靶点。
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