课题基金基金详情
PGE2/EP2介导间充质干细胞向急性肺损伤肺组织归巢的机制研究
结题报告
批准号:
81201489
项目类别:
青年科学基金项目
资助金额:
25.0 万元
负责人:
陆晓旻
依托单位:
学科分类:
H1602.器官功能衰竭与支持
结题年份:
2015
批准年份:
2012
项目状态:
已结题
项目参与者:
周韶霞、刘玲、陈秋华、贺宏丽、许晓蓉、谢剑锋
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中文摘要
肺实质细胞广泛受损及弥漫性炎症反应是ALI的主要特点,MSC治疗是其重要方向,但MSC向损伤肺组织归巢率低且机制不清,探索MSC归巢的机制及可能的干预手段是MSC修复肺损伤的关键。PGE2是ALI的重要产物,它不仅参与炎症调控,还参与肿瘤细胞迁移,MSC可诱导性表达PGE2受体EP2,PGE2是否参与MSC向肺组织归巢尚不清楚。本研究拟通过基因转染,构建高表达EP2的MSC,通过细胞实验及LPS 诱导ALI模型的动物实验,①观察PGE2对EP2高表达的MSC定向迁移及向肺组织归巢的影响,证实PGE2对MSC的趋化作用;②观察MSC表面粘附分子表达,明确PGE2能否增加MSC表面粘附分子水平进一步促进MSC的归巢;③观察EP2高表达的MSC向损伤肺组织归巢及肺损伤修复情况,阐明PGE2促进EP2高表达的MSC向肺组织归巢而发挥肺保护作用。既明确了MSC的归巢机制又为ALI治疗提供新的途径。
英文摘要
Acute lung injury(ALI) is a devastating clinical syndrome which characterized by diffuse damage of lung parenchymal cells and excessive inflammatory response, mesenchymal stem cells (MSC) may be useful for the treatment of ALI and can be found within the lung tissues after transplantation. The mechanisms determining MSC recruitment to the lung remain unclear and the rate of engraftment is very low.Prostaglandin E2(PGE2) is highly expressed in the injuried lung tissues and acts as an anti-inflammatory cytokine which is in contrast to pro-inflammatory properties previously considered.Recently,A number of studies have showed that PGE2 plays an important role in the process of cancer metastasis,which increased both cell migration and proliferation. Interestingly, in our previous study, we found that there was expression of E-type prostaglandin receptor 2 (EP2) in MSC,whether PGE2 particpate in the engrafment process of MSC is still unknown. In this study, We investigate the role of PGE2 and its receptor EP2 in the homing process of MSC. MSCs are isolated from 6 week-old C57BL/6 male mice and transduce with the EP2 gene, using a lentivirus vector. In vitro study and in vivo mouse model, the LPS-induced lung injury, we quantify the migration and engraftment of MSC carrying EP2 to the injured lung. In addition, we examine the expression of factors potentially involved in the homing and retention of stem cells in the lung tissues, including vascular cell adhesion molecule-1 (VCAM-1), very late antigen-4(VLA-4),focal adhesion kinase (FAK) and so on,in order to clarify the role of PGE2/EP2 in MSC homing.What is more,we also evaluate the injuried lung restoration to demostrate the protective effect of PGE2/EP2 for ALI.
急性呼吸窘迫综合征(ARDS)是严重威胁患者生命的常见临床危急重症,是由多种原因导致的肺泡上皮细胞和肺毛细血管内皮细胞损伤,临床上表现为急性呼吸衰竭。外源性间充质干细胞(MSC)移植为ARDS损伤细胞修复提供了可能的治疗途径。然而,MSC特异性归巢至损伤肺组织是MSC发挥肺保护作用的必要前提,但目前为止MSC向肺组织归巢率低。前列腺素E2(PGE2)是肺损伤(ALI)发生后的重要产物,在体外能促进MSC的定向迁移和增殖,可能具有促进MSC向ALI小鼠肺组织定向归巢的作用,有可能提高MSCs对ARDS的治疗效果。.本研究通过分离培养小鼠骨髓MSC并采用基因工程技术,以MSC为载体,通过慢病毒导入EP2受体基因,构建EP2受体高表达的MSC。通过体外细胞实验,观察PGE2/EP2与MSC的趋化迁移的相关性,证实PGE2/EP2对MSC具有趋化作用,并可增加MSC表面粘附分子的表达。将高表达EP2受体的MSC移植入小鼠体内,应用病理学、免疫组织化学和细胞分子生物学等方法综合评价细胞移植后MSC向损伤肺组织归巢的情况以及肺损伤修复情况,进一步在体证实PGE2/EP2可促进MSC向损伤肺组织归巢,并能促进肺损伤的修复。.本研究通过体内外研究证实,PGE2能够促进EP2高表达的MSC定向迁移,在ARDS时,高表达EP2的MSC向损伤肺组织的归巢增加,进一步增强了肺损伤的修复情况,本研究的重要科学意义在于明确PGE2能够通过EP2受体促进MSC归巢至损伤肺组织,为促进肺损伤修复开辟新的治疗途径。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Mesenchymal Stem Cells Overexpressing Angiotensin-Converting Enzyme 2 Rescue Lipopolysaccharide-Induced Lung Injury
过度表达血管紧张素转换酶 2 的间充质干细胞可挽救脂多糖诱导的肺损伤。
DOI:10.3727/096368914x685087
发表时间:2015-01-01
期刊:CELL TRANSPLANTATION
影响因子:3.3
作者:He, Hongli;Liu, Ling;Qiu, Haibo
通讯作者:Qiu, Haibo
国内基金
海外基金