Mesenchymal stem cell-based developmental endothelial locus-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice.
Mesenchymal stem cell-based developmental endothelial locus-1 gene therapy for acute lung injury induced by lipopolysaccharide in mice.
复制标题
DOI：
10.3892/mmr.2014.1988
复制
发表时间：
2014-05
影响因子：
3.4
通讯作者：
Yun-feng Zhao;Wei Xiong;Xueling Wu
中科院分区：
文献类型：
--
作者：
Yun-feng Zhao;Wei Xiong;Xueling Wu
研究表明，骨髓间充质干细胞(MSCs)可作为基因治疗的工具。发育中的内皮细胞位点-1(Del-1)通过抑制主要的白细胞黏附受体LFA-1的功能来抑制白细胞与内皮细胞的黏附，是细胞迁移和渗透的关键因子。在本研究中，我们假设基于MSC的Del-1基因治疗对内毒素(LPS)诱导的肺损伤有潜在的治疗应用。本实验中的MSCs取自6周龄雄性小鼠。为探讨Del-1基因对脂多糖诱导的ALI小鼠的治疗作用，构建了含Del-1基因的慢病毒载体，并将其导入MSCs。在体内实验中，通过注射脂多糖诱导小鼠肺损伤，并用不同剂量的MSCs治疗，与单纯MSCs治疗组比较，携带Del-1的MSCs(MSCs-Del1)治疗组小鼠肺损伤明显减轻。治疗组小鼠肺泡灌洗液中性粒细胞数量及血清肿瘤坏死因子-α和IL-6水平均显著降低。此外，与单独治疗的MSCs相比，Del1-MSC治疗的小鼠也表现出低的肺损伤评分，高的蛋白质浓度和髓过氧化物酶活性。总之，表达Del-1的MSCs治疗显著降低了内毒素诱导的小鼠急性肺损伤的严重程度和炎性细胞因子的水平。
Studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be used as a tool for gene therapy. Developmental endothelial locus-1 (Del-1) is a critical factor for cell migration and infiltration via the inhibition of the function of a major leukocyte adhesion receptor LFA-1 which prevents leukocyte adhesion to the endothelium. In the present study, we hypothesized that MSC-based Del-1 gene therapy may have potential therapeutic applications for lipopolysaccharide (LPS)-induced lung injury. The MSCs in the present assay were isolated from 6 week-old male mice. In order to investigate the therapeutic effect of the Del-1 gene on LPS-induced ALI mice, a lentivirus vector containing the Del-1 gene was constructed and transduced into the MSCs. In the in vivo assay, we induced lung injury with LPS injection and treated mice with different groups of MSCs, and compared with groups treated with MSCs alone, we observed that the administration with MSCs carrying Del-1 (MSCs-Del1) markedly alleviated the LPS-induced lung injury. There were significant decreases in the number of neutrophils in bronchoalveolar lavage (BAL) and the serum levels of TNF-α and IL-6 in the Del-1-expressed MSC-treated mice. Furthermore, compared with MSCs treated alone, Del1-MSC-treated mice also exhibited low lung injury scores, high protein concentrations and myeloperoxidase activity. In conclusion, treatment with Del-1-expressed MSCs significantly decreases the severity of endotoxin-induced acute lung injury and the level of inflammatory cytokines in mice.