Yang Jing-Xian, Zhang Nan, Wang Han-Wei, Gao Peng, Yang Qing-Ping, Wen Qing-Ping
From the School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China.
From the School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China, School of Pharmacy, China Medical University, Shenyang 110013, China.
J Biol Chem. 2015 Jan 23;290(4):1994-2006. doi: 10.1074/jbc.M114.605063. Epub 2014 Dec 9.
Novel therapeutic regimens for tissue renewal incorporate mesenchymal stem cells (MSCs) as they differentiate into a variety of cell types and are a stem cell type that is easy to harvest and to expand in vitro. However, surface chemokine receptors, such as CXCR4, which are involved in the mobilization of MSCs, are expressed only on the surface of a small proportion of MSCs, and the lack of CXCR4 expression may underlie the low efficiency of homing of MSCs toward tissue damage, which results in a poor curative effect. Here, a rat CXCR4 expressing lentiviral vector was constructed and introduced into MSCs freshly prepared from rat bone marrow. The influence of CXCR4 expression on migration, proliferation, differentiation, and paracrine effects of MSCs was examined in vitro. The in vivo properties of CXCR4-MSCs were also investigated in a model of acute lung injury in rats induced by lipopolysaccharide. Expression of CXCR4 in MSCs significantly enhanced the chemotactic and paracrine characteristics of the cells in vitro but did not affect self-renewal or differentiation into alveolar and vascular endothelial cells. In vivo, CXCR4 improved MSC homing and colonization of damaged lung tissue, and furthermore, the transplanted CXCR4-MSCs suppressed the development of acute lung injury in part by modulating levels of inflammatory molecules and the neutrophil count. These results indicated that efficient mobilization of MSCs to sites of tissue injury may be due to CXCR4, and therefore, increased expression of CXCR4 may improve their therapeutic potential in the treatment of diseases where tissue damage develops.
用于组织更新的新型治疗方案纳入了间充质干细胞（MSC），因为它们可分化为多种细胞类型，并且是一种易于获取并能在体外扩增的干细胞类型。然而，参与MSC动员的表面趋化因子受体，如CXCR4，仅在一小部分MSC表面表达，而CXCR4表达的缺失可能是MSC向组织损伤部位归巢效率低下的原因，这导致了疗效不佳。在此，构建了一种表达大鼠CXCR4的慢病毒载体，并将其导入从大鼠骨髓新鲜制备的MSC中。在体外检测了CXCR4表达对MSC迁移、增殖、分化和旁分泌作用的影响。还在脂多糖诱导的大鼠急性肺损伤模型中研究了CXCR4-MSC的体内特性。MSC中CXCR4的表达显著增强了细胞在体外的趋化和旁分泌特性，但不影响自我更新或向肺泡和血管内皮细胞的分化。在体内，CXCR4改善了MSC向受损肺组织的归巢和定植，此外，移植的CXCR4-MSC部分通过调节炎症分子水平和中性粒细胞计数抑制了急性肺损伤的发展。这些结果表明，MSC向组织损伤部位的有效动员可能归因于CXCR4，因此，CXCR4表达的增加可能会提高它们在治疗发生组织损伤的疾病中的治疗潜力。
