Chen Wei, Li Miao, Zhang Cuiping, Wang Xiangmin, Pan Bin, Zeng Lingyu, Li Zhenyu, Xu Kailin
Department of Hematology, the Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China.
Zhonghua Xue Ye Xue Za Zhi. 2014 Oct;35(10):936-40. doi: 10.3760/cma.j.issn.0253-2727.2014.10.014.
To investigate the effect of the lentiviral vector mediated CXCR4 overexpressed mesenchymal stem cell (MSCs) on graft-versus-host disease (GVHD).
Lentiviral vector containing CXCR4 was constructed. CXCR4 overexpressed MSC by lentiviral vector mediated were assessed. A major histocompatibility complex (MHC)-mismatched mouse model of bone marrow transplantation (BMT) from C57BL/6 donors to BALB/c recipients was constructed. Mice were divided into five groups: total body irradiation (TBI) group, mice received irradiation only; BMT group, mice were transplanted with bone marrow (BM) after TBI; GVHD group, mice were transplanted with BM and splencytes after TBI; CXCR4-MSC group, mice were transplanted with CXCR4-MSC, BM and splencytes after TBI; EGFP-MSC group, mice were transplanted with EGFP-MSC, BM and splencytes after TBI. The survival, body weight and clinical score of GVHD in transplanted mice were monitored. Liver, intestine and skin from mice in each group were obtained for histological examination. Plasma concentrations of inflammation factors such as interleukin (IL)-2, IFN-γ and TNF-α were also determined using a cytometric bead array cytokine kit.
All mice in TBI group died within 14 days, while all of BMT group survived. The mean survival times for GVHD, EGFP-MSC and CXCR4-MSC groups were (17.0 ± 2.3) d, (21.7 ± 4.8) d and (30.1 ± 9.1) d, respectively. Treatment with CXCR4 over-expressing MSCs could decrease the mortality rate. All mice in each group developed clinical signs such as hunched posture, dull fur, diarrhea and weight loss. Meanwhile, histopathological findings in target organs were confirmed the presence of GVHD. While, clinical GVHD scores and histopathological scores in CXCR4-MSC group were significantly lower than that of GVHD group. Moreover, compared with control groups, the plasma IL-2, IFN-γ and TNF-α level in recipients infused with CXCR4-MSC were significantly decreased (P<0.05).
The results revealed that CXCR4- transduced MSCs could effectively control the occurrence of mouse GVHD following allogeneic BM transplantation.
探讨慢病毒载体介导CXCR4过表达的间充质干细胞（MSCs）对移植物抗宿主病（GVHD）的影响。
构建含CXCR4的慢病毒载体。评估慢病毒载体介导的CXCR4过表达的MSCs。构建从C57BL/6供体到BALB/c受体的主要组织相容性复合体（MHC）不匹配的骨髓移植（BMT）小鼠模型。将小鼠分为五组：全身照射（TBI）组，仅接受照射的小鼠；BMT组，TBI后移植骨髓（BM）的小鼠；GVHD组，TBI后移植BM和脾细胞的小鼠；CXCR4-MSC组，TBI后移植CXCR4-MSC、BM和脾细胞的小鼠；EGFP-MSC组，TBI后移植EGFP-MSC、BM和脾细胞的小鼠。监测移植小鼠GVHD的存活率、体重和临床评分。获取每组小鼠的肝脏、肠道和皮肤进行组织学检查。还使用细胞计数珠阵列细胞因子试剂盒测定血浆中白细胞介素（IL）-2、干扰素-γ和肿瘤坏死因子-α等炎症因子的浓度。
TBI组所有小鼠在14天内死亡，而BMT组所有小鼠均存活。GVHD组、EGFP-MSC组和CXCR4-MSC组的平均存活时间分别为（17.0±2.3）天、（21.7±4.8）天和（30.1±9.1）天。用CXCR4过表达的MSCs治疗可降低死亡率。每组所有小鼠均出现弓背姿势、毛发暗淡、腹泻和体重减轻等临床症状。同时，靶器官的组织病理学检查结果证实存在GVHD。而CXCR4-MSC组的临床GVHD评分和组织病理学评分均显著低于GVHD组。此外，与对照组相比，输注CXCR4-MSC的受体血浆中IL-2、IFN-γ和TNF-α水平显著降低（P<0.05）。
结果显示，转导CXCR4的MSCs可有效控制异基因BM移植后小鼠GVHD的发生。
