Cao Xiao-Pei, Han Dong-Mei, Zhao Li, Guo Zi-Kuan, Xiao Feng-Jun, Zhang Yi-Kun, Zhang Xiao-Yan, Wang Li-Sheng, Wang Heng-Xiang, Wang Hua
HeBei North University, Zhangjiakou, China; Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, China.
Department of Hematology, Air Force General Hospital, Beijing, China.
Cytotherapy. 2016 Mar;18(3):402-12. doi: 10.1016/j.jcyt.2015.12.006.
Specific and effective therapy for prevention or reversal of bronchiolitis obliterans (BO) is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stromal cells (MSCs) on BO.
A mouse model of experimental BO was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients, which were then administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using fluorescence-activated cell sorting (FACS) for lymphocyte immunophenotype of spleen, enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (rt-PCR) for cytokine expression, and histopathological analysis for the transplanted trachea.
The histopathologic recovery of allograft tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGF-treated mice. Furthermore, the allo-transplantation-induced immunophenotype disorders of the spleen, including regulatory T (Treg), T helper (Th)1, Th2 and Th17, were attenuated in both cell-treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma (IFN-γ), and increased expression of anti-inflammatory cytokine interleukin (IL)-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor (TGF)-β.
Treatment of BO with HGF gene modified MSCs results in reduction of local inflammation and promotion in recovery of allograft trachea histopathology. These findings might provide an effective therapeutic strategy for BO.
目前缺乏预防或逆转闭塞性细支气管炎（BO）的特异性有效疗法。在本研究中，我们评估了肝细胞生长因子（HGF）基因修饰的间充质基质细胞（MSCs）对BO的治疗效果。
通过将C57BL/6小鼠的气管皮下移植到Balb/C受体小鼠中建立实验性BO小鼠模型，然后分别给予生理盐水、腺病毒介导的HGF修饰的人脐带间充质基质细胞（MSCs-HGF）或腺病毒空载体修饰的间充质基质细胞（MSCs-Null）。通过流式细胞术（FACS）检测脾脏淋巴细胞免疫表型、酶联免疫吸附测定（ELISA）和实时聚合酶链反应（rt-PCR）检测细胞因子表达，以及对移植气管进行组织病理学分析，评估MSCs-Null和MSCs-HGF的治疗效果。
MSCs-Null和MSCs-HGF治疗后，同种异体移植气管的组织病理学恢复明显改善，尤其在MSCs-HGF治疗的小鼠中观察到有益效果。此外，两个细胞治疗组均减轻了同种异体移植诱导的脾脏免疫表型紊乱，包括调节性T细胞（Treg）、辅助性T细胞（Th）1、Th2和Th17。MSCs-HGF治疗降低了炎症细胞因子干扰素-γ（IFN-γ）的表达和分泌，并增加了抗炎细胞因子白细胞介素（IL）-4和IL-10的表达。它还降低了促纤维化因子转化生长因子（TGF）-β的表达水平。
用HGF基因修饰的MSCs治疗BO可减轻局部炎症，促进同种异体移植气管组织病理学的恢复。这些发现可能为BO提供一种有效的治疗策略。
