The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6.
The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6.
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DOI：
10.1186/s12974-015-0284-x
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发表时间：
2015-04-01
影响因子：
9.3
通讯作者：
Duan C
中科院分区：
文献类型：
--
作者：
Chen M;Li X;Zhang X;He X;Lai L;Liu Y;Zhu G;Li W;Li H;Fang Q;Wang Z;Duan C
间充质干细胞（MSC）在以前的研究中被认为对脑出血（ICH）有有益的作用。其治疗机制主要是研究增殖、分化和免疫调节。然而，很少有研究使用MSC治疗ICH后血脑屏障（BBB）渗漏。本研究将MSCs移植到大鼠脑出血模型中，观察MSCs对血脑屏障的影响及其相关机制。成年雄性SD大鼠随机分为假手术组、PBS组（ICH + PBS）和MSC组（ICH + MSC）。脑内注射胶原酶诱导脑出血。MSC治疗组于脑出血诱导后2 h静脉移植MSC。比较了以下因素：炎症、细胞凋亡、行为变化、诱导型一氧化氮合酶（iNOS）、基质金属蛋白酶9（MMP-9）、过氧亚硝基阴离子（ONOO−）、内皮完整性、脑水肿含量、BB B渗漏、TNF-α刺激的基因/蛋白6（TSG-6）和核因子-κB（NF-κB）信号通路。在ICH + MSC组中，MSC降低了促炎细胞因子和细胞凋亡的水平，下调了ICH部位小胶质细胞/巨噬细胞和中性粒细胞浸润的密度，降低了iNOS和MMP-9的水平，减弱了ONOO−的形成，并增加了闭合小带-1（ZO-1）和claudin-5的水平。MSCs还可改善脑水肿和血脑屏障渗漏的程度。MSCs对脑出血大鼠脑B区的保护作用可能与TSG-6表达增加有关，TSG-6可能通过抑制NF-κB信号通路的激活而发挥作用。TSG-6对NF-κB信号通路的抑制作用导致在BB B破坏中起重要作用的iNOS和ONOO−水平降低。我们的研究结果表明，静脉内移植骨髓间充质干细胞降低了ONOO-水平和BBB渗漏程度，并改善了大鼠ICH模型的神经恢复。这一策略可能为未来的治疗提供新的见解，旨在预防脑出血患者的BBB破裂，并最终为脑出血提供治疗选择。
Mesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies. The therapeutic mechanisms are mainly to investigate proliferation, differentiation, and immunomodulation. However, few studies have used MSCs to treat blood–brain barrier (BBB) leakage after ICH. The influence of MSCs on the BBB and its related mechanisms were investigated when MSCs were transplanted into rat ICH model in this study. Adult male Sprague–Dawley (SD) rats were randomly divided into sham-operated group, PBS-treated (ICH + PBS) group, and MSC-treated (ICH + MSC) group. ICH was induced by injection of IV collagenase into the rats’ brains. MSCs were transplanted intravenously into the rats 2 h after ICH induction in MSC-treated group. The following factors were compared: inflammation, apoptosis, behavioral changes, inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP-9), peroxynitrite (ONOO−), endothelial integrity, brain edema content, BBB leakage, TNF-α stimulated gene/protein 6 (TSG-6), and nuclear factor-κB (NF-κB) signaling pathway. In the ICH + MSC group, MSCs decreased the levels of proinflammatory cytokines and apoptosis, downregulated the density of microglia/macrophages and neutrophil infiltration at the ICH site, reduced the levels of iNOS and MMP-9, attenuated ONOO− formation, and increased the levels of zonula occludens-1 (ZO-1) and claudin-5. MSCs also improved the degree of brain edema and BBB leakage. The protective effect of MSCs on the BBB in ICH rats was possibly invoked by increased expression of TSG-6, which may have suppressed activation of the NF-κB signaling pathway. The levels of iNOS and ONOO−, which played an important role in BBB disruption, decreased due to the inhibitory effects of TSG-6 on the NF-κB signaling pathway. Our results demonstrated that intravenous transplantation of MSCs decreased the levels of ONOO− and degree of BBB leakage and improved neurological recovery in a rat ICH model. This strategy may provide a new insight for future therapies that aim to prevent breakdown of the BBB in patients with ICH and eventually offer therapeutic options for ICH.
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DOI：
10.1038/nrmicro1952
发表时间：
2008-08
期刊：
Nature reviews. Microbiology
影响因子：
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影响因子：
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