骨髓间充质干细胞移植治疗脑损伤抗炎及免疫调节机制研究
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摘要
背景
脑损伤(Traumatic brain injury, TBI)是导致人口高死亡率和高致残率的主要原因之一。TBI后引起炎症联锁反应导致继发性脑损伤,其中炎症反应被认为是关键因素之一。TBI后脑组织细胞释放多种促炎因子和抗炎因子,介导炎症联锁反应的激活。TBI导致的强烈的炎症反应特点是：血脑屏障破坏后,外周白细胞浸润进入脑实质以及内源性免疫细胞的激活。外周浸入到脑组织的的中性粒细胞、单核细胞、淋巴细胞等直接影响神经系细胞的存活和死亡。此外,脑组织内活化的小胶质细胞迁移到损伤部位,并释放细胞因子、趋化细胞因子、活性氧、一氧化氮、蛋白酶和其他具有细胞毒性作用物质,继而可能加重神经元死亡。
然而,这些免疫细胞和炎症介质也可以在TBI病理过程中起到神经保护作用。比如,T淋巴细胞在TBI的后期可能起到促进神经修复的作用。促炎因子IL-1、IL-6和TNF-a在对神经细胞的影响作用上都是具有双重作用,既有有害的一面也有有利的一面。另外,小胶质细胞在脑组织中能清除坏死的细胞碎片、促进脑神经细胞的重塑以及在某些特定的条件下发挥神经保护的作用。总之,TBI导致的炎症反应是继发性脑损伤中关键因素,这就表明我们可以通过抗炎或者免疫调节的治疗手段可能对TBI导致的一系列病理过程起到有效的治疗或保护作用。
以往的研究表明,间充质干细胞(Mesenchymal stem cells, MSCs)移植治疗中枢神经系统(Central nervous system, CNS)损伤,包括TBI、中风和脊髓损伤(Spinal cord injury, SCI)的动物模型中发挥有益作用。这些研究的主要结果表明：干细胞促进神经功能的恢复,减少细胞凋亡,增加内源性细胞增殖,促进血管生成,减少病灶大小。移植的MSCs在CNS损伤中发挥有益作用的可能机制包括：MSCs具有迁移到损伤灶的能力；能分化成神经细胞,以取代受损的神经细胞；以及MSCs分泌的各种的生长因子发挥作用。然而,最近的证据表明,MSCs移植的治疗效果可能不是通过直接的细胞替代作用,而是通过调节宿主微环境发挥作用。MSCs可分泌多种生物活性分子,比如各种营养因子及多种抗凋亡分子,这些物质可能是发挥治疗作用的主要机制。
最近研究表明,MSCs具有免疫调节特性。MSCs可以直接抑制T淋巴细胞和小胶质细胞的增殖,并且可以影响树突状细胞和单核细胞和／或巨噬细胞分泌炎症因子。另外,MSCs还可以抑制中性粒细胞产生的活性氧化物质fMLP(甲酰基-甲硫氨基-亮氨酰基-苯丙氨酸)的活性。在实验性自身免疫性脑脊髓炎(Experimental autoimmune encephalomyelitis, EAE)模型中,移植的MSCs能抑制髓鞘特异的T细胞并且诱导外周免疫耐受。移植的MSCs的免疫抑制效应也被证明在急性、严重的移植物抗宿主病(Graft-versus-host disease, GVHD)和多系统萎缩(Multiple system atrophy,MSA)有效。此外,MSCs还可诱导外周耐受并且迁移到到受伤的组织,抑制促炎症细胞因子的释放,促进受损细胞的生存。这些作用在急性肺损伤、心肌梗死、急性肾功能衰竭、脑缺血及阿尔茨海默氏病中已经获得证实。一些研究还发现,其他干细胞也具有炎症调节功能。其中有一项研究证实,移植的人脐带血干细胞在大鼠中风模型中具有抗炎作用；另有一项研究报告,在中风超急性期通过静脉注射神经干细胞(Neural stem cells, NSCs), NSCs可通过与外周炎症系统相互作用调节脑内炎症反应。
这些研究提示,通过移植MSCs来减少脑组织炎症反应和调节TBI后的免疫反应具有可行性。然而,很少有研究同时关注MSCs对炎症相关的细胞因子和免疫细胞在CNS损伤的作用,尤其是在TBI模型中的这种研究更鲜有报道。因此,在本研究中,我们使用SD大鼠的TBI动物模型,通过静脉系统移植MSCs,探索MSCs在体内对TBI诱导的抗炎反应的抗炎作用及免疫调节性的特性,为深入理解MSCs移植治疗TBI机制提供实验基础。
第一章大鼠骨髓MSCs的体外分离、培养与鉴定
目的
建立分离和培养大鼠骨髓MSCs的方法。
方法
从SD大鼠骨髓中生提取、分离、培养MSCs。当细胞生长达到80-90%融合时,用胰蛋白酶消化贴壁细胞,进行传代、扩增。扩增的第3-8代MSCs用于进一步的检测或移植。使用流式细胞仪对MSCs的表型包括：CD44、CD90和CD105,以及造血干细胞标志物CD14、CD34、CD45和HLA-DR进行鉴定。
结果
流式细胞仪检测的第3代MSCs结果为,表型CD44(99.01%)、CD90(99.28%)及CD105(97.71%)高表达；造血干细胞表型CD14(0.79%)、CD34(0.78%)、CD45(0.67%)及HLA-DR (1.11%)低表达。结论
通过本研究,我们在体外成功建立了分离、培养MSCs的可靠方法。MSCs具有较强的体外扩增能力,细胞表型符合国际MSCs的标准,可作为干细胞移植治疗的理想种子。
第二章创伤性脑损伤脑皮层中炎症相关免疫细胞和炎症因子的时间变化研究目的
创伤性脑损伤(TBI)可诱导强烈的炎症反应,其可以持续数天至数月、导致严重的继发性脑损伤。然而,尚鲜见炎症相关免疫细胞与细胞因子在脑损伤过程中的动态关联变化情况,尤其少见TBI后炎症变化过程中其连续动态变化研究。方法
本研究中,我们使用SD大鼠脑冲击伤的实验动物TBI模型,采用免疫组织化学技术检测炎症相关的细胞(中性粒细胞、T淋巴细胞、星形胶质细胞和小胶质细胞/巨噬细胞)在脑组织内的聚集变化情况,同时应用multiplex assays检测系统,同步检测炎症相关的细胞因子(IL-1α、IL-1β、IL-4、IL-6、IL-10、 IL-17、TNF-a、IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)在TBI后连续4周的变化情况。结果
TBI后第7天,小胶质细胞和星形胶质细胞的数量达到高峰。MPO+中性粒细胞和CD3+淋巴细胞分别在TBI后第1天和第3天达到高峰。细胞因子IL-1a, TNF-a、IL-17、IL-10和TGF-β1均在TBI后第1天和3天增加,接着开始逐渐下降,到第28天又开始出现增加的趋势。趋化因子MCP-1、MIP-2和RANTES在TBI后第1天开始增加,随后逐渐下降,直到第28天达到最低值。IL-1β从TBI后第1天开始增加,第3天达到高峰,之后逐渐下降。IL-6在TBI后第7天才开始增加,在第28天达到高峰。IFN-y在TBI后第14天到第28天才开始增高,并在第21天时达到高峰。IL-4从TBI后第14天才开始出现显著增加,持续到第28天仍处于增高水平。
结论
炎症相关细胞(星形胶质细胞、小胶质细胞、中性粒细胞及淋巴细胞)及其分泌的细胞因子(IL-α、IL-1β、IL-4、IL-6、IL-10、IL-17、TNF-a、 IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)随着TBI时间的延长,出现不同的时间变化规律。
第三章骨髓间充质干细胞移植治疗脑损伤的免疫调节机制研究
目的
有很多研究表明MSCs移植治疗脑损伤有效,其机制可能是通过MSCs转分化作用或营养因子分泌作用,但很少有研究者关注MSCs对炎症相关的细胞因子和免疫细胞在CNS损伤中的调节作用,尤其TBI模型中的该类研究。在本课题中,我们选用SD大鼠的TBI动物模型,通过静脉系统移植MSCs,研究MSCs在体内对TBI诱导炎性反应的抗炎作用及免疫调节性的特性。
方法
大鼠TBI后2小时,通过静脉移植MSCs。采用mNSS评分系统,评估TBI后第1、3、7、14、21和28天大鼠的神经运动功能情况。TBI后72小时,我们通过免疫组织化学技术来确定GFAP+星形胶质细胞、Iba-1+小胶质细胞/巨噬细胞、MPO+嗜中性粒细胞和CD3+淋巴细胞的密度。应用multiplex assays检测系统,同步检测脑皮层匀浆液中炎症相关的细胞因子(IL-1a、IL-1β、IL-4、IL-6、IL-10、IL-17、TNF-a、IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)的浓度。采用逆转录-聚合酶链反应和免疫印迹技术分别检测免疫抑制相关因素抗炎因子TSG-6和转录因子NF-κB的表达含量。
结果
MSCs治疗组rmNSS分数从TBI后第3至28天相对于PBS治疗组明显下降。两组之间仅在TBI后24小时无显著差异。PBS治疗对照组和假手术组比较,PBS治疗对照组脑组织含水量明显升高；MSCs治疗组和PBS治疗对照组比较,MSCs治疗后显著降低脑组织含水量。MSCs治疗TBI后,受损的脑实质中小胶质细胞/巨噬细胞的激活有所减少,同时降低了脑组织损伤部位外周血白细胞浸润的数量,以及减少了部分促炎性细胞因子,同时增加了一些抗炎细胞因子的表达。此外MSCs能增强TSG-6的表达,并能抑制活化的NF-κB信号传导途径。
结论
TBI引起的炎症反应中,MSCs具有调节炎症相关的细胞因子(IL-1p、IL-6、IL-10、IL-17、TNF-a、IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)的释放及调节炎症相关免疫细胞(小胶质细胞、中性粒细胞及淋巴细胞)功能活性的能力。这一现象可能是通过MSCs增强TSG-6的表达、进一步抑制活化的NF-κB信号传导途径,从而降低促炎细胞因子而实现。
Traumatic brain injury (TBI) is a major cause of mortality and morbidity among the population worldwide. The inflammatory response is regarded as a key factor in the secondary injury cascade following TBI. Activation of the inflammatory cascade is mediated by the release of pro-and anti-inflammatory cytokines. TBI induces a strong inflammatory response characterized by the recruitment of peripheral leukocytes into the cerebral parenchyma and the activation of resident immune cells. The infiltration of neutrophils, monocytes, and lymphocytes to the injured site directly affects neuronal survival and death. Moreover, activated microglia migrate to injured sites and release cytokines, chemotactic cytokines, reactive oxygen species, nitric oxide, proteases and other factors with cytotoxic effects, which may in turn exacerbate neuronal death.
However, these immune cells and inflammatory mediators can also have neuroprotective effects in TBI. For example, T lymphocytes may contribute to later repair processes in brain injury, pro-inflammatory cytokines such as interleukin (IL)-1,IL-6, and tumor necrosis factor (TNF)-a have both deleterious and beneficial effects on neural cells, and microglia can remove cell debris, promote tissue remodeling and exert numerous neuroprotective effects under certain condition. Of these, TBI-induced inflammation appears to be a key factor in secondary brain damage, which suggests that anti-inflammatory or immunoregulatory strategies could provide effective treatments for the management of TBI-induced pathology.
Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in central nervous system (CNS) injuries, including TBI, stroke, and spinal cord injury animal models. The main findings of these studies suggested that MSCs improved neurological functional recovery, decreased apoptosis, increased endogenous cell proliferation, promoted angiogenesis and reduced lesion size. The potential mechanisms whereby transplanted MSCs might exert beneficial effects in CNS injury include their ability to migrate to injured tissues, transdifferentiation to replace damaged neural cells, and the production of growth factors by MSCs. However, recent evidence indicates that the therapeutic effect of MSCs transplantation may not be through direct cell replacement, but via modulating the host microenvironment. MSCs can secrete a variety of bioactive molecules such as trophic factors and anti-apoptotic molecules, which may provide the main mechanism responsible for their therapeutic effect.
More recently, many studies demonstrated that MSCs possess immunomodulatory properties. MSCs can directly inhibit the proliferation of T lymphocytes and microglial cells, and can modulate the cytokine-secretion profile of dendritic cells (DC) and monocytes and/or macrophages. MSCs are also known to inhibit basal and formyl-methionyl-leucyl-phenylalanine-stimulated production of reactive oxygen species by neutrophils. In experimental autoimmune encephalomyelitis models, MSCs inhibited myelin-specific T cells and induced peripheral tolerance. The immunosuppressive effect of transplanted MSCs has also been demonstrated in acute, severe graft-versus-host disease and in multiple system atrophy. In addition, MSCs can induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. For example, the therapeutic benefit of MSCs transplantation has been observed in acute lung injury, myocardial infarction, acute renal failure, cerebral ischemia and Alzheimer's disease (AD). Furthermore, some studies have found an inflammation-modulatory function for transplanted stem cells. One study demonstrated anti-inflammatory effects of human cord blood cells in a rat model of stroke. Another study reported that intravenous nerve stem cells (NSCs), administered during the hyperacute stage in stroke, could modulate innate cerebral inflammatory responses by interacting with peripheral inflammatory systems.
These studies indicate the feasibility of using MSCs to reduce cerebral inflammation and modulate the immune response after TBI. However, few studies have focused simultaneously on the effects of MSCs on inflammation-associated cytokines and immune cells in CNS injury, especially in an experimental TBI model. In this study, we therefore investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation using systemic bone marrow MSCs transplantation in a rat TBI model.
Chapter I Isolation, culture and characterization of Sprague Dawley rats'bone marrow MSCs
Objective
To establish the protocol to isolation, culture and identification of MSCs.
Methods
MSCs were generated from the bone marrow of SD rats. When the cells reached90%confluent, adherent cells were trypsinized, harvested, and expanded. The expanded cells from passages three-eight were used for further testing or transplantation. MSCs were assessed by flow cytometry analysis of positive CD44, CD90and CD105, the negative hematopoietic markers CD14, CD34, CD45, and HLA-DR.
Results
MSCs were isolated from SD rats'bone marrow and maintained in culture for several passages. Before intravenous transplantation, third-and eighth-passage cells were characterized, and flow cytometry analysis confirmed that the cells at transplantation were positive for CD44(99.01%), CD90(99.28%), and CD105(97.71%), and had low expression of CD14(0.79%), CD34(0.78%), CD45(0.67%) and HLA-DR (1.11%).
Conclusion
MSCs have the similar morphologies and phenotype with classic MSCs, and also have very strong proliferation ability, were promising cell types for future studies.
Chapter Ⅱ Temporal changes of inflammation-associated immune cells and cytokines in rat cortex after experimental traumatic brain injury
Objective
Traumatic brain injury (TBI) induces an intense inflammatory response, which can persist for days to months, resulting in severe secondary brain injury. However, few information is available related to the underlying mechanisms and effects of inflammation-associated cells and cytokines in the injured brain, particularly in long-term studies.
Methods
In the present study, temporal changes of peripherally infiltrating neutrophils, lymphocytes and resident astrocytes and microglia were analyzed after TBI using immunohistochemistry throughout a4-week period. Meanwhile, inflammation-associated cytokines in the injured brain were measured by multiplex assays.
Results
The numbers of microglia and astrocytes peaked at the7th day after TBI. MPO+neutrophils and CD3+lymphocytes peaked at the1st and3rd day after TBI, respectively. Cytokines IL-1a, TNF-a, IL-17, IL-10and TGF-β1were increased at the1st and3rd day after TBI, followed by a decrease and then a subsequent increase to day28. Chemokines, including MCP-1, MIP-2and RANTES, increased and peaked at the1st day after TBI, and then gradually decreased. The IL-1β increased at the1st day after TBI and peaked at the3rd day post-injury. The level of IL-6did not increase until7d after TBI, and peaked at the28th day. Interferon (IFN)-γ levels significantly increased from14d to28d, and peaked at the21st day. IL-4was significantly elevated beginning at the14th day after injury, and maintained a significantly high level through day28.
Conclusions
Both the inflammation-correlated cells including astrocytes, microglia, neutrophils, and lymphocytes and the secreted cytokines such as IL-1, tNF-α, IL-1β, IL-4, IL-6, IL-10, IL-17, TNF-a, IFN-γ, RANTES, MCP-1, MIP-2and TGF-β1, showed temporal changes along with the time extension after TBI.
Chapter III Anti-inflammatory and immunomodulatory
mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury
Objective
Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model.
Methods
MSCs were transplanted intravenously into rats at the2nd hour after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes on days1,3,7,14,21and28after TBI. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α,IL-1β,IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-a (TNF-a), interferon-γ (IFN-γ), regulated upon activation normal T cell expressed and secreted factor (RANTES), macrophage chemotactic protein-1(MCP-1), macrophage inflammatory protein2(MIP-2) and transforming growth factor-β1(TGF-β1)] in brain homogenates. The immunosuppression-related factors TNF-a stimulated gene/protein6(TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and western blotting.
Results
Treatment with MSCs significantly lowered mNSS from days3-28compared with the PBS group. There was no significant difference in scores between the MSC-and PBS-treated groups only at the24th hour post-TBI. The PBS group had a significantly higher brain water content than the sham-injured control group. MSC treatment significantly reduced brain water content compared with the PBS group. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of pro-inflammatory cytokines, and increased anti-inflammatory cytokines, and enhanced expression of TSG-6and suppress activation of the NF-κB signaling pathway.
Conclusions
The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in the TBI-induced cerebral inflammatory responses, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway.
脑损伤(Traumatic brain injury, TBI)是导致人口高死亡率和高致残率的主要原因之一。TBI后引起炎症联锁反应导致继发性脑损伤,其中炎症反应被认为是关键因素之一。TBI后脑组织细胞释放多种促炎因子和抗炎因子,介导炎症联锁反应的激活。TBI导致的强烈的炎症反应特点是：血脑屏障破坏后,外周白细胞浸润进入脑实质以及内源性免疫细胞的激活。外周浸入到脑组织的的中性粒细胞、单核细胞、淋巴细胞等直接影响神经系细胞的存活和死亡。此外,脑组织内活化的小胶质细胞迁移到损伤部位,并释放细胞因子、趋化细胞因子、活性氧、一氧化氮、蛋白酶和其他具有细胞毒性作用物质,继而可能加重神经元死亡。
然而,这些免疫细胞和炎症介质也可以在TBI病理过程中起到神经保护作用。比如,T淋巴细胞在TBI的后期可能起到促进神经修复的作用。促炎因子IL-1、IL-6和TNF-a在对神经细胞的影响作用上都是具有双重作用,既有有害的一面也有有利的一面。另外,小胶质细胞在脑组织中能清除坏死的细胞碎片、促进脑神经细胞的重塑以及在某些特定的条件下发挥神经保护的作用。总之,TBI导致的炎症反应是继发性脑损伤中关键因素,这就表明我们可以通过抗炎或者免疫调节的治疗手段可能对TBI导致的一系列病理过程起到有效的治疗或保护作用。
以往的研究表明,间充质干细胞(Mesenchymal stem cells, MSCs)移植治疗中枢神经系统(Central nervous system, CNS)损伤,包括TBI、中风和脊髓损伤(Spinal cord injury, SCI)的动物模型中发挥有益作用。这些研究的主要结果表明：干细胞促进神经功能的恢复,减少细胞凋亡,增加内源性细胞增殖,促进血管生成,减少病灶大小。移植的MSCs在CNS损伤中发挥有益作用的可能机制包括：MSCs具有迁移到损伤灶的能力；能分化成神经细胞,以取代受损的神经细胞；以及MSCs分泌的各种的生长因子发挥作用。然而,最近的证据表明,MSCs移植的治疗效果可能不是通过直接的细胞替代作用,而是通过调节宿主微环境发挥作用。MSCs可分泌多种生物活性分子,比如各种营养因子及多种抗凋亡分子,这些物质可能是发挥治疗作用的主要机制。
最近研究表明,MSCs具有免疫调节特性。MSCs可以直接抑制T淋巴细胞和小胶质细胞的增殖,并且可以影响树突状细胞和单核细胞和／或巨噬细胞分泌炎症因子。另外,MSCs还可以抑制中性粒细胞产生的活性氧化物质fMLP(甲酰基-甲硫氨基-亮氨酰基-苯丙氨酸)的活性。在实验性自身免疫性脑脊髓炎(Experimental autoimmune encephalomyelitis, EAE)模型中,移植的MSCs能抑制髓鞘特异的T细胞并且诱导外周免疫耐受。移植的MSCs的免疫抑制效应也被证明在急性、严重的移植物抗宿主病(Graft-versus-host disease, GVHD)和多系统萎缩(Multiple system atrophy,MSA)有效。此外,MSCs还可诱导外周耐受并且迁移到到受伤的组织,抑制促炎症细胞因子的释放,促进受损细胞的生存。这些作用在急性肺损伤、心肌梗死、急性肾功能衰竭、脑缺血及阿尔茨海默氏病中已经获得证实。一些研究还发现,其他干细胞也具有炎症调节功能。其中有一项研究证实,移植的人脐带血干细胞在大鼠中风模型中具有抗炎作用；另有一项研究报告,在中风超急性期通过静脉注射神经干细胞(Neural stem cells, NSCs), NSCs可通过与外周炎症系统相互作用调节脑内炎症反应。
这些研究提示,通过移植MSCs来减少脑组织炎症反应和调节TBI后的免疫反应具有可行性。然而,很少有研究同时关注MSCs对炎症相关的细胞因子和免疫细胞在CNS损伤的作用,尤其是在TBI模型中的这种研究更鲜有报道。因此,在本研究中,我们使用SD大鼠的TBI动物模型,通过静脉系统移植MSCs,探索MSCs在体内对TBI诱导的抗炎反应的抗炎作用及免疫调节性的特性,为深入理解MSCs移植治疗TBI机制提供实验基础。
第一章大鼠骨髓MSCs的体外分离、培养与鉴定
目的
建立分离和培养大鼠骨髓MSCs的方法。
方法
从SD大鼠骨髓中生提取、分离、培养MSCs。当细胞生长达到80-90%融合时,用胰蛋白酶消化贴壁细胞,进行传代、扩增。扩增的第3-8代MSCs用于进一步的检测或移植。使用流式细胞仪对MSCs的表型包括：CD44、CD90和CD105,以及造血干细胞标志物CD14、CD34、CD45和HLA-DR进行鉴定。
结果
流式细胞仪检测的第3代MSCs结果为,表型CD44(99.01%)、CD90(99.28%)及CD105(97.71%)高表达；造血干细胞表型CD14(0.79%)、CD34(0.78%)、CD45(0.67%)及HLA-DR (1.11%)低表达。结论
通过本研究,我们在体外成功建立了分离、培养MSCs的可靠方法。MSCs具有较强的体外扩增能力,细胞表型符合国际MSCs的标准,可作为干细胞移植治疗的理想种子。
第二章创伤性脑损伤脑皮层中炎症相关免疫细胞和炎症因子的时间变化研究目的
创伤性脑损伤(TBI)可诱导强烈的炎症反应,其可以持续数天至数月、导致严重的继发性脑损伤。然而,尚鲜见炎症相关免疫细胞与细胞因子在脑损伤过程中的动态关联变化情况,尤其少见TBI后炎症变化过程中其连续动态变化研究。方法
本研究中,我们使用SD大鼠脑冲击伤的实验动物TBI模型,采用免疫组织化学技术检测炎症相关的细胞(中性粒细胞、T淋巴细胞、星形胶质细胞和小胶质细胞/巨噬细胞)在脑组织内的聚集变化情况,同时应用multiplex assays检测系统,同步检测炎症相关的细胞因子(IL-1α、IL-1β、IL-4、IL-6、IL-10、 IL-17、TNF-a、IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)在TBI后连续4周的变化情况。结果
TBI后第7天,小胶质细胞和星形胶质细胞的数量达到高峰。MPO+中性粒细胞和CD3+淋巴细胞分别在TBI后第1天和第3天达到高峰。细胞因子IL-1a, TNF-a、IL-17、IL-10和TGF-β1均在TBI后第1天和3天增加,接着开始逐渐下降,到第28天又开始出现增加的趋势。趋化因子MCP-1、MIP-2和RANTES在TBI后第1天开始增加,随后逐渐下降,直到第28天达到最低值。IL-1β从TBI后第1天开始增加,第3天达到高峰,之后逐渐下降。IL-6在TBI后第7天才开始增加,在第28天达到高峰。IFN-y在TBI后第14天到第28天才开始增高,并在第21天时达到高峰。IL-4从TBI后第14天才开始出现显著增加,持续到第28天仍处于增高水平。
结论
炎症相关细胞(星形胶质细胞、小胶质细胞、中性粒细胞及淋巴细胞)及其分泌的细胞因子(IL-α、IL-1β、IL-4、IL-6、IL-10、IL-17、TNF-a、 IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)随着TBI时间的延长,出现不同的时间变化规律。
第三章骨髓间充质干细胞移植治疗脑损伤的免疫调节机制研究
目的
有很多研究表明MSCs移植治疗脑损伤有效,其机制可能是通过MSCs转分化作用或营养因子分泌作用,但很少有研究者关注MSCs对炎症相关的细胞因子和免疫细胞在CNS损伤中的调节作用,尤其TBI模型中的该类研究。在本课题中,我们选用SD大鼠的TBI动物模型,通过静脉系统移植MSCs,研究MSCs在体内对TBI诱导炎性反应的抗炎作用及免疫调节性的特性。
方法
大鼠TBI后2小时,通过静脉移植MSCs。采用mNSS评分系统,评估TBI后第1、3、7、14、21和28天大鼠的神经运动功能情况。TBI后72小时,我们通过免疫组织化学技术来确定GFAP+星形胶质细胞、Iba-1+小胶质细胞/巨噬细胞、MPO+嗜中性粒细胞和CD3+淋巴细胞的密度。应用multiplex assays检测系统,同步检测脑皮层匀浆液中炎症相关的细胞因子(IL-1a、IL-1β、IL-4、IL-6、IL-10、IL-17、TNF-a、IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)的浓度。采用逆转录-聚合酶链反应和免疫印迹技术分别检测免疫抑制相关因素抗炎因子TSG-6和转录因子NF-κB的表达含量。
结果
MSCs治疗组rmNSS分数从TBI后第3至28天相对于PBS治疗组明显下降。两组之间仅在TBI后24小时无显著差异。PBS治疗对照组和假手术组比较,PBS治疗对照组脑组织含水量明显升高；MSCs治疗组和PBS治疗对照组比较,MSCs治疗后显著降低脑组织含水量。MSCs治疗TBI后,受损的脑实质中小胶质细胞/巨噬细胞的激活有所减少,同时降低了脑组织损伤部位外周血白细胞浸润的数量,以及减少了部分促炎性细胞因子,同时增加了一些抗炎细胞因子的表达。此外MSCs能增强TSG-6的表达,并能抑制活化的NF-κB信号传导途径。
结论
TBI引起的炎症反应中,MSCs具有调节炎症相关的细胞因子(IL-1p、IL-6、IL-10、IL-17、TNF-a、IFN-γ、RANTES、MCP-1、MIP-2和TGF-β1)的释放及调节炎症相关免疫细胞(小胶质细胞、中性粒细胞及淋巴细胞)功能活性的能力。这一现象可能是通过MSCs增强TSG-6的表达、进一步抑制活化的NF-κB信号传导途径,从而降低促炎细胞因子而实现。
Traumatic brain injury (TBI) is a major cause of mortality and morbidity among the population worldwide. The inflammatory response is regarded as a key factor in the secondary injury cascade following TBI. Activation of the inflammatory cascade is mediated by the release of pro-and anti-inflammatory cytokines. TBI induces a strong inflammatory response characterized by the recruitment of peripheral leukocytes into the cerebral parenchyma and the activation of resident immune cells. The infiltration of neutrophils, monocytes, and lymphocytes to the injured site directly affects neuronal survival and death. Moreover, activated microglia migrate to injured sites and release cytokines, chemotactic cytokines, reactive oxygen species, nitric oxide, proteases and other factors with cytotoxic effects, which may in turn exacerbate neuronal death.
However, these immune cells and inflammatory mediators can also have neuroprotective effects in TBI. For example, T lymphocytes may contribute to later repair processes in brain injury, pro-inflammatory cytokines such as interleukin (IL)-1,IL-6, and tumor necrosis factor (TNF)-a have both deleterious and beneficial effects on neural cells, and microglia can remove cell debris, promote tissue remodeling and exert numerous neuroprotective effects under certain condition. Of these, TBI-induced inflammation appears to be a key factor in secondary brain damage, which suggests that anti-inflammatory or immunoregulatory strategies could provide effective treatments for the management of TBI-induced pathology.
Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in central nervous system (CNS) injuries, including TBI, stroke, and spinal cord injury animal models. The main findings of these studies suggested that MSCs improved neurological functional recovery, decreased apoptosis, increased endogenous cell proliferation, promoted angiogenesis and reduced lesion size. The potential mechanisms whereby transplanted MSCs might exert beneficial effects in CNS injury include their ability to migrate to injured tissues, transdifferentiation to replace damaged neural cells, and the production of growth factors by MSCs. However, recent evidence indicates that the therapeutic effect of MSCs transplantation may not be through direct cell replacement, but via modulating the host microenvironment. MSCs can secrete a variety of bioactive molecules such as trophic factors and anti-apoptotic molecules, which may provide the main mechanism responsible for their therapeutic effect.
More recently, many studies demonstrated that MSCs possess immunomodulatory properties. MSCs can directly inhibit the proliferation of T lymphocytes and microglial cells, and can modulate the cytokine-secretion profile of dendritic cells (DC) and monocytes and/or macrophages. MSCs are also known to inhibit basal and formyl-methionyl-leucyl-phenylalanine-stimulated production of reactive oxygen species by neutrophils. In experimental autoimmune encephalomyelitis models, MSCs inhibited myelin-specific T cells and induced peripheral tolerance. The immunosuppressive effect of transplanted MSCs has also been demonstrated in acute, severe graft-versus-host disease and in multiple system atrophy. In addition, MSCs can induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. For example, the therapeutic benefit of MSCs transplantation has been observed in acute lung injury, myocardial infarction, acute renal failure, cerebral ischemia and Alzheimer's disease (AD). Furthermore, some studies have found an inflammation-modulatory function for transplanted stem cells. One study demonstrated anti-inflammatory effects of human cord blood cells in a rat model of stroke. Another study reported that intravenous nerve stem cells (NSCs), administered during the hyperacute stage in stroke, could modulate innate cerebral inflammatory responses by interacting with peripheral inflammatory systems.
These studies indicate the feasibility of using MSCs to reduce cerebral inflammation and modulate the immune response after TBI. However, few studies have focused simultaneously on the effects of MSCs on inflammation-associated cytokines and immune cells in CNS injury, especially in an experimental TBI model. In this study, we therefore investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation using systemic bone marrow MSCs transplantation in a rat TBI model.
Chapter I Isolation, culture and characterization of Sprague Dawley rats'bone marrow MSCs
Objective
To establish the protocol to isolation, culture and identification of MSCs.
Methods
MSCs were generated from the bone marrow of SD rats. When the cells reached90%confluent, adherent cells were trypsinized, harvested, and expanded. The expanded cells from passages three-eight were used for further testing or transplantation. MSCs were assessed by flow cytometry analysis of positive CD44, CD90and CD105, the negative hematopoietic markers CD14, CD34, CD45, and HLA-DR.
Results
MSCs were isolated from SD rats'bone marrow and maintained in culture for several passages. Before intravenous transplantation, third-and eighth-passage cells were characterized, and flow cytometry analysis confirmed that the cells at transplantation were positive for CD44(99.01%), CD90(99.28%), and CD105(97.71%), and had low expression of CD14(0.79%), CD34(0.78%), CD45(0.67%) and HLA-DR (1.11%).
Conclusion
MSCs have the similar morphologies and phenotype with classic MSCs, and also have very strong proliferation ability, were promising cell types for future studies.
Chapter Ⅱ Temporal changes of inflammation-associated immune cells and cytokines in rat cortex after experimental traumatic brain injury
Objective
Traumatic brain injury (TBI) induces an intense inflammatory response, which can persist for days to months, resulting in severe secondary brain injury. However, few information is available related to the underlying mechanisms and effects of inflammation-associated cells and cytokines in the injured brain, particularly in long-term studies.
Methods
In the present study, temporal changes of peripherally infiltrating neutrophils, lymphocytes and resident astrocytes and microglia were analyzed after TBI using immunohistochemistry throughout a4-week period. Meanwhile, inflammation-associated cytokines in the injured brain were measured by multiplex assays.
Results
The numbers of microglia and astrocytes peaked at the7th day after TBI. MPO+neutrophils and CD3+lymphocytes peaked at the1st and3rd day after TBI, respectively. Cytokines IL-1a, TNF-a, IL-17, IL-10and TGF-β1were increased at the1st and3rd day after TBI, followed by a decrease and then a subsequent increase to day28. Chemokines, including MCP-1, MIP-2and RANTES, increased and peaked at the1st day after TBI, and then gradually decreased. The IL-1β increased at the1st day after TBI and peaked at the3rd day post-injury. The level of IL-6did not increase until7d after TBI, and peaked at the28th day. Interferon (IFN)-γ levels significantly increased from14d to28d, and peaked at the21st day. IL-4was significantly elevated beginning at the14th day after injury, and maintained a significantly high level through day28.
Conclusions
Both the inflammation-correlated cells including astrocytes, microglia, neutrophils, and lymphocytes and the secreted cytokines such as IL-1, tNF-α, IL-1β, IL-4, IL-6, IL-10, IL-17, TNF-a, IFN-γ, RANTES, MCP-1, MIP-2and TGF-β1, showed temporal changes along with the time extension after TBI.
Chapter III Anti-inflammatory and immunomodulatory
mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury
Objective
Previous studies have shown beneficial effects of mesenchymal stem cells (MSCs) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model.
Methods
MSCs were transplanted intravenously into rats at the2nd hour after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes on days1,3,7,14,21and28after TBI. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α,IL-1β,IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-a (TNF-a), interferon-γ (IFN-γ), regulated upon activation normal T cell expressed and secreted factor (RANTES), macrophage chemotactic protein-1(MCP-1), macrophage inflammatory protein2(MIP-2) and transforming growth factor-β1(TGF-β1)] in brain homogenates. The immunosuppression-related factors TNF-a stimulated gene/protein6(TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and western blotting.
Results
Treatment with MSCs significantly lowered mNSS from days3-28compared with the PBS group. There was no significant difference in scores between the MSC-and PBS-treated groups only at the24th hour post-TBI. The PBS group had a significantly higher brain water content than the sham-injured control group. MSC treatment significantly reduced brain water content compared with the PBS group. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of pro-inflammatory cytokines, and increased anti-inflammatory cytokines, and enhanced expression of TSG-6and suppress activation of the NF-κB signaling pathway.
Conclusions
The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in the TBI-induced cerebral inflammatory responses, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway.
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35. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007, 104:11002-11007.
36. Uccelli A, Moretta L, Pistoia V:Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008,8:726-736.
37. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA:Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007, 179:1855-1863.
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1. Xiong Y, Mahmood A, Chopp M:. Neurorestorative treatments for traumatic brain injury. Discov Med.2010,10:434-442.
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4. d'Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA:Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation 2012,9:31.
5. Lau LT, Yu AC:Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 2001,18:351-359.
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5. Rhodes J:Peripheral immune cells in the pathology of traumatic brain injury? Curr Opin Crit Care 2011,17:122-130.
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15. Aloisi F:Immune function of microglia. Glia 2001,36:165-179.
16. Parr AM, Tator CH, Keating A:Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007, 40:609-619.
17. Chopp M, Li Y:Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002,1:92-100.
18. Si YL, Zhao YL, Hao HJ, Fu XB, Han WD:MSCs:Biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev 2011,10:93-103.
19. Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G: Mesenchymal stem cells neuronal differentiation ability:a real perspective for nervous system repair? Curr Stem Cell Res Ther 2011,6:82-92.
20. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI:Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 2009,20:419-427.
21.Uccelli A, Moretta L, Pistoia V:Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008,8:726-736.
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23. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM:Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002, 99:3838-3843.
24. Ooi YY, Ramasamy R, Rahmat Z, Subramaiam H, Tan SW, Abdullah M, Israf DA, Vidyadaran S:Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide. Int Immunopharmacol 2010, 10:1532-1540.
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26. Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F, Ottonello L, Pistoia V:Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 2008, 26:151-162.
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28. Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A:Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 2007,61:219-227.
29. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O:Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004,363:1439-1441.
30. Stemberger S, Jamnig A, Stefanova N, Lepperdinger G, Reindl M, Wenning GK:Mesenchymal stem cells in a transgenic mouse model of multiple system atrophy:immunomodulation and neuroprotection. PLoS One 2011,6:e19808.
31. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007, 104:11002-11007.
32. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA:Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007, 179:1855-1863.
33. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ:Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009,5:54-63.
34. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C:Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005, 289:F31-42.
35. Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, Kim SU:Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia:contribution of fractalkine and IL-5. Neurobiol Dis 2011,41:717-724.
36. Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS:Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells 2010,28:329-343.
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6. Xiong Y, Mahmood A, Chopp M:Neurorestorative treatments for traumatic brain injury. Discov Med 2010,10:434-442.
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20. Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV: Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 1974,17:331-340.
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22. Parr AM, Tator CH, Keating A:Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007, 40:609-619.
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24. Chopp M, Li Y: Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002,1:92-100.
25. Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G: Mesenchymal stem cells neuronal differentiation ability:a real perspective for nervous system repair? Curr Stem Cell Res Ther 2011,6:82-92.
26. Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG: Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 2006, 198:54-64.
27. Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M:Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001,32:1005-1011.
28. Lu D, Li Y, Wang L, Chen J, Mahmood A, Chopp M:Intraarterial administration of marrow stromal cells in a rat model of traumatic brain injury. J Neurotrauma 2001,18:813-819.
29. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI:Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 2009,20:419-427.
30. Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G:How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 2012,33:136-143.
31. Ooi YY, Ramasamy R, Rahmat Z, Subramaiam H, Tan SW, Abdullah M, Israf DA, Vidyadaran S:Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide. Int Immunopharmacol 2010, 10:1532-1540.
32. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, et al:Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005,106:1755-1761.
33. Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A:Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 2007,61:219-227.
34. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C:Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005, 289:F31-42.
35. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007, 104:11002-11007.
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37. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA:Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007, 179:1855-1863.
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1. Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV:Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974,17:331-340.
2. Caplan AI:Mesenchymal stem cells. J Orthop Res 1991,9:641-650.
3. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E:Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006,8:315-317.
4. da Silva Meirelles L, Chagastelles PC, Nardi NB:Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006,119:2204-2213.
5. Parr AM, Tator CH, Keating A:Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007, 40:609-619.
6. Xiong Y, Mahmood A, Chopp M:Neurorestorative treatments for traumatic brain injury. Discov Med 2010,10:434-442.
7. Si YL, Zhao YL, Hao HJ, Fu XB, Han WD:MSCs:Biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev 2011,10:93-103.
8. Chopp M, Li Y:Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002,1:92-100.
9. Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G: Mesenchymal stem cells neuronal differentiation ability:a real perspective for nervous system repair? Curr Stem Cell Res Ther 2011,6:82-92.
10. Meirelles Lda S, Fontes AM, Covas DT, Caplan AI:Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 2009,20:419-427.
11. Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, et al:Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005,106:1755-1761.
12. Gerdoni E, Gallo B, Casazza. S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A:Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 2007,61:219-227.
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16. Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007, 104:11002-11007.
17. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA:Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007, 179:1855-1863.
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19. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C:Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005, 289:F31-42.
20. Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, Kim SU:Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia:contribution of fractalkine and IL-5. Neurobiol Dis 2011,41:717-724.
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1. Xiong Y, Mahmood A, Chopp M:. Neurorestorative treatments for traumatic brain injury. Discov Med.2010,10:434-442.
2. Ziebell JM, Morganti-Kossmann MC:Involvement of pro-and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 2010,7:22-30.
3. Lucas SM, Rothwell NJ, Gibson RM:The role of inflammation in CNS injury and disease. Br J Pharmacol 2006,147 Suppl 1:S232-240.
4. d'Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA:Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation 2012,9:31.
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1. Xiong Y, Mahmood A, Chopp M:Neurorestorative treatments for traumatic brain injury. Discov Med.2010,10:434-442.
2. Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ:The cytokine response to human traumatic brain injury:temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab 2011,31:658-670.
3. Correale J, Villa A:The neuroprotective role of inflammation in nervous system injuries. J Neurol 2004,251:1304-1316.
4. Ziebell JM, Morganti-Kossmann MC:Involvement of pro-and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 2010,7:22-30.
5. Rhodes J:Peripheral immune cells in the pathology of traumatic brain injury? Curr Opin Crit Care 2011,17:122-130.
6. Lucas SM, Rothwell NJ, Gibson RM:The role of inflammation in CNS injury and disease. Br J Pharmacol 2006,147 Suppl 1:S232-240.
7. Helmy A, De Simoni MG, Guilfoyle MR, Carpenter KL, Hutchinson PJ: Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury. Prog Neurobiol 2011,95:352-372.
8. d'Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA:Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation 2012,9:31.
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10. Brait VH, Arumugam TV, Drummond GR, Sobey CG:Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J Cereb Blood Flow Metab 2012,32:598-611.
11. Arneth BM:Protective autoimmunity and protein localization. J Neuroimmunol 2010,219:123-125.
12. Winter CD, Pringle AK, Clough GF, Church MK:Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain 2004,127:315-320.
13. Turrin NP, Rivest S:Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity. J Neurosci 2006,26:143-151.
14. Biber K, Neumann H, Inoue K, Boddeke HW:Neuronal'On' and 'Off signals control microglia. Trends Neurosci 2007,30:596-602.
15. Aloisi F:Immune function of microglia. Glia 2001,36:165-179.
16. Parr AM, Tator CH, Keating A:Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007, 40:609-619.
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