摘要
研究背景和目的
脑出血(intracerebral hemorrhage,ICH)是一种严重危害人类健康的常见疾病,在我国,ICH病人占全部脑卒中病人的25～30%。尽管比例不高,但死亡率是脑缺血病人的2～6倍,存活者也多遗留神经功能缺损症状。ICH可导致脑组织的直接破坏,神经组织和神经纤维受压移位、变形甚至中断。血肿分解释放的活性物质产生细胞毒性、破坏血脑屏障,引起脑水肿。缺血、缺氧导致神经细胞死亡和神经纤维中断。新生血管发生和神经细胞再生或神经保护作用是实现神经功能重塑的前提。本课题前期研究表明,Flk1~+人骨髓间充质干细胞(human bonemarrow-derived mesenchymal stem cells,hBMSC)具有向内皮细胞分化形成新生血管的能力,分泌的血管内皮生长因子(vascular endothelial growth factor,VEGF)也具有刺激新生血管形成的作用,干细胞分泌的其它神经营养因子如脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)、神经营养素-3(neurotrophicfactor-3,NT-3)等具有神经保护效应。
BMSC是中胚层来源的多能干细胞,具有向神经细胞、骨、软骨、脂肪分化的能力,Flk1~+的hBMSC尚有向血管内皮方向分化的能力。由于BMSC容易获得、体外培养能快速扩增、可自体移植、诱导免疫耐受、减轻或抑制移植物抗宿主病(graft-versus-host disease,GVHD)等,在神经系统疾病、自身免疫性疾病及血液病的临床前期及临床研究中颇受重视。
但是,BMSC移植后在体内能存活多长时间?治疗脑卒中的确切机制是什么?移植细胞和宿主细胞之间是否建立了神经突触联系并发挥生理作用?目前尚不明确。国内外学者对BMSC的体外研究做了大量工作并取得较多共识。然而,在临床前期体内实验方面仍然面临着众多困惑,细胞治疗的安全性和有效性方面存在诸多亟待解决的难点。本课题组前期工作证实了hBMSC治疗大鼠脑卒中的有效性。但由于物种的差异,不能推断其对灵长类动物或人是否有效、安全。因此,本课题的目的是研究hBMSC脑内移植治疗食蟹猴ICH的有效性和安全性,探讨其治疗ICH的可能机制及磁共振活体示踪技术,为hBMSC治疗ICH的临床应用提供临床前研究资料。
研究方法
本研究课题共分为四部分。第一部分:采用食蟹猴自体股动脉血脑内三次注血法来建立ICH模型,通过灵长类脑卒中神经功能评分表、磁共振成像(magneticresonance imaging,MRI)、正电子发射断层显像(positron emission tomography,PET)以及病理检查来评价动物模型;第二部分:食蟹猴分为急性期治疗组(造模后1周移植hBMSC)、慢性期治疗组(造模后1个月移植hBMSC),通过神经功能评分、MRI、PET、免疫荧光技术、微血管密度测定(microvessel density,MVD)、病理来评价hBMSC治疗食蟹猴ICH的有效性及可能的作用机制。第三部分:利用超顺磁性氧化铁(superparamagnetic iron oxide,SPIO)标记hBMSC,将SPIO标记的hBMSC移植到正常和ICH食蟹猴脑内,通过MRI活体示踪干细胞,以研究细胞的存活、迁移。第四部分:在前三部分研究基础上,获得有效治疗剂量,进行hBMSC食蟹猴脑内单次给药的毒性实验,通过一般状况、神经功能评分、脑脊液常规及生化检查、血常规、血凝指标、血生化、心电图、MRI及全身重要脏器病理等指标来评估hBMSC治疗的安全性。
研究结果
1.食蟹猴脑内三次注血法建立ICH模型后,1) MRI可显示右侧基底节区血肿信号,周围结构包括侧脑室前角、基底节核团、中线结构受压移位。2)食蟹猴左侧偏瘫,向右侧呈转圈样动作,灵长类脑卒中神经功能评分结果高剂量组、低剂量组、对照组间无显著性差异。3) PET示造模后右侧基底节区血肿周围皮层、壳核、丘脑、尾状核标准摄取值(standardized uptake value,SUV)SUV减低,以壳核最明显,与对侧相应区域比较有显著性差异。4)病理结果示注血局部可见多量炎性细胞浸润,部分损伤脑组织已被肉芽组织机化,大部分损伤部位的脑组织已被吞噬含铁血黄素的泡沫细胞所取代,可见少许未吸收的血液。
2.1) hBMSC移植后1-4周,急性期治疗组神经功能评分结果为高、低剂量组较对照组有显著性差异,高、低剂量组间无显著性差异。慢性期治疗组神经功能评分结果为hBMSC移植后2-4周,高、低剂量组较对照组有显著性差异,高、低剂量组间无显著性差异。2) PET显示急性期治疗组ICH周围皮层及基底节核团的SUV明显升高,hBMSC移植后第2～3周时尤为明显,其中移植后第2周高剂量组与对照组壳核的SUV%有显著性差异。移植后第3周高剂量组与对照组壳核、丘脑的SUV%有显著性差异。3)磁共振波谱(magnetic resonance spectroscopy,MRS)测量血肿周围ROI的NAA/Cr,急性期治疗组hBMSC移植后5周内的高剂量组NAA/Cr水平高于对照组。4)病理结果显示hBMSC移植后,神经组织变性坏死范围减小,血肿吸收较快,低剂量组稍优于高剂量组,均优于对照组,ICH周围形成大量新生血管。
3.ICH食蟹猴脑内移植SPIO标记的hBMSC后12周,MRI仍可显示移植的干细胞,但未见干细胞明显迁移。
4.食蟹猴脑内单次移植hBMSC后,食蟹猴行为学、心电图、脑脊液学、血液学指标及全身重要脏器病理检查结果证实hBMSC移植对宿主无毒性作用。
结论
脑内三次注血法可以建立稳定的食蟹猴ICH模型,较好的模拟ICH的病理改变,重复性好;Flk1~+hBMSC移植可以促进食蟹猴ICH周围新生血管形成,增加脑组织的血流灌注,保护神经组织,促进ICH血肿吸收和神经功能恢复;SPIO可以有效的标记hBMSC,MRI可以活体状态下示踪移植的干细胞;hBMSC单次给药的毒性实验初步证实了其脑内移植的安全性。
Background and Objective
Intracerebral hemorrhage(ICH) is one of the common diseases which hurt the people.In China,ICH accounts about 25～30%of all cerebral stroke patients. Although the rate is not very high,the mortality of ICH is 2～6 times that of the ICD. Many survivals have remaining neurological impairments.ICH can induce direct destroy to the brain tissue.The brain tissue and nerve fibers are compressed and displaced,deformed or discontinued.The active materials delivered from the hemorrhage produce cytotoxicity,breakdown the blood brain barrier,induce brain edema.Ischemia and hypoxia induce the death of nerve cells and discontinue of the nerve fiber.Angiogenesis and neuroprotection are preconditions to implement the nerve remodeling.Flk1~+ human bone marrow-derived mesenchymal stem cells have the ability to differentiate into endothelial cells.Vascular endothelial growth factor (VEGF) can stimulate neovascularization.And other neurotrophic factors such as brain-derived neurotrophic factor(BDNF) and nreurotrophic-3(NT-3) can also have the ability to protect nerves.
Bone marrow-derived mesenchymal stem cells(BMSC),sourcing from mesoderm,are multipotent and represent one group ofnon-hematopoietic stem cells in the marrow,which can differentiate into multiple lineages,such as nerve cells,bone, cartilage or fat.Flk1~+ hBMSC have the ability to differentiate into endothelial cells. Because BMSC can be easily obtained,quickly amplificated ex vivo,autoplastic transplanted,induce immune tolerance,relieve or inhibit graft-versus-host diseases. So BMSC was widely used in the preclinical or clinical research in nerve system disease,autoimmune diseases or blood diseases.
How long can the stem cells survive and what is the exact mechanism of the treatment? Is there a certain information connection between transplanted hBMSC and host neurons? There are no consensuses about all these questions.There are still a lot of controversial issues about BMSC therapy for stroke in the preclinical research.There are many difficulties to solve on the effect and safety of the cell therapy.We confirmed the efficacy of hBMSC treated rat ischemia in our prophase work.But great disparation exists between species.We cannot conclude that hBMSC are also effective and safe in the treatment of nonhuman primates.So,in present study we designed a series of experiments to explore the effects and the mechanism of BMSC transplantation to macaca fascicularis with ICH in order to supply the preclinical data for the stem cell therapy.
Methods
The study includes four parts:
1.To set up macaca fascicularis ICH animal model by injection of autoallergic femoral artery blood.And the model was evaluated by stroke neurological deficits score for monkeys,MRI,PET and pathology.
2.The monkeys were divided into two groups,acute-phase-therapy group and chronic-phase-group.Using stroke neurological deficits score,MRI,PET, immunofluorescence technique,pathology to estimate the availability and possible mechanism of stem cell therapy.
3.hBMSC labeled with superparamagnetic iron oxide(SPIO) were injected into the cortex of normal and ICH monkeys.Tracing the cells in vivo by Magnetic resonance imaging(MRI) aim to study the survival and migration of BMSC.
4.We got the therapeutic dose by the three parts of work above and continue to do the toxicity experiment of hBMSC.By the test of general state of monkeys,stroke neurological deficits score,the routine and biochemistry exam of cerebrospinal fluid (CSF) and blood,MRI and pathological exam of organs,we confirmed the safety of hBMSC single administration.
Results
1.The macaca fascicularis ICH model was successly set up by three-injection method.Using neurological deficit score for monkeys,PET,MRI,pathology,we found the model can well analogue the pathological change of ICH.
2.After hBMSC transplantation,PET reveals standardized uptake value(SUV) heightened in the areas of cortex and basal ganglion nucleus surrounding ICH.It is obvious in 2～3 weeks after BMSC transplantation.Magnetic resonance spectroscopy (MRS),MRI and pathology display that after hBMSC transplantation,nerve tissue necrosis was lessened,and hecatomb was absorbed more quickly than the control. Immunofluorescence,microvessel density measurement,PET and pathology show that many new vessels formation beside ICH after hBMSC transplantation.
3.MRI can display hBMSC 12 weeks after transplantation in the brain of macaca fascicularis.But we did not found obvious migration of stem cells.
4.Single injection of hBMSC into the brain of macaca fascicularis had no toxicity to nerve function,CSF,blood,or organs.
Conclusion
The macaca fascicularis model was successly set up by three-injection method and it can analogue the pathological change of ICH.hBMSC transplantation can promote the formation of new vessels,increase the blood flow of brain tissue,protect nerve tissue,and enhance the absorption of hematoma and functional recovery of monkeys.SPIO can effectively label hBMSC and MRI can trace transplanted stem cells in vivo.Single administration of hBMSC into the brain of macaca fascicularis had no toxicity.
引文
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1.吴兆苏,姚崇华,赵冬.我国人群脑卒中发病率、死亡率的流行病学研究.中华流行病学杂志.2003:24:236-239
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6.Zhang H,Huang Z,Xu Y,et al.Differentiation and neurological benefit of the mesenchymal stem cells transplanted into the rat brain following intracerebral hemorrhage.Neurol Res.2006;28:104-112
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1.吴兆苏,姚崇华,赵冬.我国人群脑卒中发病率、死亡率的流行病学研究.中华流行病学杂志.2003:24:236-239
2.刘承基.脑血管外科学.南京:江苏科学技术出版社;2001.
3.Dennis MS,Burn JP,Sandercock PA,et al.Long-term survival after first-ever stroke:The oxfordshire community stroke project.Stroke.1993;24:796-800
4.Aronowski J,Hall CE.New horizons for primary intracerebral hemorrhage treatment:Experience from preclinical studies.Neurol Res.2005;27:268-279
5.Bianco P,Riminucci M,Gronthos S,et al.Bone marrow stromal stem cells:Nature,biology,and potential applications.Stem Cells.2001;19:180-192
6.Deans RJ,Moseley AB.Mesenchymal stem cells:Biology and potential clinical uses.Exp Hematol.2000;28:875-884
7.Cho KJ,Trzaska KA,Greco SJ,et al.Neurons derived from human mesenchymal stem cells show synaptic transmission and can be induced to produce the neurotransmitter substance p by interleukin- 1 alpha.Stem Cells.2005;23:383-391
8.Greco SJ,Zhou C,Ye JH,et al.An interdisciplinary approach and characterization of neuronal cells transdifferentiated from human mesenchymal stem cells.Stem Cells Dev.2007;16:811-826
9.Li Y,Chen J,Wang L,et al.Treatment of stroke in rat with intracarotid administration of marrow stromal cells.Neurology.2001;56:1666-1672
10.Mezey E,Chandross KJ,Harta G,et al.Turning blood into brain:Cells bearing neuronal antigens generated in vivo from bone marrow.Science.2000;290:1779-1782
11.Lu P,Blesch A,Tuszynski MH.Induction of bone marrow stromal cells to neurons:Differentiation,transdifferentiation,or artifact? J Neurosci Res.2004;77:174-191
12.Ohta M,Suzuki Y,Noda T,et al.Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation.Exp Neurol.2004;187:266-278
13.Sanchez-Ramos J,Song S,Cardozo-Pelaez F,et al.Adult bone marrow stromal cells differentiate into neural cells in vitro.Exp Neurol.2000;164:247-256
14.Jeong SW,Chu K,Jung KH,et al.Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage.Stroke.2003;34:2258-2263
15.Zhang H,Huang Z,Xu Y,et al.Differentiation and neurological benefit of the mesenchymal stem cells transplanted into the rat brain following intracerebral hemorrhage.Neurol Res.2006;28:104-112
16.Nan Z,Grande A,Sanberg CD,et al.Infusion of human umbilical cord blood ameliorates neurologic deficits in rats with hemorrhagic brain injury.Ann N Y Acad Sci.2005;1049:84-96
17.Lee ST,Chu K,Jung KH,et al.Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke.Brain.2008;131:616-629
18.Lee HJ,Kim KS,Kim EJ,et al.Brain transplantation of immortalized human neural stem cells promotes functional recovery in mouse intracerebral hemorrhage stroke model.Stem Cells.2007;25:1204-1212
19.Kito G,Nishimura A,Susumu T,et al.Experimental thromboembolic stroke in cynomolgus monkey.J Neurosci Methods.2001;105:45-53
20.He J,Gu D,Wu X,et al.Major causes of death among men and women in china.N Engl J Med.2005;353:1124-1134
21.吴桂贤,吴兆苏,刘军.北京部分地区15年心脑血管病死亡率变化趋势.中华预防医学杂志.2001:35:98-101
22.Broderick JP,Brott T,Tomsick T,et al.The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites.N Engl J Med.1992;326:733-736
23.Furlan AJ,Whisnant JP,Elveback LR.The decreasing incidence of primary intracerebral hemorrhage:A population study.Ann Neurol.1979;5:367-373
24.Broderick JP,Brott T,Tomsick T,et al.Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage.J Neurosurg.1993;78:188-191
25.Lyden PD,Zivin JA.Hemorrhagic transformation after cerebral ischemia:Mechanisms and incidence.Cerebrovasc Brain Metab Rev.1993;5:1-16
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