hBMSCs脑内移植的安全评价、迁移、分化及迁移机制初探
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摘要
背景中枢神经系统疾病是一组严重威胁人类健康的疾病,主要包括脑血管疾病和神经变性疾病,多表现为神经元的变性缺失,神经系统无法产生新的神经元,建立新的突触联系,致使中枢神经系统损伤后结构和功能难以恢复,而目前现有的临床治疗方法有限,不能达到有效恢复神经功能的目的。因此寻找新的方法对神经系统疾病的治疗至为关键。而干细胞移植为治疗中枢神经系统疾病建立了一个新的技术平台。
MSCs为中胚层来源的多能干细胞,主要存在于全身结缔组织和器官间质中,以骨髓组织中含量最为丰富。来源于骨髓的MSCs称为骨髓MSCs (bone marrow-derived MSCs, BMSCs),其具有多向分化的潜力,获取方便,易于分离培养和鉴定,遗传背景稳定,体内植入免疫反应比较弱等优点。自从首次报道间充质干细胞(mesenchymal stem cells, MSCs)在脑内可以向神经细胞分化后,MSCs移植治疗中枢神经系统疾病就成为了非常感兴趣的课题。本实验采用的人BMSCs (human hBMSCs)来源于健康志愿者,前期工作已证实其在体外具有多向分化的潜能、并能快速扩增、可诱导免疫耐受、能减轻或抑制移植物抗宿主病等,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。
目前MSCs的移植途径主要包括直接脑内注射和间接通过静脉、动脉及腹腔注射等。间接途径移植为全身治疗,到达病变部位的时间较长,细胞数量较少,发挥作用较慢等,而脑内注射移植为局部治疗,创伤小,起效快,并且脑内的免疫应答能力比较弱,因此直接脑内注射成为局部治疗中枢神经系统疾病的一个很好的选择。已有研究报道同种异体BMSCs小鼠脑内移植没有发现明显副作用,并能在大脑内迁移和向神经细胞方向分化。但hBMSCs直接脑内移植的安全性如何?其脑内移植后能否进行迁移?能否分化为神经元及其他神经细胞?如果hBMSCs能够在脑内进行迁移,其迁移途径及迁移机制如何?这些都是hBMSCs临床应用前期亟需解决的问题。
方法我们分别利用小动物Wistar大鼠和与人类最为接近的非人灵长类动物食蟹猴作为研究对象,脑内直接注射hBMSCs,观察hBMSCs直接脑内注射的安全性,通过对hBMSCs体外标记示踪和携带的男性特异基因的检测观察hBMSCs在脑内的迁移及迁移途径,应用免疫荧光双标记观察移植的hBMSCs在脑内的分化。Real-time PCR及免疫组织化学的方法用来检测部分神经营养因子、细胞因子以及黏附分子在hBMSCs移植后的表达情况。
结果我们的结果显示直接脑内注射hBMSCs未引起受试动物出现全身症状,包括精神、饮食、运动等方面。移植hBMSCs的局部脑组织炎症反应比较局限,未观察到明显的免疫反应,未观察到脑组织的变性坏死和明显胶质细胞聚集。hBMSCs移植4周后,仍大量存活,并可在脑内广泛迁移,且迁移分布具有一定的规律性,可观察到不同移植受体细胞分布重叠现象。hBMSCs迁移分布模式图显示不管是在大鼠,还是在食蟹猴,hBMSCs有从前脑向后脑迁移的趋势。在大鼠,hBMSCs主要沿胼胝体-外囊轴线和室管膜下方向迁移,而且随着移植时间的推移,hBMSCs逐渐向对侧迁移；在食蟹猴,hBMSCs有向血管和室管膜下迁移的趋势。因此我们推测血液循环和脑脊液循环可能是hBMSCs迁移的一个途径之一。
免疫荧光双标记结果显示移植的hBMSCs能表达神经元的标记物NeuN和神经胶质细胞的标记物GFAP,说明hBMSCs可在脑内向神经细胞方向分化。hBMSCs移植后,部分神经营养因子和生长因子和神经钙粘素(N-cadherin)表达明显升高。神经钙粘素介导神经系统发育过程中神经细胞的迁移,在细胞的迁移过程中也发挥重要作用,因此, N-cadherin也可能诱导hBMSCs在脑内的迁移。我们应用hUCMSCs作为研究对象,应用transwell小室迁移系统检测了N-cadherin对hUCMSCs的体外迁移作用,结果表明N-cadherin具有明显趋化hUMSCs迁移的作用,并且发现其能够上调细胞内源性N-cadherin和p连环蛋白的表达,因此N-cadherin也可能介导了hBMSCs在脑内的迁移。
结论hBMSCs直接脑内注射移植,没有引起明显的副作用；hBMSCs可以在脑内长期存活,并能进行迁移和分化；hBMSCs移植后上调脑组织内部分细胞因子和神经钙粘素的表达,这可能是其在脑内迁移的一个机制之一
目的探讨食蟹猴脑缺血模型在人骨髓间充质干细胞(human bone marrow2derived mesenchymal stem cells, hBMSCs)移植后对脑缺血损伤的保护作用和IL-10的表达情况。
方法食蟹猴8只,在脑定位仪定位下,应用光化学法构建食蟹猴脑缺血模型,并将其随机分为高剂量治疗组、低剂量治疗组和模型组,分别在脑缺血部位附近注射高、低密度的hBMSCs和生理盐水。术后,通过影像学、神经功能评分及组织病理学观察对hBMSC的治疗效果进行评价。并应用原位细胞凋亡检测的方法观察脑缺血周围脑组织神经细胞的凋亡情况,免疫组织化学的方法被用来观察脑缺血周围脑组织神经胶质细胞反应和室管膜下细胞的增殖情况,并应用免疫组织化学、real-time PCR和Western blot检测检测脑损伤周围IL-10的表达水平。
结果与模型组相比,hBMSCs移植能明显改善脑缺血模型的症状,hBMSC治疗能够减少损伤部位周围细胞的凋亡,减轻脑缺血周围脑组织的胶质细胞反应,促进室管膜下细胞的增殖。免疫组织化学显示IL-10阳性细胞的数量及染色强度均较模型组明显升高,real-time PCR和Western Blot也证明IL-10在hBMSCs移植治疗后表达升高。
结论hBMSCs对食蟹猴脑缺血模型具有修复作用,其治疗机制可能与上调炎症抑制因子IL-10的表达有关。
Central nervous system disorders (CNS) mainly including cerebrovascular diseases (intracerebral hemorrhage and intracerebral ischemsia), neural degenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc), seriously threaten peoples'life. The neruological function and brain struction are difficult to recover from injury because neurons can not regenergate. At present, there are no ideal therapeutic methods for those disorders which affect the life quality of patients seriously. Stem cell therapy is a promsing treatment for neulogical disorders.
MSCs exist in connective tissue and the interstitium of organ all over the body and maily reside in bone marrow, which belong to mesodermal multipotent stem cells. MSCs are readily obtained, can be expanded rapidly in vitro, and have low immunogenicity. The MSCs derived from bone marrow were called bone marrow derived-MSCs (BMSCs). MSCs become an attractive candidate for cell therapy and tissue engineering since MSCs were reported that can differentiated into neural cells in the brain. hBMSCs used in this experiment derived from healthy male bone marrow, were confimed having the ablity of multi-directional differentiation. Beacuse hBMSCs can be easily obtained, quickly amplificated ex vivo, autoplastic transplanted, induce immune tolerance, relieve or inhibit graft-versus-host diseases, hBMSCs was widely used in the preclinical or clinical research in nerve system disease, autoimmune diseases or blood diseases.
The routes of stem cell adminsteration mainly include intracerebral injection, veno-or arterio-injection, abdominal cavity injection and cerebrospinal fluid injection. MSCs reached to brain lesions need time and the onset time was later by the indirectly routes. On the contary, intracerebral injection has many advantages. It has been reported that there were no obvius side effects when MSCs form homogeneity transplanted into the variant brain. How about the safety of intracerebral injection? Can hBMSCs migrate into the brain? Can MSCs differentiate into neural cells? What's the routes and mechanism of migration of hBMSCs if hBMSCs can migrate throughout the brain? So, the safety evaluation of hBMSCs engraftment, the distribution and differentiation of hBMSCs are very important and critical. Small animals (Wistar rats) and non-human primate animals (Macaca Fascicularis) were used to evaluate the safety of intracerebral injection, and engraftment, distribution and differentiation of transplanted-hBMSCs and its migrated mechanisms in the CNS. The transplanted cells were traced by detecting male DNA and labeling in vivo. Double immunofluorescence staining was used to observe the differentiation of hBMSCs. We also detected the mRNA level of neurophins, cytokines, and adhesion molecules by real-time PCR and immunohistochemical staining.
Our results indicated that no inflammatory reaction and immunological rejection was detected, and negeneration and necrosis of neural cells were absent in the local injection sites. The transplanted hBMSCs survived, and migrated into the brain after 2 and 4 weeks transplantation. Although hBMSCs were injected unilaterally, male DNA was detected in both brain hemispheres and its distribution was overlapping between transplant recipients. Male DNA also tended to extend rostrally into the forebrain as a function of time posttransplantation, although the difference between 2 and 4 weeks posttransplant was not statistically significant. In rats, hBMSCs migrated along the asllosum-external capsule to the opposite side. We also observed tranlplanted hBMSCs tended to migrate toward vascular and ependymal layer, which may suggest one migratory route of hBSMCs.
We also observed transplanted-hBMSCs expressed neuron maker (NeuN) and glial cell maker (GFAP) rather than neural stem cell marker (Nestin). In addtion, the mRNA levels of parts of neurotrophins and growth factors tended to upregulate. Therefore, we speculated that neurotrophins and growth factors might paly great roles in survival and differentiation of stem cells. The expression of N-cadherin increased too after hBMSCs transplantation. N-cadherin plays great roles in migration of neural cells during the devopment of CNS. So, N-cadherin may be one chemotatic factor for hBMSCs' migration. Human UCMSCs were used to detect the role of N-cadherin in stem cells' migration. The results demonstrated that N-cadherin induced the migration of hUCMSCs and increased the expression of endogenous N-cadherin andβ-catenin of hUCMSCs. N-cadherin/β-catenin signalling pathway may paly a role in migration of stem cells.
In conclusion, intracerebral transplantation is safe in four weeks. And hBMSCs can migrate into the brain and differentiate into neural cells. The upregulated expression of neurotrophins, growth factors, and N-cadherin in response to hMSCs transplantion may be one mechanism of migration.
Objective To investigate the role of IL-10 in treatment of cynomolgus macaques brain ischemia by human bone marrow-derived msenchymal stem cell (hBMSCs) transplantation.
Methods A non-human primate ischemia model was used to test the hypothesis that transplanted human bone-marrow-derived MSCs (hBMSCs) exert a neuroprotective effects on cerebral ischemia and upregulate IL-10 expression. We also assessed neuronal apoptosis and astroglial activity in the area around the ischemic lesion and proliferating cells in thesubventricular zone (SVZ).
Results Results showed that hBMSC transplantation in ischemic tissues improved the neurological functions and induced an increase in IL-10 expression. In addition, neuronal apoptosis and astroglial activity in the peri-ischemic area decreased, and the number of proliferating cells in the SVZ increased.
Conclusion hBMSC transplantation does greatly help the repair of ischemic injury in cynomolgus macaques and the effectiveness of treatment may be associated with the increase of anti2inflammary factor IL-10.
MSCs为中胚层来源的多能干细胞,主要存在于全身结缔组织和器官间质中,以骨髓组织中含量最为丰富。来源于骨髓的MSCs称为骨髓MSCs (bone marrow-derived MSCs, BMSCs),其具有多向分化的潜力,获取方便,易于分离培养和鉴定,遗传背景稳定,体内植入免疫反应比较弱等优点。自从首次报道间充质干细胞(mesenchymal stem cells, MSCs)在脑内可以向神经细胞分化后,MSCs移植治疗中枢神经系统疾病就成为了非常感兴趣的课题。本实验采用的人BMSCs (human hBMSCs)来源于健康志愿者,前期工作已证实其在体外具有多向分化的潜能、并能快速扩增、可诱导免疫耐受、能减轻或抑制移植物抗宿主病等,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。
目前MSCs的移植途径主要包括直接脑内注射和间接通过静脉、动脉及腹腔注射等。间接途径移植为全身治疗,到达病变部位的时间较长,细胞数量较少,发挥作用较慢等,而脑内注射移植为局部治疗,创伤小,起效快,并且脑内的免疫应答能力比较弱,因此直接脑内注射成为局部治疗中枢神经系统疾病的一个很好的选择。已有研究报道同种异体BMSCs小鼠脑内移植没有发现明显副作用,并能在大脑内迁移和向神经细胞方向分化。但hBMSCs直接脑内移植的安全性如何?其脑内移植后能否进行迁移?能否分化为神经元及其他神经细胞?如果hBMSCs能够在脑内进行迁移,其迁移途径及迁移机制如何?这些都是hBMSCs临床应用前期亟需解决的问题。
方法我们分别利用小动物Wistar大鼠和与人类最为接近的非人灵长类动物食蟹猴作为研究对象,脑内直接注射hBMSCs,观察hBMSCs直接脑内注射的安全性,通过对hBMSCs体外标记示踪和携带的男性特异基因的检测观察hBMSCs在脑内的迁移及迁移途径,应用免疫荧光双标记观察移植的hBMSCs在脑内的分化。Real-time PCR及免疫组织化学的方法用来检测部分神经营养因子、细胞因子以及黏附分子在hBMSCs移植后的表达情况。
结果我们的结果显示直接脑内注射hBMSCs未引起受试动物出现全身症状,包括精神、饮食、运动等方面。移植hBMSCs的局部脑组织炎症反应比较局限,未观察到明显的免疫反应,未观察到脑组织的变性坏死和明显胶质细胞聚集。hBMSCs移植4周后,仍大量存活,并可在脑内广泛迁移,且迁移分布具有一定的规律性,可观察到不同移植受体细胞分布重叠现象。hBMSCs迁移分布模式图显示不管是在大鼠,还是在食蟹猴,hBMSCs有从前脑向后脑迁移的趋势。在大鼠,hBMSCs主要沿胼胝体-外囊轴线和室管膜下方向迁移,而且随着移植时间的推移,hBMSCs逐渐向对侧迁移；在食蟹猴,hBMSCs有向血管和室管膜下迁移的趋势。因此我们推测血液循环和脑脊液循环可能是hBMSCs迁移的一个途径之一。
免疫荧光双标记结果显示移植的hBMSCs能表达神经元的标记物NeuN和神经胶质细胞的标记物GFAP,说明hBMSCs可在脑内向神经细胞方向分化。hBMSCs移植后,部分神经营养因子和生长因子和神经钙粘素(N-cadherin)表达明显升高。神经钙粘素介导神经系统发育过程中神经细胞的迁移,在细胞的迁移过程中也发挥重要作用,因此, N-cadherin也可能诱导hBMSCs在脑内的迁移。我们应用hUCMSCs作为研究对象,应用transwell小室迁移系统检测了N-cadherin对hUCMSCs的体外迁移作用,结果表明N-cadherin具有明显趋化hUMSCs迁移的作用,并且发现其能够上调细胞内源性N-cadherin和p连环蛋白的表达,因此N-cadherin也可能介导了hBMSCs在脑内的迁移。
结论hBMSCs直接脑内注射移植,没有引起明显的副作用；hBMSCs可以在脑内长期存活,并能进行迁移和分化；hBMSCs移植后上调脑组织内部分细胞因子和神经钙粘素的表达,这可能是其在脑内迁移的一个机制之一
目的探讨食蟹猴脑缺血模型在人骨髓间充质干细胞(human bone marrow2derived mesenchymal stem cells, hBMSCs)移植后对脑缺血损伤的保护作用和IL-10的表达情况。
方法食蟹猴8只,在脑定位仪定位下,应用光化学法构建食蟹猴脑缺血模型,并将其随机分为高剂量治疗组、低剂量治疗组和模型组,分别在脑缺血部位附近注射高、低密度的hBMSCs和生理盐水。术后,通过影像学、神经功能评分及组织病理学观察对hBMSC的治疗效果进行评价。并应用原位细胞凋亡检测的方法观察脑缺血周围脑组织神经细胞的凋亡情况,免疫组织化学的方法被用来观察脑缺血周围脑组织神经胶质细胞反应和室管膜下细胞的增殖情况,并应用免疫组织化学、real-time PCR和Western blot检测检测脑损伤周围IL-10的表达水平。
结果与模型组相比,hBMSCs移植能明显改善脑缺血模型的症状,hBMSC治疗能够减少损伤部位周围细胞的凋亡,减轻脑缺血周围脑组织的胶质细胞反应,促进室管膜下细胞的增殖。免疫组织化学显示IL-10阳性细胞的数量及染色强度均较模型组明显升高,real-time PCR和Western Blot也证明IL-10在hBMSCs移植治疗后表达升高。
结论hBMSCs对食蟹猴脑缺血模型具有修复作用,其治疗机制可能与上调炎症抑制因子IL-10的表达有关。
Central nervous system disorders (CNS) mainly including cerebrovascular diseases (intracerebral hemorrhage and intracerebral ischemsia), neural degenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, etc), seriously threaten peoples'life. The neruological function and brain struction are difficult to recover from injury because neurons can not regenergate. At present, there are no ideal therapeutic methods for those disorders which affect the life quality of patients seriously. Stem cell therapy is a promsing treatment for neulogical disorders.
MSCs exist in connective tissue and the interstitium of organ all over the body and maily reside in bone marrow, which belong to mesodermal multipotent stem cells. MSCs are readily obtained, can be expanded rapidly in vitro, and have low immunogenicity. The MSCs derived from bone marrow were called bone marrow derived-MSCs (BMSCs). MSCs become an attractive candidate for cell therapy and tissue engineering since MSCs were reported that can differentiated into neural cells in the brain. hBMSCs used in this experiment derived from healthy male bone marrow, were confimed having the ablity of multi-directional differentiation. Beacuse hBMSCs can be easily obtained, quickly amplificated ex vivo, autoplastic transplanted, induce immune tolerance, relieve or inhibit graft-versus-host diseases, hBMSCs was widely used in the preclinical or clinical research in nerve system disease, autoimmune diseases or blood diseases.
The routes of stem cell adminsteration mainly include intracerebral injection, veno-or arterio-injection, abdominal cavity injection and cerebrospinal fluid injection. MSCs reached to brain lesions need time and the onset time was later by the indirectly routes. On the contary, intracerebral injection has many advantages. It has been reported that there were no obvius side effects when MSCs form homogeneity transplanted into the variant brain. How about the safety of intracerebral injection? Can hBMSCs migrate into the brain? Can MSCs differentiate into neural cells? What's the routes and mechanism of migration of hBMSCs if hBMSCs can migrate throughout the brain? So, the safety evaluation of hBMSCs engraftment, the distribution and differentiation of hBMSCs are very important and critical. Small animals (Wistar rats) and non-human primate animals (Macaca Fascicularis) were used to evaluate the safety of intracerebral injection, and engraftment, distribution and differentiation of transplanted-hBMSCs and its migrated mechanisms in the CNS. The transplanted cells were traced by detecting male DNA and labeling in vivo. Double immunofluorescence staining was used to observe the differentiation of hBMSCs. We also detected the mRNA level of neurophins, cytokines, and adhesion molecules by real-time PCR and immunohistochemical staining.
Our results indicated that no inflammatory reaction and immunological rejection was detected, and negeneration and necrosis of neural cells were absent in the local injection sites. The transplanted hBMSCs survived, and migrated into the brain after 2 and 4 weeks transplantation. Although hBMSCs were injected unilaterally, male DNA was detected in both brain hemispheres and its distribution was overlapping between transplant recipients. Male DNA also tended to extend rostrally into the forebrain as a function of time posttransplantation, although the difference between 2 and 4 weeks posttransplant was not statistically significant. In rats, hBMSCs migrated along the asllosum-external capsule to the opposite side. We also observed tranlplanted hBMSCs tended to migrate toward vascular and ependymal layer, which may suggest one migratory route of hBSMCs.
We also observed transplanted-hBMSCs expressed neuron maker (NeuN) and glial cell maker (GFAP) rather than neural stem cell marker (Nestin). In addtion, the mRNA levels of parts of neurotrophins and growth factors tended to upregulate. Therefore, we speculated that neurotrophins and growth factors might paly great roles in survival and differentiation of stem cells. The expression of N-cadherin increased too after hBMSCs transplantation. N-cadherin plays great roles in migration of neural cells during the devopment of CNS. So, N-cadherin may be one chemotatic factor for hBMSCs' migration. Human UCMSCs were used to detect the role of N-cadherin in stem cells' migration. The results demonstrated that N-cadherin induced the migration of hUCMSCs and increased the expression of endogenous N-cadherin andβ-catenin of hUCMSCs. N-cadherin/β-catenin signalling pathway may paly a role in migration of stem cells.
In conclusion, intracerebral transplantation is safe in four weeks. And hBMSCs can migrate into the brain and differentiate into neural cells. The upregulated expression of neurotrophins, growth factors, and N-cadherin in response to hMSCs transplantion may be one mechanism of migration.
Objective To investigate the role of IL-10 in treatment of cynomolgus macaques brain ischemia by human bone marrow-derived msenchymal stem cell (hBMSCs) transplantation.
Methods A non-human primate ischemia model was used to test the hypothesis that transplanted human bone-marrow-derived MSCs (hBMSCs) exert a neuroprotective effects on cerebral ischemia and upregulate IL-10 expression. We also assessed neuronal apoptosis and astroglial activity in the area around the ischemic lesion and proliferating cells in thesubventricular zone (SVZ).
Results Results showed that hBMSC transplantation in ischemic tissues improved the neurological functions and induced an increase in IL-10 expression. In addition, neuronal apoptosis and astroglial activity in the peri-ischemic area decreased, and the number of proliferating cells in the SVZ increased.
Conclusion hBMSC transplantation does greatly help the repair of ischemic injury in cynomolgus macaques and the effectiveness of treatment may be associated with the increase of anti2inflammary factor IL-10.
引文
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