人脐带间充质干细胞移植治疗脑血管疾病的实验研究
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摘要
背景：脑血管疾病是一类严重威胁人类健康的神经系统疾病，脑血管疾病包括脑缺血和脑出血两种亚型，因出血或缺血导致神经组织损伤从而引起神经功能的障碍或缺失，至今临床上仍无有效的治疗办法。干细胞技术的发展为治疗甚至治愈脑血管疾病提供了可能。胚胎干细胞和成体干细胞都可以作为治疗神经系统疾病的种子细胞。间充质干细胞(Mesenchymal stem cells，MSC)属于成体干细胞，相对于胚胎干细胞和其它成体干细胞如神经干细胞等具有多方面的优点，因此近年来倍受研究者们的关注。实验证明，间充质干细胞对神经退行性疾病、神经免疫性疾病、神经系统损伤性疾病和脑血管疾病都有积极的治疗意义，尽管其潜在的作用机制尚未明确。最近，脐带(Umbilical cord，UC)被发现可以作为MSC的理想来源，因此脐带MSC(UC-MSC)是否可以成为治疗脑血管疾病的理想种子细胞，值得进我们去研究。
目的：建立大鼠脑出血和脑缺血两种脑血管疾病模型，探讨人UC-MSC移植对大鼠脑血管的作用和作用机制，为人UC-MSC在神经科学领域的临床应用提供理论依据和实验基础。
方法：利用酶消化法从足月妊娠剖宫产健康新生儿的脐带，通过贴壁法取得到原代培养的细胞，消化传代后，取P4-P6代的细胞移植用。线栓法制备SD大鼠大脑中动脉缺血再灌注(MCAO)模型，纹状体内定点注射细菌Ⅶ型胶原酶制备大鼠脑出血(ICH)模型。于24小时后，将体外荧光标记的人脐带MSC损伤局部注射到脑缺血或脑出血模型中，在移植后的4周(或5周)每周进行一次mNSS和Morris水迷宫两种神经功能的评价，在移植后14天，行TTC染色分析脑缺血梗死面积的大小。脑出血的体积在28天检测，并进行结晶紫/速兰蓝色显示其损伤区域。移植后7天，用vWF或ASMA染色脑组织切片，统计脑缺血/脑出血周围区域的血管密度，并且用相应的促血管增生因子抗体染色分析分析脑组织VEGF和bFGF的水平。另外，在脑出血大鼠移植实验中，细胞移植后3天，我们还分析了损伤组织周围的炎症细胞浸润程度、神经元凋亡程度、以及活性氧簇(ROS)和基质金属蛋白酶(MMPs)的浓度。同时，我们还评价了UC-MSC在体外的成血管能力和向神经诱导分化的情况。
结果：UC-MSC在体外能够分化成为血管细胞和神经细胞，移植到脑缺血和脑出血模型中mNSS评分和Morris水迷宫潜伏期明显短于PBS对照组。移植后七天接受UC-MSC治疗的脑缺血或脑出血大鼠损伤周围去的血管密度明显高于它们的对照组，在MCAO实验中，UC-MSC移植后的大鼠血管密度也明显高于对照组。此外，在ICH中，UC-MSC治疗能够有效的抑制炎症细胞的浸润，降低ROS和MMPs的浓度。
结论：人脐带MSC可以有效促进脑缺血和脑出血大鼠的神经功能恢复，其潜在的机制和血管新生、抑制炎症相关。
Background: Cerebrovascular diseases, which include cerebral ischemia and hemorrhage, represent severe clinical events of central nervous system disorder. Until today, effective therapeutic strategy is still lacking as to the neurological deficits after the occurrence of these diseases. The advancement of stem cell technology bring about prospectives in the treatment of these disorders. The candidate of stem cells includes embryonic stem cells (ESC) as well as adult stem cells, among which, mesenchymal stem cells (MSC) seem to be a more promising one regarding their advantages over ESC and other type of adult stem cells like neural stem cells (NSC). It has been proven that MSC could be beneficial in the treatment of a variety of diseases in central nervous system, though the underlying mechanisms are still unknown. Umbilical cord tissue has been recently regarded as a rich and ideal source of MSC thus umbilical cord derived MSC (UC-MSC) are deserved to be investigated in the treatment of cerebrovascular diseases.
Objective: This study was designed to determine if UC-MSC intracerebarl transplantation of UC-MSC could promote the recovery of neurological functions after middle cerebral artery occlusion (MCAO) and intracerebral hemorrhage (ICH) in rats, and meantime to analyze the potential mechanisms.
Methods: UC-MSC were isolated by cocktail enzyme digestion of human umbilical cords, CM-DiI labeled passage 4-6 UC-MSC were injected intracerebrally into the MCAO or ICH rats. Neurological evaluation including mNSS and Morris water maze test were conducted every week after transplantation. The injured volume of MCAO and ICH rats were calculated at 14 days and 28 days post-transplantation, respectively. In addition, vascular density and pro-angiogenic factors VEGF and bFGF were detected at 7 days after treatment in use of specific antibodies. In ICH rats, infiltration of inflammatory cells, reactive oxygen species (ROS) level and matrix metalloproteinase (MMPs) activity were detected at 3 days after transplantation. We also evaluated angiogenic and neurogenic potentials of UC-MSC in vitro.
Results: UC-MSC could differentiate into both vascular cells and neural cells in vitro. Rats of MCAO and ICH received UC-MSC treatment show significant improved neurological functions as revealed by mNSS and water maze test. In addition, at 7 days after injection, the vascular density around injured region was drastically increased in UC-MSC treated rats in both MCAO and ICH model as compared to PBS groups. In ICH model, UC-MSC treatment can inhibit the leucocytes infiltration and microglial activation, ROS production and MMPs activity around ICH region.
Conclusions: Human UC-MSC could effectively accelerate the recovery of neurological function after cerebrovascular diseases, and the underlying mechanisms may be associated with their ability to promote angiogenesis and inhibit inflammation.
目的：建立大鼠脑出血和脑缺血两种脑血管疾病模型，探讨人UC-MSC移植对大鼠脑血管的作用和作用机制，为人UC-MSC在神经科学领域的临床应用提供理论依据和实验基础。
方法：利用酶消化法从足月妊娠剖宫产健康新生儿的脐带，通过贴壁法取得到原代培养的细胞，消化传代后，取P4-P6代的细胞移植用。线栓法制备SD大鼠大脑中动脉缺血再灌注(MCAO)模型，纹状体内定点注射细菌Ⅶ型胶原酶制备大鼠脑出血(ICH)模型。于24小时后，将体外荧光标记的人脐带MSC损伤局部注射到脑缺血或脑出血模型中，在移植后的4周(或5周)每周进行一次mNSS和Morris水迷宫两种神经功能的评价，在移植后14天，行TTC染色分析脑缺血梗死面积的大小。脑出血的体积在28天检测，并进行结晶紫/速兰蓝色显示其损伤区域。移植后7天，用vWF或ASMA染色脑组织切片，统计脑缺血/脑出血周围区域的血管密度，并且用相应的促血管增生因子抗体染色分析分析脑组织VEGF和bFGF的水平。另外，在脑出血大鼠移植实验中，细胞移植后3天，我们还分析了损伤组织周围的炎症细胞浸润程度、神经元凋亡程度、以及活性氧簇(ROS)和基质金属蛋白酶(MMPs)的浓度。同时，我们还评价了UC-MSC在体外的成血管能力和向神经诱导分化的情况。
结果：UC-MSC在体外能够分化成为血管细胞和神经细胞，移植到脑缺血和脑出血模型中mNSS评分和Morris水迷宫潜伏期明显短于PBS对照组。移植后七天接受UC-MSC治疗的脑缺血或脑出血大鼠损伤周围去的血管密度明显高于它们的对照组，在MCAO实验中，UC-MSC移植后的大鼠血管密度也明显高于对照组。此外，在ICH中，UC-MSC治疗能够有效的抑制炎症细胞的浸润，降低ROS和MMPs的浓度。
结论：人脐带MSC可以有效促进脑缺血和脑出血大鼠的神经功能恢复，其潜在的机制和血管新生、抑制炎症相关。
Background: Cerebrovascular diseases, which include cerebral ischemia and hemorrhage, represent severe clinical events of central nervous system disorder. Until today, effective therapeutic strategy is still lacking as to the neurological deficits after the occurrence of these diseases. The advancement of stem cell technology bring about prospectives in the treatment of these disorders. The candidate of stem cells includes embryonic stem cells (ESC) as well as adult stem cells, among which, mesenchymal stem cells (MSC) seem to be a more promising one regarding their advantages over ESC and other type of adult stem cells like neural stem cells (NSC). It has been proven that MSC could be beneficial in the treatment of a variety of diseases in central nervous system, though the underlying mechanisms are still unknown. Umbilical cord tissue has been recently regarded as a rich and ideal source of MSC thus umbilical cord derived MSC (UC-MSC) are deserved to be investigated in the treatment of cerebrovascular diseases.
Objective: This study was designed to determine if UC-MSC intracerebarl transplantation of UC-MSC could promote the recovery of neurological functions after middle cerebral artery occlusion (MCAO) and intracerebral hemorrhage (ICH) in rats, and meantime to analyze the potential mechanisms.
Methods: UC-MSC were isolated by cocktail enzyme digestion of human umbilical cords, CM-DiI labeled passage 4-6 UC-MSC were injected intracerebrally into the MCAO or ICH rats. Neurological evaluation including mNSS and Morris water maze test were conducted every week after transplantation. The injured volume of MCAO and ICH rats were calculated at 14 days and 28 days post-transplantation, respectively. In addition, vascular density and pro-angiogenic factors VEGF and bFGF were detected at 7 days after treatment in use of specific antibodies. In ICH rats, infiltration of inflammatory cells, reactive oxygen species (ROS) level and matrix metalloproteinase (MMPs) activity were detected at 3 days after transplantation. We also evaluated angiogenic and neurogenic potentials of UC-MSC in vitro.
Results: UC-MSC could differentiate into both vascular cells and neural cells in vitro. Rats of MCAO and ICH received UC-MSC treatment show significant improved neurological functions as revealed by mNSS and water maze test. In addition, at 7 days after injection, the vascular density around injured region was drastically increased in UC-MSC treated rats in both MCAO and ICH model as compared to PBS groups. In ICH model, UC-MSC treatment can inhibit the leucocytes infiltration and microglial activation, ROS production and MMPs activity around ICH region.
Conclusions: Human UC-MSC could effectively accelerate the recovery of neurological function after cerebrovascular diseases, and the underlying mechanisms may be associated with their ability to promote angiogenesis and inhibit inflammation.
引文
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