兔骨髓间充质干细胞对肿瘤局部免疫功能影响的实验研究
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摘要
目的观察兔骨髓间充质干细胞(MSCs)体外对T淋巴细胞免疫功能的影响。
方法密度梯度离心法联合细胞贴壁法分离培养扩增MSCs,流式细胞仪检测MSCs表面抗原,培养的MSCs行酸性磷酸酶染色(ACP)、过碘酸—雪夫染色(PAS)、碱性磷酸酶染色(NAP);应用尼龙棉柱分离T淋巴细胞;用植物血凝素(PHA)刺激与或未与MSCs共培养3天的T淋巴细胞,应用MTT法测定T淋巴细胞的增殖,ELISA法检测反应体系中IL-2、IL-4、IL-10、IFN-γ的分泌。
结果MSCs形态均匀,生长曲线显示增长能力强,MSCs鉴定:ACP(-),PAS(+),NAP(-),CD29(+),CD34(-),CD44(+),CD45(-),Ⅰ型胶原和Ⅱ型胶原均有表达。MSCs及其培养上清抑制PHA刺激引起的T淋巴细胞的增殖,且这种抑制作用是呈剂量依赖性的。MSCs及其培养上清抑制T淋巴细胞IL-2、IFN-γ的分泌;MSCs促进T淋巴细胞IL-4、IL-10的分泌。
结论本实验获得性能可靠的兔MSCs;MSCs及其培养上清对T淋巴细胞增殖表现为抑制效应,MSCs抑制Th1细胞分泌IL-2和IFN-γ,但对Th2细胞分泌Ⅱ-4和IL-10的作用相反。此外,MSCs培养上清液亦可抑制IL-2和IFN-γ。其抑制T淋巴细胞增殖的作用机制可能包括直接接触及通过改变T淋巴细胞分泌细胞因子的种类和数量影响T淋巴细胞增殖。
意义本实验结果表明MSCs可能通过可溶性因子调节Th1/Th2反应平衡,抑制Th1细胞亚群的功能发挥免疫调节作用,诱导免疫耐受,为MSCs治疗自身免疫性疾病提供了理论依据。
目的探讨兔骨髓间充质干细胞对肿瘤局部免疫功能的影响。
方法22只新西兰大白兔随机分为实验组与对照组,每只动物均行胫骨近端骨髓穿刺抽取骨髓培养间充质干细胞。间充质干细胞培养成功后,所有新西兰大白兔均采用大腿肌肉瘤块包埋法制作肿瘤动物模型。两组动物移植肿瘤1周后,实验组培养的自体骨髓间充质干细胞回输入生成的肿瘤内,每周1次,连续3次,其中第一次输入的F2代间充质干细胞用DAPI标记,用以定位回输入肿瘤组织中的间充质干细胞,对照组回输等量的DMEM。两组动物移植瘤块后第1、2、3、4周各行B超检查一次,记录每只动物生成的肿瘤最大径并计算每组动物肿瘤最大经平均值。第3周两组各处死1只肿瘤直径接近各组平均值的动物,第4周处死所有动物,解剖观察肿瘤生长及转移情况。所有肿瘤标本均连续冰冻切片,免疫组化法检测CD4~+T、CD8~+T淋巴细胞数量。ELISA试剂盒检测肿瘤组织中IL-2、IL-4、IL-10及IFN-γ的含量。
结果种植瘤块后第一周与第二周肿瘤生长缓慢,实验组与对照组肿瘤最大径平均值相比较差异无显著统计学意义(P＞0.05)。第三、四周实验组肿瘤的生长速度逐渐增快,两组肿瘤最大径平均值的差异逐渐增大,且两组相比差异均出现显著统计学意义(P＜0.05)。经DAPI标记的骨髓间充质干细胞回输入肿瘤组织后分布于肿瘤间质组织或浸润边缘。免疫组化染色结果显示实验组CD4~+T及CD8~+T淋巴细胞均较对照组明显减少,主要分布在肿瘤细胞周边,肿瘤组织内也有少量浸润。ELISA结果显示实验组IL-2、IFN-γ较对照组明显减少,差异有显著统计学意义(P＜0.05),而IL-4较对照组增加,两组比较差异有显著统计学意义(P＜0.05),IL-10分泌也较对照组增加,但差异无显著统计学意义(P＞0.05)。
结论兔骨髓间充质干细胞进入肿瘤组织后,在肿瘤局部抑制机体抗肿瘤免疫。机制之一可能是通过影响细胞因子的分泌下调机体的抗肿瘤免疫。
意义我们的实验结果表明骨髓间充质干细胞在肿瘤局部发挥免疫抑制效应,下调机体对肿瘤的细胞免疫,结合本课题前期研究结果骨髓间充质干细胞在肿瘤微环境诱导下可以分化为肌纤维母细胞,因此我们推测体内骨髓间充质干细胞可能参与了肿瘤的发生与发展,这一假设从另一角度阐述了实体肿瘤发展的可能机制。由于骨髓间充质干细胞具有低免疫原性,肿瘤又具有富集骨髓间充质干细胞的能力,很多学者已利用这些特点将骨髓间充质干细胞作为肿瘤治疗药物的载体;由于我们的研究结果已经提示骨髓间充质干细胞有助于肿瘤的发展,因此将骨髓间充质干细胞作为肿瘤治疗药物的载体的生物安全性问题值得进一步深入研究。
OBJECTIVE To investigate the immunoregulatory effect of rabbit bone marrow mesenchymal stem cells on T lymphocytes in vitro.
METHODS MSCs were obtained by density gradient centrifugation with Percoll solution and sticking plastic bottle repeatedly;The surface markers CD29,CD34, CD44 and CD45 were tested by flow cytometry;The cultured MSCs were stained by ACP,PAS and NAP;T lymphocytes were harvested by using nylon column and T lymphocyte proliferation in the presence of PHA was evaluated by MTT;ELISA was used to detect the secretion of IL-2、IL-4、IL-10 and IFN-γ.
RESULTS MSCs were homogenous population,the cell curve showed MSCs had a good ability of proliferation.The cultured MSCs were ACP(-),PAS(+),NAP(-), CD29(+),CD34(-),CD44(+),CD45(-).MSCs and the supernatant inhibited T lymphocytes proliferation and the inhibitory effect depended on the amount of MSCs.IL-2 and IFN-γsecretion of T lymphocytes were suppressed by MSCs or the supematant significantly,IL-4 and IL-10 secretion were promoted by MSCs at the same time.
CONCLUSION MSCs obtained in this study was reliable.MSCs and the supernatant suppressed the proliferation of T lymphocytes.MSCs or the supernatant could suppress the secretion of IL-2 and IFN-γ,but MSCs had a different result on the secretion of IL-4 and IL-10.MSCs and the supematant might suppress T lymphocytes proliferation through alter cytokine variety and amount of T lymphocytes secretion.
SIGNIFICANCE This experiment proved that MSCs could regulate the balance of Th1/Th2 by secretion of cytokines,induce the immunotolerance by inhibiting Th1 subset,which provided the theoretic support to treat autoimmune diseases.
OBJECTIVE To study the effect of bone marrow mesenchymal stem cells on immunoregulation in tumor tissue in rabbit.
METHODS 22 New Zealand white rabbits were randomly classified into the control group and the test group equally.Bone marrow mesenchymal stem cells were isolated from tibia of each animal.When the mesenchymal stem cells of each animal were cultured successfully,VX-2 tumor tissue was embedded in the thigh muscle of each animal.One week after the transplantation,the mesenchymal stem cells were self transplanted into tumor tissue in the test group while equal DMEM was injected in the control group one time every week for three weeks.F2 passage mesenchymal stem cells were marked by DAPI for locating the distribution in tumor tissue.The ultrasonography was performed for each animal 1,2,3,4 week(s)after the tumor mass was embedded in the thigh muscle.The maximum tumor diameter of each animal was recorded and the mean value of each group was calculated.One animal of each group was put to death in the third week and all the left animals were killed in the fourth week to observe the tumor development.All the tumor samples were made successive frozen section.Immunohistochemical stain and ELISA were performed to determine the content of CD4~+T,CD8~+T and cytokines.
RESULTS The ultrasonography showed the tumor was growing slowly in the first and second week after the VX-2 tumor mass transplantation.The mean maximum tumor diameter of the control group and test group was no significant difference between them(P＞0.05).The tumor growth velocity of the test group increased gradually in the third and fourth week,and the difference of the mean maximum tumor diameter between the two groups increased gradually too,statistical significance appeared when comparing each other(P＜0.05).The mesenchymal stem cells were more likely to distribute in tumor stroma or the invasive border,only very few mesenchymal stem cells were seen in the tumor nest.The result of immunohistochemical stain showed that the contents of CD4~+T cells and CD8~+ T cells were decreased obviously,there was significant difference between the test group and the control group.The result of ELISA showed that the secretion of IL-2 and IFN-γwas decreased obviously in the test group while the secretion of IL-4 of test group was increased inversely,and there was significant difference between the test group and the control group.The secretion of IL-10 of the test group was also increase,but there was no significant difference between the two groups.
CONCLUSIONS Rabbit bone marrow mesenchymal stem cells could make the balance of Th1/Th2 to drift to Th2 so that inhibit the anti-tumor immune response through altering the cytokines secretion.
SIGNIFICANCE The results of our study show that rabbit bone marrow mesenchymal stem cells can inhibit the immune response in the tumor tissue,in addition,our topic prophase finding bone marrow mesenchymal stem cells may differentiate into myofibroblast under the induction of local tumor microenvironment, we thereby presume these cells may be related with tumor development.This hypothesis can explain the mechanism of tumor progression on another point of view. Because bone marrow mesenchymal stem cells possess the character of low immunogenicity and tumor have the ability to enrich mesenchymal stem cells,some researches have utilized mesenchymal stem cells as the drug carrier for tumor treatment.We have proved that mesenchymal stem cells can accelerate the tumor development in this study,so we think utilizing mesenchymal stem cells as the drug cartier for tumor treatment needs further researches to prove the biological safety.
方法密度梯度离心法联合细胞贴壁法分离培养扩增MSCs,流式细胞仪检测MSCs表面抗原,培养的MSCs行酸性磷酸酶染色(ACP)、过碘酸—雪夫染色(PAS)、碱性磷酸酶染色(NAP);应用尼龙棉柱分离T淋巴细胞;用植物血凝素(PHA)刺激与或未与MSCs共培养3天的T淋巴细胞,应用MTT法测定T淋巴细胞的增殖,ELISA法检测反应体系中IL-2、IL-4、IL-10、IFN-γ的分泌。
结果MSCs形态均匀,生长曲线显示增长能力强,MSCs鉴定:ACP(-),PAS(+),NAP(-),CD29(+),CD34(-),CD44(+),CD45(-),Ⅰ型胶原和Ⅱ型胶原均有表达。MSCs及其培养上清抑制PHA刺激引起的T淋巴细胞的增殖,且这种抑制作用是呈剂量依赖性的。MSCs及其培养上清抑制T淋巴细胞IL-2、IFN-γ的分泌;MSCs促进T淋巴细胞IL-4、IL-10的分泌。
结论本实验获得性能可靠的兔MSCs;MSCs及其培养上清对T淋巴细胞增殖表现为抑制效应,MSCs抑制Th1细胞分泌IL-2和IFN-γ,但对Th2细胞分泌Ⅱ-4和IL-10的作用相反。此外,MSCs培养上清液亦可抑制IL-2和IFN-γ。其抑制T淋巴细胞增殖的作用机制可能包括直接接触及通过改变T淋巴细胞分泌细胞因子的种类和数量影响T淋巴细胞增殖。
意义本实验结果表明MSCs可能通过可溶性因子调节Th1/Th2反应平衡,抑制Th1细胞亚群的功能发挥免疫调节作用,诱导免疫耐受,为MSCs治疗自身免疫性疾病提供了理论依据。
目的探讨兔骨髓间充质干细胞对肿瘤局部免疫功能的影响。
方法22只新西兰大白兔随机分为实验组与对照组,每只动物均行胫骨近端骨髓穿刺抽取骨髓培养间充质干细胞。间充质干细胞培养成功后,所有新西兰大白兔均采用大腿肌肉瘤块包埋法制作肿瘤动物模型。两组动物移植肿瘤1周后,实验组培养的自体骨髓间充质干细胞回输入生成的肿瘤内,每周1次,连续3次,其中第一次输入的F2代间充质干细胞用DAPI标记,用以定位回输入肿瘤组织中的间充质干细胞,对照组回输等量的DMEM。两组动物移植瘤块后第1、2、3、4周各行B超检查一次,记录每只动物生成的肿瘤最大径并计算每组动物肿瘤最大经平均值。第3周两组各处死1只肿瘤直径接近各组平均值的动物,第4周处死所有动物,解剖观察肿瘤生长及转移情况。所有肿瘤标本均连续冰冻切片,免疫组化法检测CD4~+T、CD8~+T淋巴细胞数量。ELISA试剂盒检测肿瘤组织中IL-2、IL-4、IL-10及IFN-γ的含量。
结果种植瘤块后第一周与第二周肿瘤生长缓慢,实验组与对照组肿瘤最大径平均值相比较差异无显著统计学意义(P＞0.05)。第三、四周实验组肿瘤的生长速度逐渐增快,两组肿瘤最大径平均值的差异逐渐增大,且两组相比差异均出现显著统计学意义(P＜0.05)。经DAPI标记的骨髓间充质干细胞回输入肿瘤组织后分布于肿瘤间质组织或浸润边缘。免疫组化染色结果显示实验组CD4~+T及CD8~+T淋巴细胞均较对照组明显减少,主要分布在肿瘤细胞周边,肿瘤组织内也有少量浸润。ELISA结果显示实验组IL-2、IFN-γ较对照组明显减少,差异有显著统计学意义(P＜0.05),而IL-4较对照组增加,两组比较差异有显著统计学意义(P＜0.05),IL-10分泌也较对照组增加,但差异无显著统计学意义(P＞0.05)。
结论兔骨髓间充质干细胞进入肿瘤组织后,在肿瘤局部抑制机体抗肿瘤免疫。机制之一可能是通过影响细胞因子的分泌下调机体的抗肿瘤免疫。
意义我们的实验结果表明骨髓间充质干细胞在肿瘤局部发挥免疫抑制效应,下调机体对肿瘤的细胞免疫,结合本课题前期研究结果骨髓间充质干细胞在肿瘤微环境诱导下可以分化为肌纤维母细胞,因此我们推测体内骨髓间充质干细胞可能参与了肿瘤的发生与发展,这一假设从另一角度阐述了实体肿瘤发展的可能机制。由于骨髓间充质干细胞具有低免疫原性,肿瘤又具有富集骨髓间充质干细胞的能力,很多学者已利用这些特点将骨髓间充质干细胞作为肿瘤治疗药物的载体;由于我们的研究结果已经提示骨髓间充质干细胞有助于肿瘤的发展,因此将骨髓间充质干细胞作为肿瘤治疗药物的载体的生物安全性问题值得进一步深入研究。
OBJECTIVE To investigate the immunoregulatory effect of rabbit bone marrow mesenchymal stem cells on T lymphocytes in vitro.
METHODS MSCs were obtained by density gradient centrifugation with Percoll solution and sticking plastic bottle repeatedly;The surface markers CD29,CD34, CD44 and CD45 were tested by flow cytometry;The cultured MSCs were stained by ACP,PAS and NAP;T lymphocytes were harvested by using nylon column and T lymphocyte proliferation in the presence of PHA was evaluated by MTT;ELISA was used to detect the secretion of IL-2、IL-4、IL-10 and IFN-γ.
RESULTS MSCs were homogenous population,the cell curve showed MSCs had a good ability of proliferation.The cultured MSCs were ACP(-),PAS(+),NAP(-), CD29(+),CD34(-),CD44(+),CD45(-).MSCs and the supernatant inhibited T lymphocytes proliferation and the inhibitory effect depended on the amount of MSCs.IL-2 and IFN-γsecretion of T lymphocytes were suppressed by MSCs or the supematant significantly,IL-4 and IL-10 secretion were promoted by MSCs at the same time.
CONCLUSION MSCs obtained in this study was reliable.MSCs and the supernatant suppressed the proliferation of T lymphocytes.MSCs or the supernatant could suppress the secretion of IL-2 and IFN-γ,but MSCs had a different result on the secretion of IL-4 and IL-10.MSCs and the supematant might suppress T lymphocytes proliferation through alter cytokine variety and amount of T lymphocytes secretion.
SIGNIFICANCE This experiment proved that MSCs could regulate the balance of Th1/Th2 by secretion of cytokines,induce the immunotolerance by inhibiting Th1 subset,which provided the theoretic support to treat autoimmune diseases.
OBJECTIVE To study the effect of bone marrow mesenchymal stem cells on immunoregulation in tumor tissue in rabbit.
METHODS 22 New Zealand white rabbits were randomly classified into the control group and the test group equally.Bone marrow mesenchymal stem cells were isolated from tibia of each animal.When the mesenchymal stem cells of each animal were cultured successfully,VX-2 tumor tissue was embedded in the thigh muscle of each animal.One week after the transplantation,the mesenchymal stem cells were self transplanted into tumor tissue in the test group while equal DMEM was injected in the control group one time every week for three weeks.F2 passage mesenchymal stem cells were marked by DAPI for locating the distribution in tumor tissue.The ultrasonography was performed for each animal 1,2,3,4 week(s)after the tumor mass was embedded in the thigh muscle.The maximum tumor diameter of each animal was recorded and the mean value of each group was calculated.One animal of each group was put to death in the third week and all the left animals were killed in the fourth week to observe the tumor development.All the tumor samples were made successive frozen section.Immunohistochemical stain and ELISA were performed to determine the content of CD4~+T,CD8~+T and cytokines.
RESULTS The ultrasonography showed the tumor was growing slowly in the first and second week after the VX-2 tumor mass transplantation.The mean maximum tumor diameter of the control group and test group was no significant difference between them(P＞0.05).The tumor growth velocity of the test group increased gradually in the third and fourth week,and the difference of the mean maximum tumor diameter between the two groups increased gradually too,statistical significance appeared when comparing each other(P＜0.05).The mesenchymal stem cells were more likely to distribute in tumor stroma or the invasive border,only very few mesenchymal stem cells were seen in the tumor nest.The result of immunohistochemical stain showed that the contents of CD4~+T cells and CD8~+ T cells were decreased obviously,there was significant difference between the test group and the control group.The result of ELISA showed that the secretion of IL-2 and IFN-γwas decreased obviously in the test group while the secretion of IL-4 of test group was increased inversely,and there was significant difference between the test group and the control group.The secretion of IL-10 of the test group was also increase,but there was no significant difference between the two groups.
CONCLUSIONS Rabbit bone marrow mesenchymal stem cells could make the balance of Th1/Th2 to drift to Th2 so that inhibit the anti-tumor immune response through altering the cytokines secretion.
SIGNIFICANCE The results of our study show that rabbit bone marrow mesenchymal stem cells can inhibit the immune response in the tumor tissue,in addition,our topic prophase finding bone marrow mesenchymal stem cells may differentiate into myofibroblast under the induction of local tumor microenvironment, we thereby presume these cells may be related with tumor development.This hypothesis can explain the mechanism of tumor progression on another point of view. Because bone marrow mesenchymal stem cells possess the character of low immunogenicity and tumor have the ability to enrich mesenchymal stem cells,some researches have utilized mesenchymal stem cells as the drug carrier for tumor treatment.We have proved that mesenchymal stem cells can accelerate the tumor development in this study,so we think utilizing mesenchymal stem cells as the drug cartier for tumor treatment needs further researches to prove the biological safety.
引文
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