原儿茶酸对脂肪干细胞体外增殖和迁移的影响
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摘要
间充质干细胞移植对缺血缺氧性和神经退行性等中枢神经系统疾病的治疗发挥了积极的作用。研究发现,移植入体内的间充质干细胞可以向病变部位迁移,并可在局部微环境的诱导下向组织损伤修复所急需的组织细胞分化,还可以分泌多种细胞因子,通过旁分泌的作用对受损组织发挥营养和保护作用。但是,移植后向病变部位迁移的间充质干细胞的比例较低,在一定程度上限制了细胞移植的作用。因此,在间充质干细胞移植的同时,应用药物等辅助手段促进细胞的迁移和增殖,提高病变局部的移植细胞数量,有可能提高细胞移植的治疗效果。
在具有神经保护作用的药物中,中药活性单体成分单一、结构明确、易于其作用机制的深入分析。在这些单体中找到具有促进间充质干细胞增殖和迁移作用的成分,辅助应用于中枢神经系统疾病的间充质干细胞移植治疗,可以在提高病变部位移植细胞数量的同时,发挥其对受损神经的保护作用,从而提高疾病治疗的综合效果。但是,具有神经保护作用的中药活性单体成分对间充质干细胞增殖和迁移的影响的研究尚未见报道。因此,在前期筛选工作的基础上,本文深入研究了具有神经保护作用的中药活性单体—原儿茶酸,对人脂肪干细胞体外增殖能力和体外迁移能力的影响,并对其相关机制进行了初步的探讨。
原儿茶酸处理后,人脂肪干细胞的形态没有显著变化,而且仍表达细胞表面抗原标志CD29、CD13和CD44,不表达CD34、CD45和HLADR。各表面抗原标记的表达量与对照组相比没有显著差异:经体外诱导分化实验证明,原儿茶酸处理后,人脂肪干细胞向成骨细胞、脂肪细胞、心肌细胞和神经细胞分化的能力没有显著变化;酶联免疫吸附实验结果显示,原儿茶酸处理没有影响人脂肪干细胞细胞因子IL-6和生长因子IGF-Ⅰ的分泌能力。因此,原儿茶酸处理后,人脂肪干细胞仍保持其多向分化潜能、细胞因子和生长因子分泌等生物学特性。
应用WST-8法检测了原儿茶酸对人脂肪干细胞的体外增殖的影响,发现原儿茶酸能够促进人脂肪干细胞的体外增殖能力,其作用呈现明显的剂量依赖性。0.5 mM,1.0mM和1.5 mM的原儿茶酸处理48小时后,人脂肪干细胞增殖能力分别提高51%,78%和103%。原儿茶酸发挥作用的最小浓度为0.5 mM,适宜浓度为1.5 mM。同时,1.5 mM原儿茶酸对人脂肪干细胞的体外增殖的促进作用呈现明显的时间依赖性,其发挥作用的最短时间是24小时,使细胞增殖能力提高66%;适宜作用时间是96小时,提高细胞增殖能力124%。此外,原儿茶酸对人脂肪干细胞的细胞凋亡没有明显的影响。
进一步通过DNA含量的检测分析了原儿茶酸对人脂肪干细胞细胞周期的影响,发现原儿茶酸能够促进人脂肪干细胞的细胞周期G0/G1期向S期的转换。在0.5 mM-1.5mM的浓度范围内,人脂肪干细胞的S期和G2/M期的细胞所占比例随原儿茶酸浓度的增加而呈明显上升趋势,处于G0/G1期的细胞所占比例随原儿茶酸浓度的增加呈相应的下降趋势。其中,1.5 mM原儿茶酸的作用最为明显,使S期细胞比例增加2倍。免疫蛋白印迹检测发现,原儿茶酸处理明显提高了细胞周期素D1的蛋白水平。为了进一步证明原儿茶酸对脂肪干细胞体外增殖的促进作用是否与细胞周期素D1蛋白表达的变化有关,本文应用RNA干扰技术对人脂肪干细胞的细胞周期素D1进行了转录后水平的基因沉默,结果显示,细胞周期素D1的siRNA干扰使原儿茶酸处理组人脂肪干细胞的体外增殖下降45%,与对照组细胞体外增殖的下降比例(26%)相比具有显著性差异,表明细胞周期素D1的siRNA干扰显著抑制了原儿茶酸对人脂肪干细胞体外增殖的促进作用,证实原儿茶酸通过对细胞周期素D1表达的调控促进了人脂肪干细胞的体外增殖能力。
应用明胶包被的双层细胞培养板,观察原儿茶酸对人脂肪干细胞体外迁移能力的影响。在0.5 mM-1.8 mM的浓度范围内,原儿茶酸处理人脂肪干细胞48小时能够显著提高其体外迁移能力,其作用呈现明显的剂量依赖性。0.5 mM,1.0 mM和1.5 mM的原儿茶酸处理的细胞迁移率分别提高35%,63%和82%。0.5 mM原儿茶酸是发挥其促进迁移作用的最小浓度,原儿茶酸发挥最大作用的浓度是1.5 mM。同时,原儿茶酸促进人脂肪干细胞迁移的作用具有时间依赖性。在1.5 mM原儿茶酸的作用下,细胞迁移能力显著提高的最短作用时间是24小时,适宜作用时间是48小时。
应用RT-PCR和荧光定量PCR分析发现,原儿茶酸处理能够使人脂肪干细胞膜型基质金属蛋白酶-1(MT1-MMP)的表达升高45%。明胶酶谱法分析人脂肪干细胞分泌的基质金属蛋白酶-2(MMP-2)的活性变化的结果显示,原儿茶酸对人脂肪干细胞分泌的MMP-2的总量没有明显影响,但是显著促进了MMP-2的活化,使活性型MMP-2增加至对照组的2倍左右。进一步应用MT1-MMP和MMP-2抗体进行阻断实验,分析MT1-MMP和MMP-2在原儿茶酸促进人脂肪干细胞体外迁移中的作用。结果显示,MT1-MMP和MMP-2抗体有效抑制了人脂肪干细胞的体外迁移能力,两种抗体分别使原儿茶酸对人脂肪干细胞迁移的促进作用从182%下降至60%和75%。证实原儿茶酸通过对MT1-MMP的表达和MMP-2酶原的活化的调控,调节人脂肪干细胞的迁移能力。
原儿茶酸能够提高人脂肪干细胞的迁移能力和增殖能力,因而有可能通过提高损伤组织局部的人脂肪干细胞的数量而提高移植的治疗效果。因此,原儿茶酸有可能在脂肪干细胞移植的辅助治疗中发挥重要作用。
Mesenchymal stem cells(MSCs) transplantation plays an important role in hypoxic-ischemic encephalopathy and neurodegenerative diseases.It has been reported that exogenous transplanted MSCs could migrate to the impaired sites,differentiate into the tissue-specific cells under the induction of local microenviroment,and secrete growth factors and trophic factors to protect the injured cells,thereby promote the restoration of the biological functions.However,the migration ratio of transplanted stem cells is usually low. Therefore,finding suitable pharmaceuticals for facilitating the proliferation and migration of MSCs could contribute to the development of cell therapy strategies.
There are many active ingredients in Chinese medicines with neuroprotective effect.If suitable pharmaceuticals for facilitating the migration and proliferation of transplanted stem cells are found from them,and used for hypoxic-ischemic encephalopathy and neurodegenerative diseases,combined with stem cell therapy,the therapeutic efficacy of these diseases will be improved.On the basis of screening research,we found that protocatechuic acid(PCA) from Alpinia(A.) oxyphylla could promote the proliferation of hADSCs in vitro.
The identification of PCA-treated hADSCs and control cells revealed that after PCA treatment,the morphology of hADSCs showed no obvious difference with control cells.Flow cytometric analysis of the cell surface antigens,osteogenic induction,adipogenic induction, cardiomyocyte-like cell induction and neural induction demonstrated that hADSCs retained their functional characteristics of multipotential mesenchymal progenitors after PCA treatment.Enzyme-linked immunosorbent assay showed that the capacity for the secretion of IL-6 and IGF-Ⅰof PCA-treated hADSCs was the same with control cells.
PCA could promote the proliferation capacity of hADSCs in vitro.The results of cell counts showed that the treatment of hADSCs with PCA for 48 h increased the cell number in a dose-dependent manner.0.5 mM PCA was the minimal dose to stimulate the proliferation enhancement of hADSCs,while the maximum effect of PCA appeared at the concentration of 1.5 mM.In addition,the cell number of hADSCs treated with 1.5 mM PCA at various time points increased in a time-dependent manner.The shortest treatment time for the promotion of hADSCs proliferation was observed at 24 hours,but the most effective time was at about 72 hours.
The flow cytometric analysis of DNA content demonstrated the cell cycle progressed from the G0/G1 phase to the S phase and the most pronounced effect was seen with 1.5 mM PCA,where the fraction of cells in S phase increased more than 2 folds,accompanied by a significant increase in the fraction of cells in G2/M phase and a significant decrease in the fraction of cells in G0/G1 phase.Western blot analysis revealed the elevated expression of cyclin D1 in hADSCs induced by 1.5 mM PCA treatment.Cyclin D1-siRNA transfection significantly inhibited the promotion of cell proliferation by PCA.These results suggest that PCA from A.oxyphylla promote the proliferation of hADSCs in vitro,which is partially due to the increased expression of cyclin D1.
PCA could also promote the migration capacity of hADSCs through transwell coated with gelatin in vitro.The migration of hADSCs significantly increased in a dose-dependent manner in the presence of PCA for 48 h,compared with the control.0.5 mM PCA was the minimal dose to stimulate the migration of hADSCs,while the maximum effect of PCA appeared at the concentration of 1.5 mM.In addition,the migration ratio of hADSCs treated with 1.5 mM PCA at various time points increased in a time-dependent manner.The shortest treatment time for the promotion of hADSCs migration was observed at 24 h,but the most effective time was at 48 h.
Meanwhile,RT-PCR and quantitative RT-PCR analysis revealed the elevation of membrane-type matrix metalloproteinase-1(MT1-MMP) mRNA expression in 1.5 mM PCA-treated hADSCs.In the supernatants of these cells,the active matrix metalloproteinase-2 (MMP-2) increased compared with control cells with zymography.Moreover,the promotion of cell migration by PCA could be effectively and obviously inhibited by anti-MT1-MMP or anti-MMP-2 antibodies.These results suggest that PCA from A.oxyphylla promote the migration of hADSCs in vitro,which is partially due to the increased expression of MT1-MMP and the promotion of MMP-2 zymogen activation.
The migration and proliferative enhancement of hADSCs with PCA suggests the possibility that PCA may be useful in hADSCs-mediated therapy.
在具有神经保护作用的药物中,中药活性单体成分单一、结构明确、易于其作用机制的深入分析。在这些单体中找到具有促进间充质干细胞增殖和迁移作用的成分,辅助应用于中枢神经系统疾病的间充质干细胞移植治疗,可以在提高病变部位移植细胞数量的同时,发挥其对受损神经的保护作用,从而提高疾病治疗的综合效果。但是,具有神经保护作用的中药活性单体成分对间充质干细胞增殖和迁移的影响的研究尚未见报道。因此,在前期筛选工作的基础上,本文深入研究了具有神经保护作用的中药活性单体—原儿茶酸,对人脂肪干细胞体外增殖能力和体外迁移能力的影响,并对其相关机制进行了初步的探讨。
原儿茶酸处理后,人脂肪干细胞的形态没有显著变化,而且仍表达细胞表面抗原标志CD29、CD13和CD44,不表达CD34、CD45和HLADR。各表面抗原标记的表达量与对照组相比没有显著差异:经体外诱导分化实验证明,原儿茶酸处理后,人脂肪干细胞向成骨细胞、脂肪细胞、心肌细胞和神经细胞分化的能力没有显著变化;酶联免疫吸附实验结果显示,原儿茶酸处理没有影响人脂肪干细胞细胞因子IL-6和生长因子IGF-Ⅰ的分泌能力。因此,原儿茶酸处理后,人脂肪干细胞仍保持其多向分化潜能、细胞因子和生长因子分泌等生物学特性。
应用WST-8法检测了原儿茶酸对人脂肪干细胞的体外增殖的影响,发现原儿茶酸能够促进人脂肪干细胞的体外增殖能力,其作用呈现明显的剂量依赖性。0.5 mM,1.0mM和1.5 mM的原儿茶酸处理48小时后,人脂肪干细胞增殖能力分别提高51%,78%和103%。原儿茶酸发挥作用的最小浓度为0.5 mM,适宜浓度为1.5 mM。同时,1.5 mM原儿茶酸对人脂肪干细胞的体外增殖的促进作用呈现明显的时间依赖性,其发挥作用的最短时间是24小时,使细胞增殖能力提高66%;适宜作用时间是96小时,提高细胞增殖能力124%。此外,原儿茶酸对人脂肪干细胞的细胞凋亡没有明显的影响。
进一步通过DNA含量的检测分析了原儿茶酸对人脂肪干细胞细胞周期的影响,发现原儿茶酸能够促进人脂肪干细胞的细胞周期G0/G1期向S期的转换。在0.5 mM-1.5mM的浓度范围内,人脂肪干细胞的S期和G2/M期的细胞所占比例随原儿茶酸浓度的增加而呈明显上升趋势,处于G0/G1期的细胞所占比例随原儿茶酸浓度的增加呈相应的下降趋势。其中,1.5 mM原儿茶酸的作用最为明显,使S期细胞比例增加2倍。免疫蛋白印迹检测发现,原儿茶酸处理明显提高了细胞周期素D1的蛋白水平。为了进一步证明原儿茶酸对脂肪干细胞体外增殖的促进作用是否与细胞周期素D1蛋白表达的变化有关,本文应用RNA干扰技术对人脂肪干细胞的细胞周期素D1进行了转录后水平的基因沉默,结果显示,细胞周期素D1的siRNA干扰使原儿茶酸处理组人脂肪干细胞的体外增殖下降45%,与对照组细胞体外增殖的下降比例(26%)相比具有显著性差异,表明细胞周期素D1的siRNA干扰显著抑制了原儿茶酸对人脂肪干细胞体外增殖的促进作用,证实原儿茶酸通过对细胞周期素D1表达的调控促进了人脂肪干细胞的体外增殖能力。
应用明胶包被的双层细胞培养板,观察原儿茶酸对人脂肪干细胞体外迁移能力的影响。在0.5 mM-1.8 mM的浓度范围内,原儿茶酸处理人脂肪干细胞48小时能够显著提高其体外迁移能力,其作用呈现明显的剂量依赖性。0.5 mM,1.0 mM和1.5 mM的原儿茶酸处理的细胞迁移率分别提高35%,63%和82%。0.5 mM原儿茶酸是发挥其促进迁移作用的最小浓度,原儿茶酸发挥最大作用的浓度是1.5 mM。同时,原儿茶酸促进人脂肪干细胞迁移的作用具有时间依赖性。在1.5 mM原儿茶酸的作用下,细胞迁移能力显著提高的最短作用时间是24小时,适宜作用时间是48小时。
应用RT-PCR和荧光定量PCR分析发现,原儿茶酸处理能够使人脂肪干细胞膜型基质金属蛋白酶-1(MT1-MMP)的表达升高45%。明胶酶谱法分析人脂肪干细胞分泌的基质金属蛋白酶-2(MMP-2)的活性变化的结果显示,原儿茶酸对人脂肪干细胞分泌的MMP-2的总量没有明显影响,但是显著促进了MMP-2的活化,使活性型MMP-2增加至对照组的2倍左右。进一步应用MT1-MMP和MMP-2抗体进行阻断实验,分析MT1-MMP和MMP-2在原儿茶酸促进人脂肪干细胞体外迁移中的作用。结果显示,MT1-MMP和MMP-2抗体有效抑制了人脂肪干细胞的体外迁移能力,两种抗体分别使原儿茶酸对人脂肪干细胞迁移的促进作用从182%下降至60%和75%。证实原儿茶酸通过对MT1-MMP的表达和MMP-2酶原的活化的调控,调节人脂肪干细胞的迁移能力。
原儿茶酸能够提高人脂肪干细胞的迁移能力和增殖能力,因而有可能通过提高损伤组织局部的人脂肪干细胞的数量而提高移植的治疗效果。因此,原儿茶酸有可能在脂肪干细胞移植的辅助治疗中发挥重要作用。
Mesenchymal stem cells(MSCs) transplantation plays an important role in hypoxic-ischemic encephalopathy and neurodegenerative diseases.It has been reported that exogenous transplanted MSCs could migrate to the impaired sites,differentiate into the tissue-specific cells under the induction of local microenviroment,and secrete growth factors and trophic factors to protect the injured cells,thereby promote the restoration of the biological functions.However,the migration ratio of transplanted stem cells is usually low. Therefore,finding suitable pharmaceuticals for facilitating the proliferation and migration of MSCs could contribute to the development of cell therapy strategies.
There are many active ingredients in Chinese medicines with neuroprotective effect.If suitable pharmaceuticals for facilitating the migration and proliferation of transplanted stem cells are found from them,and used for hypoxic-ischemic encephalopathy and neurodegenerative diseases,combined with stem cell therapy,the therapeutic efficacy of these diseases will be improved.On the basis of screening research,we found that protocatechuic acid(PCA) from Alpinia(A.) oxyphylla could promote the proliferation of hADSCs in vitro.
The identification of PCA-treated hADSCs and control cells revealed that after PCA treatment,the morphology of hADSCs showed no obvious difference with control cells.Flow cytometric analysis of the cell surface antigens,osteogenic induction,adipogenic induction, cardiomyocyte-like cell induction and neural induction demonstrated that hADSCs retained their functional characteristics of multipotential mesenchymal progenitors after PCA treatment.Enzyme-linked immunosorbent assay showed that the capacity for the secretion of IL-6 and IGF-Ⅰof PCA-treated hADSCs was the same with control cells.
PCA could promote the proliferation capacity of hADSCs in vitro.The results of cell counts showed that the treatment of hADSCs with PCA for 48 h increased the cell number in a dose-dependent manner.0.5 mM PCA was the minimal dose to stimulate the proliferation enhancement of hADSCs,while the maximum effect of PCA appeared at the concentration of 1.5 mM.In addition,the cell number of hADSCs treated with 1.5 mM PCA at various time points increased in a time-dependent manner.The shortest treatment time for the promotion of hADSCs proliferation was observed at 24 hours,but the most effective time was at about 72 hours.
The flow cytometric analysis of DNA content demonstrated the cell cycle progressed from the G0/G1 phase to the S phase and the most pronounced effect was seen with 1.5 mM PCA,where the fraction of cells in S phase increased more than 2 folds,accompanied by a significant increase in the fraction of cells in G2/M phase and a significant decrease in the fraction of cells in G0/G1 phase.Western blot analysis revealed the elevated expression of cyclin D1 in hADSCs induced by 1.5 mM PCA treatment.Cyclin D1-siRNA transfection significantly inhibited the promotion of cell proliferation by PCA.These results suggest that PCA from A.oxyphylla promote the proliferation of hADSCs in vitro,which is partially due to the increased expression of cyclin D1.
PCA could also promote the migration capacity of hADSCs through transwell coated with gelatin in vitro.The migration of hADSCs significantly increased in a dose-dependent manner in the presence of PCA for 48 h,compared with the control.0.5 mM PCA was the minimal dose to stimulate the migration of hADSCs,while the maximum effect of PCA appeared at the concentration of 1.5 mM.In addition,the migration ratio of hADSCs treated with 1.5 mM PCA at various time points increased in a time-dependent manner.The shortest treatment time for the promotion of hADSCs migration was observed at 24 h,but the most effective time was at 48 h.
Meanwhile,RT-PCR and quantitative RT-PCR analysis revealed the elevation of membrane-type matrix metalloproteinase-1(MT1-MMP) mRNA expression in 1.5 mM PCA-treated hADSCs.In the supernatants of these cells,the active matrix metalloproteinase-2 (MMP-2) increased compared with control cells with zymography.Moreover,the promotion of cell migration by PCA could be effectively and obviously inhibited by anti-MT1-MMP or anti-MMP-2 antibodies.These results suggest that PCA from A.oxyphylla promote the migration of hADSCs in vitro,which is partially due to the increased expression of MT1-MMP and the promotion of MMP-2 zymogen activation.
The migration and proliferative enhancement of hADSCs with PCA suggests the possibility that PCA may be useful in hADSCs-mediated therapy.
引文
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