地黄多糖通过Notch信号通路诱导BMSCs分化为神经样细胞作用的实验研究
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摘要
目的：探讨地黄多糖对大鼠骨髓间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)分化为神经样细胞的诱导效应及其诱导方案筛选,并进一步研究其在诱导过程中对Notch细胞信号通路的作用机制。
材料与方法：
实验一.取4-6周健康Wistar大鼠股骨骨髓,采用全骨髓贴壁筛选法行骨髓间充质干细胞(BMSCs)的分离培养,细胞一般状态观察,MTT法检测传代后BMSCs增殖活力,免疫细胞荧光法和流式细胞仪检测BMSCs阳性标志物CD29、CD44和阴性标志物CD34。实验二.MTT法检测不同浓度地黄多糖对大鼠BMSCs活力的影响后,将培养的BMSCs分为对照组(CON组)、化学方法诱导组(BME组)、神经生长因子组(BDNF组)及不同浓度、不同诱导时间地黄多糖诱导组(RGP组),分别进行预诱导、诱导。正常培养7天后,以ELISA法检测各组BMSCs的NSE蛋白表达情况,进行优化方案筛选,免疫细胞化学法检测各组BMSCs诱导后神经标志物阳性细胞率；Western blot检测RGP组C③诱导后各时间点Nesti、βⅢ-tubulin、NSE、GFAP的表达情况,RT-PCR检测诱导后3天各组神经细胞表面标志物的表达。
实验三.取P3-P5代BMSCs分为正常对照组(CON组)和地黄多糖诱导组(RGP组),以优化方案进行诱导培养7天,免疫细胞化学法检测各组Notchl蛋白和Jaggedl蛋白在各时间点的表达,Western blot检测各时间点Notchl蛋白胞内段NICD和Jaggedl的表达,Real-time PCR分析Notch信号通路相关分子mRNA的变化情况。
结果：
1.大鼠BMSCs的分离、培养和鉴定：
(1)原代培养的BMSCs经贴壁培养法,至10天左右,细胞生长状态良好;传至3代后,细胞形态比较均一,仍然保持良好的增殖能力。
(2)细胞生长曲线显示：P1代细胞生长不规则,P3代开始细胞生长状态良好,P3代及P5代BMSCs生长规律基本相似,传代后细胞先出现短暂的滞留期,后生长加速,对数生长期结束后,第7天细胞生长缓慢,进入平台期。
(3)免疫细胞化学鉴定BMSCs显示CD29、CD44表达阳性,而CD34表达阴性。
(4)流式细胞仪检测BMSCs显示,CD29、CD44表达阳性率分别为97.6%、93.8%,CD34为2.3%。
2.地黄多糖对大鼠BMSCs诱导分化为神经样细胞优化方案筛选：
(1)地黄多糖(RGP)在一定浓度范围内,可促进传代后BMSCs增殖。在较低浓度时,促增殖效应呈剂量依赖性关系。但在较高浓度时,BMSCs增殖并不能进一步增加,相反OD值降低。
(2)ELISA法检测结果示：随诱导时间延长,BME组、BDNF组和RGP各组NSE表达的OD值均明显增高,但CON组、BME组、BDNF组至3天、5天各时间点明显低于RGP组C③(P<0.05)。
(3)一般状态观察：CON组无神经元样细胞形态改变,BME组加入诱导剂后半小时出现细胞形态改变,6小时内神经元样细胞明显增多,24小时细胞变化明显,之后出现大量细胞死亡。BDNF组和地黄多糖组出现细胞形态改变类似,较BME组出现略晚,随着时间的延长,神经元样细胞数量逐渐增加,尤其地黄多糖组至第5天其细胞生长状态良好,持续时间长。
(4)免疫细胞化学检测示：3天时,RGP组NSE阳性表达率为(76.17±6.27)%高于其他各组(P<0.05),而GFAP阳性表达率(10.17±1.27)%明显低于BDNF组(P<0.05)。
(5)Western blot和RT-PCR检测示,各实验组诱导后均可检测到nestin, NSE, GFAP, βⅢ-tubulin mRNA的表达,与免疫细胞化学染色结果相符合。
3.地黄多糖对BMSCs分化过程中Notch信号通路的影响：
(1)RGP组诱导结束后BMSCs的Notchl蛋白表达随时间变化逐渐减少,阳性细胞率逐渐降低,与正常对照组比较有显著性差异p<0.01。RGP组Jaggedl阳性细胞率从诱导结束Od到诱导后1d具有明显的上升趋势,1d到7d其阳性细胞率显著下降,各时间点比较差异具有统计学意义(P (2) Western blot检测示：正常对照组其NICD始终为高水平表达,各时间点之间比较无显著性差异(P>0.05)。而RGP组NICD表达随时间变化呈下降趋势,其中1天、3天、7天与0天比较具有显著性差异(P<0.01)。RGP组Jagged1蛋白相对表达量在0d到诱导后1d时先上调,从1d到7d时相对表达量显著下降,差异具有统计学意义(P<0.05)。RGP组在Od、1d、3d与对照组比较,Jaggedl蛋白表达均高于对照组,7d时低于对照组,差异具有统计学意义(P<0.05)
(3) Real-time PCR检测分析：RGP组Notchl mRNA随时间变化表达下降,Presenilin1表达先降低后略有回升,Hes1表达下降,Mash1表达升高,Jagged1表达先升高后降低。各时间点与对照组比较具有显著性差异(P<0.01)
结论：
1、采用补肾益精中药熟地黄的有效成分地黄多糖成功诱导骨髓间充质干细胞(BMSCs)向神经样细胞分化。以碱性成纤维细胞生长因子(bFGF)预诱导,200μg/ml浓度地黄多糖诱导。作用缓和,诱导效率相对较高。
2、骨髓间充质干细胞(BMSCs)的增殖状态有赖于Notchl蛋白一定程度的高表达,地黄多糖诱导BMSCs向神经细胞分化过程中,导致Notchl蛋白和其胞内段NICD表达降低,并影响Notch信号通路相关分子mRNA的表达,即Notch1随诱导时间延长表达下降,Presenilin1表达先降低后略有回升,Hes1表达下降,Mash1表达升高,Jagged1表达先升高后降低。
Purposes:To explore the inductive effect of Rehmannia Glutinosa Polysaccharide (RGP) on bone marrow mesenchymal stem cells (BMSCs) differentiation into neuron-like cells and to screen its induction methods, meanwhile to further study its mechanism on Notch cell signaling pathway during induction.
Materials and Methods:
Test1:The femoral bone marrow of4-6week old healthy Wistar Rats were used. BMSCs were isolated and cultured using whole bone marrow adherence screening method, meanwhile cellular general states were observed, the proliferation vitality of BMSCs were tested by MTT method, the positive marker CD29. CD44and negative marker CD34were detected by immunocytochemistry method and flow cytometer.
Test2:The effects of different concentrations of RGP on rat BMSCs's vitality were tested by MTT method, then the cultured BMSCs were divided into the control group. BME group, BDNF group, and RGP induction groups with different concentrations and different induction durations, and then they were pre-induced and induced respectively. After7days of regular culture, the NSE protein expressions in different groups were tested by Elisa, then the screening for optimized methods was conducted. The percentages of induced BMSCs with positive neural markers were obtained by immunocytochemistry; the expression of Nestin、 βⅢ-tubuln、NSE、GFAP at different durations time point in RGP group C③were tested by Western blot, and after3days of induction, the expression of neural cells surface markers were tested by RT-PCR.
Test3:The P3-P5generations of BMSCs were divided into the control group and RGP group, and they were induced and cultured for7days using the optimized method, the Notchl and Jaggedl protein expression at different durations were tested by immunocytochemical method, the Notchl protein intracellular Domain (NICD) and Jaggedl protein expression at different durations were tested using Western blot, the Notch signaling pathway related molecular mRNA expression and changes were analyzed by Real-time PCR.
Results:
1. The isolation, culture and identification of rat BMSCs:
(1) After10days of adherent culture, the primary cultured BMSCs demonstrated healthy growth; the3rd generation had uniform morphology and maintained favorable reproductive activity.
(2) the cell growth profile reveals:P1had irregular growth, from P3, cells demonstrated regular growth, P3and P5BMSCs had similar growth patterns, each generation had a short-term detention period before cell growing, then showed apparent acceleration afterwards, double growth rate occurred, after logarithmic phase, the cells showed slow growth, entered the plateau stage.
(3) the BMSCs were identified by immunocytochemistry, which showed the CD29and CD44marker expression was positive, the CD34expression was negative.
(4) The flow cytometer testing of BMSCs showed:The CD29and CD44expression positive rates were97.6%and93.8%. The CD34expression was2.3%.
2. The screening of optimized method for RGP induced rat BMSCs differentiation into neuron-like cells:
(1) In a range of concentrations. RGP can promote the proliferation of BMSCs after passage. At lower concentrations, the proliferation effect was dose dependent. However, at higher concentrations. BMSCs proliferation was not increased accordingly, but OD value decreased.
(2) The ELISA results showed:with the increase of induction duration, the OD values of NSE expression in the BME group. BDNF group and RGP all groups become higher, while those of control group. BME group, BDNF group at3d and5d were significantly lower than RGP group C③(P<0.05).
(3) General states observation:no neuron-like were observed in control group. In BME group, cellular morphological changes occurred within half an hour after the input of inductor, within6h, neuron-like cells increased significantly, which reached its peak at24h. then large scale of cell death occurred. The cellular changes of BDNF group were similar to those in RGP group, while occurred a little later than those in BME group, as duration increase, more and more neuron-like cells occurred, especially in RGP group, cells demonstrated favorable growth and longer duration till5d.
(4) Immunocytochemistry showed:at3d. NSE positive expression rate in RGP group is (76.17±6.27)%. which was higher than those in other groups(P<0.05), while GFAP positive expression rate (10.17±1.27)%is significantly lower than BDNF group (P<0.05).
(5) Western blot and RT-PCR testing showed, in line with immunocytochemistry staining outcomes, the expression of nestin, NSE, GFAP, βⅢ-tubulin mRNA after induction were detected in all test groups.
3. The effects of RGP on Notch signaling pathway during BMSC differentiation:
(1) In RGP group, after completion of induction, the Notch1protein expression of BMSCs decrease with time, positive cell percentage decreased likewise, which was significantly different from normal control group(p<0.01). The Jagged1positive cell rate of RGP group increased from induced end Od to1d after induction, decreased significantly from1d to7d, and there was significant difference between each time point comparison(P<0.05).
(2) Western blot testing showed:the NICD expression in normal control group maintained high level, there was no significant difference between different durations(P>0.05). However, in RGP group. NICD expression decreased with time, which of ld.3d,7d was significantly different from0d(P<0.01). the Jaggedl protein relative expression of RGP group went up from Od to1d after induction, and went down significantly from1d to7d. In RGP group, the expression of Jaggedl were higher than those in control group at0d,1d,3d,however lower at7d,the difference was statistically significant (P<0.05).
(3) Real-time PCR testing analysis:in RGP group, Notchl mRNA expression decreased with time. Presenilin1expression decreased and then went up mildly afterwards. Hes1expression decreased, Mash1expression increased, Jagged1expression increased then decreased. Which were significantly different from control group at all durations(P<0.01).
Conclusions:
1. RGP, the effective ingredient of kidney invigorating Chinese medicine named prepared rehmannia root, can successfully induce bone marrow mesenchymal stem cells (BMSCs) to differentiate into neuron-like cells. With basic fibroblast growth factor (bFGF) pre-inducing, BMSCs were induced by200μg/ml concentration of Rehmannia glutinosa polysaccharides. which the induction was mild in action and relatively potent.
2. Although the proliferation of BMSCs depends on the hyperexpression of Notch protein, RGP can cause the decrease of notch protein and the expression quantity of its intracellular domain (NICD) during the induction for BMSCs to defferentiate towards neuron-like cells. Furthermore, it can influence the the expression of Notch signaling pathway related molecular mRNA. It showed that Notchl mRNA expression decreased with induction time, Presenilin1expression decreased then went up mildly afterwards, Hes1expression decreased, Mash1expression increased, Jagged1expression increased and then decreased.
材料与方法：
实验一.取4-6周健康Wistar大鼠股骨骨髓,采用全骨髓贴壁筛选法行骨髓间充质干细胞(BMSCs)的分离培养,细胞一般状态观察,MTT法检测传代后BMSCs增殖活力,免疫细胞荧光法和流式细胞仪检测BMSCs阳性标志物CD29、CD44和阴性标志物CD34。实验二.MTT法检测不同浓度地黄多糖对大鼠BMSCs活力的影响后,将培养的BMSCs分为对照组(CON组)、化学方法诱导组(BME组)、神经生长因子组(BDNF组)及不同浓度、不同诱导时间地黄多糖诱导组(RGP组),分别进行预诱导、诱导。正常培养7天后,以ELISA法检测各组BMSCs的NSE蛋白表达情况,进行优化方案筛选,免疫细胞化学法检测各组BMSCs诱导后神经标志物阳性细胞率；Western blot检测RGP组C③诱导后各时间点Nesti、βⅢ-tubulin、NSE、GFAP的表达情况,RT-PCR检测诱导后3天各组神经细胞表面标志物的表达。
实验三.取P3-P5代BMSCs分为正常对照组(CON组)和地黄多糖诱导组(RGP组),以优化方案进行诱导培养7天,免疫细胞化学法检测各组Notchl蛋白和Jaggedl蛋白在各时间点的表达,Western blot检测各时间点Notchl蛋白胞内段NICD和Jaggedl的表达,Real-time PCR分析Notch信号通路相关分子mRNA的变化情况。
结果：
1.大鼠BMSCs的分离、培养和鉴定：
(1)原代培养的BMSCs经贴壁培养法,至10天左右,细胞生长状态良好;传至3代后,细胞形态比较均一,仍然保持良好的增殖能力。
(2)细胞生长曲线显示：P1代细胞生长不规则,P3代开始细胞生长状态良好,P3代及P5代BMSCs生长规律基本相似,传代后细胞先出现短暂的滞留期,后生长加速,对数生长期结束后,第7天细胞生长缓慢,进入平台期。
(3)免疫细胞化学鉴定BMSCs显示CD29、CD44表达阳性,而CD34表达阴性。
(4)流式细胞仪检测BMSCs显示,CD29、CD44表达阳性率分别为97.6%、93.8%,CD34为2.3%。
2.地黄多糖对大鼠BMSCs诱导分化为神经样细胞优化方案筛选：
(1)地黄多糖(RGP)在一定浓度范围内,可促进传代后BMSCs增殖。在较低浓度时,促增殖效应呈剂量依赖性关系。但在较高浓度时,BMSCs增殖并不能进一步增加,相反OD值降低。
(2)ELISA法检测结果示：随诱导时间延长,BME组、BDNF组和RGP各组NSE表达的OD值均明显增高,但CON组、BME组、BDNF组至3天、5天各时间点明显低于RGP组C③(P<0.05)。
(3)一般状态观察：CON组无神经元样细胞形态改变,BME组加入诱导剂后半小时出现细胞形态改变,6小时内神经元样细胞明显增多,24小时细胞变化明显,之后出现大量细胞死亡。BDNF组和地黄多糖组出现细胞形态改变类似,较BME组出现略晚,随着时间的延长,神经元样细胞数量逐渐增加,尤其地黄多糖组至第5天其细胞生长状态良好,持续时间长。
(4)免疫细胞化学检测示：3天时,RGP组NSE阳性表达率为(76.17±6.27)%高于其他各组(P<0.05),而GFAP阳性表达率(10.17±1.27)%明显低于BDNF组(P<0.05)。
(5)Western blot和RT-PCR检测示,各实验组诱导后均可检测到nestin, NSE, GFAP, βⅢ-tubulin mRNA的表达,与免疫细胞化学染色结果相符合。
3.地黄多糖对BMSCs分化过程中Notch信号通路的影响：
(1)RGP组诱导结束后BMSCs的Notchl蛋白表达随时间变化逐渐减少,阳性细胞率逐渐降低,与正常对照组比较有显著性差异p<0.01。RGP组Jaggedl阳性细胞率从诱导结束Od到诱导后1d具有明显的上升趋势,1d到7d其阳性细胞率显著下降,各时间点比较差异具有统计学意义(P
(3) Real-time PCR检测分析：RGP组Notchl mRNA随时间变化表达下降,Presenilin1表达先降低后略有回升,Hes1表达下降,Mash1表达升高,Jagged1表达先升高后降低。各时间点与对照组比较具有显著性差异(P<0.01)
结论：
1、采用补肾益精中药熟地黄的有效成分地黄多糖成功诱导骨髓间充质干细胞(BMSCs)向神经样细胞分化。以碱性成纤维细胞生长因子(bFGF)预诱导,200μg/ml浓度地黄多糖诱导。作用缓和,诱导效率相对较高。
2、骨髓间充质干细胞(BMSCs)的增殖状态有赖于Notchl蛋白一定程度的高表达,地黄多糖诱导BMSCs向神经细胞分化过程中,导致Notchl蛋白和其胞内段NICD表达降低,并影响Notch信号通路相关分子mRNA的表达,即Notch1随诱导时间延长表达下降,Presenilin1表达先降低后略有回升,Hes1表达下降,Mash1表达升高,Jagged1表达先升高后降低。
Purposes:To explore the inductive effect of Rehmannia Glutinosa Polysaccharide (RGP) on bone marrow mesenchymal stem cells (BMSCs) differentiation into neuron-like cells and to screen its induction methods, meanwhile to further study its mechanism on Notch cell signaling pathway during induction.
Materials and Methods:
Test1:The femoral bone marrow of4-6week old healthy Wistar Rats were used. BMSCs were isolated and cultured using whole bone marrow adherence screening method, meanwhile cellular general states were observed, the proliferation vitality of BMSCs were tested by MTT method, the positive marker CD29. CD44and negative marker CD34were detected by immunocytochemistry method and flow cytometer.
Test2:The effects of different concentrations of RGP on rat BMSCs's vitality were tested by MTT method, then the cultured BMSCs were divided into the control group. BME group, BDNF group, and RGP induction groups with different concentrations and different induction durations, and then they were pre-induced and induced respectively. After7days of regular culture, the NSE protein expressions in different groups were tested by Elisa, then the screening for optimized methods was conducted. The percentages of induced BMSCs with positive neural markers were obtained by immunocytochemistry; the expression of Nestin、 βⅢ-tubuln、NSE、GFAP at different durations time point in RGP group C③were tested by Western blot, and after3days of induction, the expression of neural cells surface markers were tested by RT-PCR.
Test3:The P3-P5generations of BMSCs were divided into the control group and RGP group, and they were induced and cultured for7days using the optimized method, the Notchl and Jaggedl protein expression at different durations were tested by immunocytochemical method, the Notchl protein intracellular Domain (NICD) and Jaggedl protein expression at different durations were tested using Western blot, the Notch signaling pathway related molecular mRNA expression and changes were analyzed by Real-time PCR.
Results:
1. The isolation, culture and identification of rat BMSCs:
(1) After10days of adherent culture, the primary cultured BMSCs demonstrated healthy growth; the3rd generation had uniform morphology and maintained favorable reproductive activity.
(2) the cell growth profile reveals:P1had irregular growth, from P3, cells demonstrated regular growth, P3and P5BMSCs had similar growth patterns, each generation had a short-term detention period before cell growing, then showed apparent acceleration afterwards, double growth rate occurred, after logarithmic phase, the cells showed slow growth, entered the plateau stage.
(3) the BMSCs were identified by immunocytochemistry, which showed the CD29and CD44marker expression was positive, the CD34expression was negative.
(4) The flow cytometer testing of BMSCs showed:The CD29and CD44expression positive rates were97.6%and93.8%. The CD34expression was2.3%.
2. The screening of optimized method for RGP induced rat BMSCs differentiation into neuron-like cells:
(1) In a range of concentrations. RGP can promote the proliferation of BMSCs after passage. At lower concentrations, the proliferation effect was dose dependent. However, at higher concentrations. BMSCs proliferation was not increased accordingly, but OD value decreased.
(2) The ELISA results showed:with the increase of induction duration, the OD values of NSE expression in the BME group. BDNF group and RGP all groups become higher, while those of control group. BME group, BDNF group at3d and5d were significantly lower than RGP group C③(P<0.05).
(3) General states observation:no neuron-like were observed in control group. In BME group, cellular morphological changes occurred within half an hour after the input of inductor, within6h, neuron-like cells increased significantly, which reached its peak at24h. then large scale of cell death occurred. The cellular changes of BDNF group were similar to those in RGP group, while occurred a little later than those in BME group, as duration increase, more and more neuron-like cells occurred, especially in RGP group, cells demonstrated favorable growth and longer duration till5d.
(4) Immunocytochemistry showed:at3d. NSE positive expression rate in RGP group is (76.17±6.27)%. which was higher than those in other groups(P<0.05), while GFAP positive expression rate (10.17±1.27)%is significantly lower than BDNF group (P<0.05).
(5) Western blot and RT-PCR testing showed, in line with immunocytochemistry staining outcomes, the expression of nestin, NSE, GFAP, βⅢ-tubulin mRNA after induction were detected in all test groups.
3. The effects of RGP on Notch signaling pathway during BMSC differentiation:
(1) In RGP group, after completion of induction, the Notch1protein expression of BMSCs decrease with time, positive cell percentage decreased likewise, which was significantly different from normal control group(p<0.01). The Jagged1positive cell rate of RGP group increased from induced end Od to1d after induction, decreased significantly from1d to7d, and there was significant difference between each time point comparison(P<0.05).
(2) Western blot testing showed:the NICD expression in normal control group maintained high level, there was no significant difference between different durations(P>0.05). However, in RGP group. NICD expression decreased with time, which of ld.3d,7d was significantly different from0d(P<0.01). the Jaggedl protein relative expression of RGP group went up from Od to1d after induction, and went down significantly from1d to7d. In RGP group, the expression of Jaggedl were higher than those in control group at0d,1d,3d,however lower at7d,the difference was statistically significant (P<0.05).
(3) Real-time PCR testing analysis:in RGP group, Notchl mRNA expression decreased with time. Presenilin1expression decreased and then went up mildly afterwards. Hes1expression decreased, Mash1expression increased, Jagged1expression increased then decreased. Which were significantly different from control group at all durations(P<0.01).
Conclusions:
1. RGP, the effective ingredient of kidney invigorating Chinese medicine named prepared rehmannia root, can successfully induce bone marrow mesenchymal stem cells (BMSCs) to differentiate into neuron-like cells. With basic fibroblast growth factor (bFGF) pre-inducing, BMSCs were induced by200μg/ml concentration of Rehmannia glutinosa polysaccharides. which the induction was mild in action and relatively potent.
2. Although the proliferation of BMSCs depends on the hyperexpression of Notch protein, RGP can cause the decrease of notch protein and the expression quantity of its intracellular domain (NICD) during the induction for BMSCs to defferentiate towards neuron-like cells. Furthermore, it can influence the the expression of Notch signaling pathway related molecular mRNA. It showed that Notchl mRNA expression decreased with induction time, Presenilin1expression decreased then went up mildly afterwards, Hes1expression decreased, Mash1expression increased, Jagged1expression increased and then decreased.
引文
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