绵羊羊膜上皮细胞的分化潜能及在骨缺损模型治疗中的应用
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摘要
羊膜上皮细胞(amnion epithelial cells, AECs)是由废弃的胎盘羊膜衍生的具有干细胞特性的细胞。AECs不仅具有多向分化潜能,而且许多研究都证实其具有免疫豁免性,移植后不产生免疫排斥反应,因缺乏末端转移酶端粒,移植后不致瘤,再加上来源广、易获得,不存在伦理争议等,而成为细胞研究工作者的研究热点之一。应用AECs进行一些疑难症的治疗是临床研究工作者的最终目标。临床应用治疗顺利进行的前提是以安全可靠的动物实验为基础。目前,AECs的研究主要以人的为主,在临床治疗研究中以人AECs治疗肝病、肺病、心脏病、糖尿病、神经系统疾病等疑难病症。而绵羊AECs的研究在国内尚未见报道,国外的相关研究也极少。因此,本研究对绵羊AECs的分离培养、干细胞特性的鉴定、体内分化及体外定向诱导分化进行了系统的研究。
1.绵羊羊膜上皮细胞的分离与培养
实验参照人羊膜消化分离获得原代细胞的方法,对绵羊羊膜的消化分离方法进行了探索,最终选用胰酶替代物TrypLE消化绵羊羊膜分离获得原代细胞,获得的原代细胞活力高,纯度好。细胞培养过程中选用了15%的胎牛血清浓度的培养液进行细胞的培养,很好地维持细胞良好的生长态势。
在不同密度梯度培养情况下,通过观察比较,确定了细胞接种的最适密度培养密度范围。在最适密度培养范围内,进行细胞生长周期的观察发现：绵羊AECs的潜伏期是1-2d,指数生长期是3-5d,以后为平台期。
通过细胞冻存实验确定了细胞的冻存方案,采用DMSO作为冻存保护剂,FBS：DMSO=9:1的比列为冻存液,并且取-80℃到液氮的简捷冻存途径,有效地保存了绵羊AECs。
2.绵羊羊膜上皮细胞的干细胞特性的鉴定
采用细胞免疫荧光和RT-PCR技术分别检测绵羊AECs的ES细胞表面标志物Oct-4、SSEA-1、SSEA-3、SSEA-4、TRA-1-60和TRA-1-81及于细胞全能性相关基因Oct-4、Sox-2、Nanog和Rex-1等。检测结果显示绵羊AECs的Oct-4、SSEA-1、SSEA-3、 SSEA-4、TRA-1-60和TRA-1-81的ES细胞标志物均有表达。干细胞全能性相关基因Oct-4、Sox-2和Rex-1表达,而Nanog基因未见表达。检测结果提示,绵羊AECs具有干细胞特性的多向分化潜能。
3.绵羊羊膜上皮细胞在体外的定向诱导分化研究
为了检验绵羊AECs在体外的多向分化潜能,在一定条件下,利用一些外源因子诱导绵羊AECs向神经系统细胞、成骨细胞和脂肪细胞进行定向分化。然后分别用细胞免疫荧光检测和RT-PCR技术、细胞AKP活性检测、茜素红染色、油红0染色等方法进行了诱导分化细胞的鉴定。结果显示：①神经方向诱导分化28d后,细胞免疫荧光显示神经细胞特异性标志物β-Ⅲ-tubulin和神经胶质细胞特异性标志物GFAP均呈阳性表达；RT-PCR显示nestin和β-Ⅲ-tubulin和MAP-2等基因均有表达。②成骨诱导分化细胞AKP活性检测显示,诱导分化培养的第28d细胞AKP活性略有升高,第35d开始明显高于对照组,而且随培养时间的延长而继续增高,诱导组和基础培养组差异显著；茜素红染色有明显的钙化结节形成。③脂肪细胞诱导分化的第42d,油红0染色观察到有脂滴形成；细胞内AKP活性检测结果显示,基础培养组细胞AKP活性最高,各诱导组细胞AKP活性明显低于基础培养组。从上述鉴定中细胞的阳性及染色结果和诱导分化细胞的形态特征,可以推测本研究可以将绵羊AECs诱导分化为了表达β-Ⅲ-tubulin阳性的未成熟神经细胞及MAP-2阳性的成熟神经细胞、GFAP阳性的神经胶质细胞,有钙化结节形成的成骨细胞及有脂滴形成的脂肪细胞。
4.绵羊羊膜上皮细胞治疗兔桡骨缺损模型的研究
国外有文献报道,将绵羊AECs直接注射到绵羊体内,来治疗绵羊跟腱损伤的报道,且治疗效果极佳。为了进一步检验我们获得的绵羊AECs是否能够在异种动物兔体内进行分化,从而达到类似的治疗效果。手术制作30只兔桡骨13mm缺损模型,随机分成3组,即高剂量组,低剂量组和对照组。将AECs处理后,按设定剂量通过静脉注射进行细胞移植。在细胞移植前、手术后、细胞移植后2周、4周、8周拍摄X光片,细胞移植后的2周、4周、8周进行组织形态学观察。结果提示：移植的绵羊AECs高剂量组在第8周无论从X光片还是新生骨组织切片,缺损组织都修复完好,高剂量组优于低剂量组,低剂量组修复效果优于对照组。因此可以推测绵羊AECs在兔桡骨缺损模型的体内,向成骨方向进行了分化,加速了骨缺损的修复速度和质量。提示绵羊AECs治疗小段骨缺损是可行的。
综上,本研究成功获得了具有干细胞特性的绵羊AECs,其无论在体内还是在体外均具有多向分化能力。本研究结果补充了绵羊AECs在干细胞特性方面及在体内和体外分化的理论知识,为临床进一步应用研究奠定了理论基础,提供了实践依据。
The amnion epithelial cells(AECs) is a type of cells possessed with stem cell characteristics and derive from superseded placenta amnion. AECs are not only have multi-directional differentiation potentiality, but possess immune exemption potency that immunological rejection and tumorigenesis are not generated after post transplant because of terminal transferas telomere defected, and AECs are gained readily and not cause ethics dispute, which make it become one hot spot of cell researches. To apply AECs curing some serious disease is the final objective of clinical researchers. Furthermore, successful clinical application and treat are base on safe and reliable animal experiment. At present, human amnion epithelial cells are studied chiefly and adopted to treat liver disease, pulmonary tuberculosis, heart disease, diabetes, nervous system disease and so on. However, the research on ovine amnion epithelial cells is not report in domestic and scarced in internationally. Therefore, isolating, culture and assessing stem cell characteristics, differentiation in vivo and direction location induction and differentiation in vitro of ovine amnion epithelial cells are proceed system research in this study.
1. Isolating and culture of ovine amnion epithelial cells
The isolating and digestion methods of ovine amnion epithelial cells in accordance with the means of digestion human amnion epithelial cells were explored. And pancreatic enzyme surrogate TrypLE was adopted lastly to digest ovine amnion and isolate primary cell that are obtained with the features of high vigor and purity coefficient. The culture solution contained with15%fetal bovine serum was applied and maintained excellently the favourable growth tendency of ovine amnion epithelial cells.
The optimum density and scope of cultural density of cells inoculation were detected through observation and comparision in different density gradient culture experiment. It was found, via observing cell growth cycle in optimum density scope, that the incubation period of ovine amnion epithelial cells was1to2days, and exponential growth phase was3to5days, afterward maintaining invariably.
The freezing and storing scheme of cells was definited by freezing and storing experiments, which DMSO was conducted as freezing and storing protective additive and FBS and DMSO were mingled according to certain ratio(FBS:DMSO=9:1) as freezing and storing solution.Moreover, to adopt the simple and quick freezing and storing ways that removed cells from-80℃to liquid nitrogen were efficiently preserve ovine amnion epithelial cells.
2. Assessment the stem cell characteristics of ovine amnion epithelial cells
Cell immunofluorescence and RT-PCR were performed to detect respectively the expression of embryonic stem cell of ovine AECs marker proteins Oct-4, SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81and totipotency related genes OCT-4, SOX-2, Nanog, Rex-1and so on. The observed Oct-4, SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81immunoreactivity of ovine AECs were predominant. RT-PCR experiments confirmed that the genes of Oct-4, Sox-2, Rex-1were expressed and Nanog was not expressed. The results indicated that the ovine AECs have the multi-directional differentiation potentiality of stem cell properties.
3. Directional induction and differentiation of ovine amnion epithelial cells in vitro
To check the multi-directional differentiation potentiality of ovine amnion epithelial cells in vitro, ovine AECs were induced to directional differentiate into nervous systemcells, osteoblast and adipocyte utilizing some additional factors. Cell immunofluorescence and RT-PCR technologies, alkaline phosphatase activities detection, alizarin bordeaux stain, oil red O dyeing were performed respectively to accredit induced and differentiated cells. The results showed:①the specific marker β-Ⅲ-tubulin in cellula nervosa and GFAP in nerve cement cells were observed positive immunofluorescence signals after28day in induced nerves direction; the genes of nestin, β-Ⅲ-tubulin and MAP-2were expressed.②alkaline phosphatase activities in bone formation induction and differentiation were elevate slightly after28day and begin to higher obviously than control group after35days. Moreover, the activities were to continue increase as cultural time prolong and the differences between induce and control group were evident; calcify nodus were visible in alizarin monosulfonate stain.③it could be observed lipid droplet formation by oil red O dyeing in cellula adiposa induction and differentiation on42d; alkaline phosphatase activities in foundation culture group were reach to maximum and higher conspicuously than each induced group. From above research to the morphous characteristics of differentiated cells, we may safely draw the suppose that ovine amnion epithelial cells have already induced and differentiated into positive pro-mature neuron cells expressed β-Ⅲ-tubulin, positive mature neuron cells expressed MAP-2, positive nerve cement cells expressed GFAP, osteoblast with calcify nodus and cellula adiposa with lipid droplet.
4. study of therapy efficacy applied ovine amnion epithelial cells in rabbit radius defected models
Injecting directly ovine amnion epithelial cells into ovine vivo to cure achilles tendon injury had reported and therapeutic efficacy was extremely excellent. To test the possibility of acquired ovine amnion epithelial cells differentiation in rabbit vivo and similar therapeutic efficacy with reported above, the13-centimetre long radius defected models were made artificially in30rabbits, divided into high dose group, low dose group and control group randomly. To carry out cellular transplant by intravenous injection according to setting dose after dealing with ovine aminion epithelial cells. Took the models for X-ray in2weeks,4weeks and8weeks before the ovine aminion epithelial cells transplantations, after operation and injection cells respectively and meanwhile observed histomorphology. The resultes hint:defect tissues were repaired in the high dose group at8weeks, observed from the X-ray and histological section of new bone, and the quality and quantities of trabecular bones in high dose group were better and higher than in the low dose group and it was the same situation between the low dose group and the control group. Accordingly, it was presume that ovine amnion epithelial cells in rabbit radius defected models in vivo were differentiated into bone and accelerated repaired speed and quality of bone coloboma.And the study indicated that it is feasible to apply ovine amnion epithelial cells to heal small bone defect.
In this study successfully gain ovine amnion epithelial cells possessed with stem cell characteristics are have the multi-directional differentiation potency in vivo and in vitro. And the results in this research supply with the theory knowledges of AECs in stem cell characteristics and differentiation in vivo and in vitro, and establish rationale and provide practice base for clinical exploratory development.
1.绵羊羊膜上皮细胞的分离与培养
实验参照人羊膜消化分离获得原代细胞的方法,对绵羊羊膜的消化分离方法进行了探索,最终选用胰酶替代物TrypLE消化绵羊羊膜分离获得原代细胞,获得的原代细胞活力高,纯度好。细胞培养过程中选用了15%的胎牛血清浓度的培养液进行细胞的培养,很好地维持细胞良好的生长态势。
在不同密度梯度培养情况下,通过观察比较,确定了细胞接种的最适密度培养密度范围。在最适密度培养范围内,进行细胞生长周期的观察发现：绵羊AECs的潜伏期是1-2d,指数生长期是3-5d,以后为平台期。
通过细胞冻存实验确定了细胞的冻存方案,采用DMSO作为冻存保护剂,FBS：DMSO=9:1的比列为冻存液,并且取-80℃到液氮的简捷冻存途径,有效地保存了绵羊AECs。
2.绵羊羊膜上皮细胞的干细胞特性的鉴定
采用细胞免疫荧光和RT-PCR技术分别检测绵羊AECs的ES细胞表面标志物Oct-4、SSEA-1、SSEA-3、SSEA-4、TRA-1-60和TRA-1-81及于细胞全能性相关基因Oct-4、Sox-2、Nanog和Rex-1等。检测结果显示绵羊AECs的Oct-4、SSEA-1、SSEA-3、 SSEA-4、TRA-1-60和TRA-1-81的ES细胞标志物均有表达。干细胞全能性相关基因Oct-4、Sox-2和Rex-1表达,而Nanog基因未见表达。检测结果提示,绵羊AECs具有干细胞特性的多向分化潜能。
3.绵羊羊膜上皮细胞在体外的定向诱导分化研究
为了检验绵羊AECs在体外的多向分化潜能,在一定条件下,利用一些外源因子诱导绵羊AECs向神经系统细胞、成骨细胞和脂肪细胞进行定向分化。然后分别用细胞免疫荧光检测和RT-PCR技术、细胞AKP活性检测、茜素红染色、油红0染色等方法进行了诱导分化细胞的鉴定。结果显示：①神经方向诱导分化28d后,细胞免疫荧光显示神经细胞特异性标志物β-Ⅲ-tubulin和神经胶质细胞特异性标志物GFAP均呈阳性表达；RT-PCR显示nestin和β-Ⅲ-tubulin和MAP-2等基因均有表达。②成骨诱导分化细胞AKP活性检测显示,诱导分化培养的第28d细胞AKP活性略有升高,第35d开始明显高于对照组,而且随培养时间的延长而继续增高,诱导组和基础培养组差异显著；茜素红染色有明显的钙化结节形成。③脂肪细胞诱导分化的第42d,油红0染色观察到有脂滴形成；细胞内AKP活性检测结果显示,基础培养组细胞AKP活性最高,各诱导组细胞AKP活性明显低于基础培养组。从上述鉴定中细胞的阳性及染色结果和诱导分化细胞的形态特征,可以推测本研究可以将绵羊AECs诱导分化为了表达β-Ⅲ-tubulin阳性的未成熟神经细胞及MAP-2阳性的成熟神经细胞、GFAP阳性的神经胶质细胞,有钙化结节形成的成骨细胞及有脂滴形成的脂肪细胞。
4.绵羊羊膜上皮细胞治疗兔桡骨缺损模型的研究
国外有文献报道,将绵羊AECs直接注射到绵羊体内,来治疗绵羊跟腱损伤的报道,且治疗效果极佳。为了进一步检验我们获得的绵羊AECs是否能够在异种动物兔体内进行分化,从而达到类似的治疗效果。手术制作30只兔桡骨13mm缺损模型,随机分成3组,即高剂量组,低剂量组和对照组。将AECs处理后,按设定剂量通过静脉注射进行细胞移植。在细胞移植前、手术后、细胞移植后2周、4周、8周拍摄X光片,细胞移植后的2周、4周、8周进行组织形态学观察。结果提示：移植的绵羊AECs高剂量组在第8周无论从X光片还是新生骨组织切片,缺损组织都修复完好,高剂量组优于低剂量组,低剂量组修复效果优于对照组。因此可以推测绵羊AECs在兔桡骨缺损模型的体内,向成骨方向进行了分化,加速了骨缺损的修复速度和质量。提示绵羊AECs治疗小段骨缺损是可行的。
综上,本研究成功获得了具有干细胞特性的绵羊AECs,其无论在体内还是在体外均具有多向分化能力。本研究结果补充了绵羊AECs在干细胞特性方面及在体内和体外分化的理论知识,为临床进一步应用研究奠定了理论基础,提供了实践依据。
The amnion epithelial cells(AECs) is a type of cells possessed with stem cell characteristics and derive from superseded placenta amnion. AECs are not only have multi-directional differentiation potentiality, but possess immune exemption potency that immunological rejection and tumorigenesis are not generated after post transplant because of terminal transferas telomere defected, and AECs are gained readily and not cause ethics dispute, which make it become one hot spot of cell researches. To apply AECs curing some serious disease is the final objective of clinical researchers. Furthermore, successful clinical application and treat are base on safe and reliable animal experiment. At present, human amnion epithelial cells are studied chiefly and adopted to treat liver disease, pulmonary tuberculosis, heart disease, diabetes, nervous system disease and so on. However, the research on ovine amnion epithelial cells is not report in domestic and scarced in internationally. Therefore, isolating, culture and assessing stem cell characteristics, differentiation in vivo and direction location induction and differentiation in vitro of ovine amnion epithelial cells are proceed system research in this study.
1. Isolating and culture of ovine amnion epithelial cells
The isolating and digestion methods of ovine amnion epithelial cells in accordance with the means of digestion human amnion epithelial cells were explored. And pancreatic enzyme surrogate TrypLE was adopted lastly to digest ovine amnion and isolate primary cell that are obtained with the features of high vigor and purity coefficient. The culture solution contained with15%fetal bovine serum was applied and maintained excellently the favourable growth tendency of ovine amnion epithelial cells.
The optimum density and scope of cultural density of cells inoculation were detected through observation and comparision in different density gradient culture experiment. It was found, via observing cell growth cycle in optimum density scope, that the incubation period of ovine amnion epithelial cells was1to2days, and exponential growth phase was3to5days, afterward maintaining invariably.
The freezing and storing scheme of cells was definited by freezing and storing experiments, which DMSO was conducted as freezing and storing protective additive and FBS and DMSO were mingled according to certain ratio(FBS:DMSO=9:1) as freezing and storing solution.Moreover, to adopt the simple and quick freezing and storing ways that removed cells from-80℃to liquid nitrogen were efficiently preserve ovine amnion epithelial cells.
2. Assessment the stem cell characteristics of ovine amnion epithelial cells
Cell immunofluorescence and RT-PCR were performed to detect respectively the expression of embryonic stem cell of ovine AECs marker proteins Oct-4, SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81and totipotency related genes OCT-4, SOX-2, Nanog, Rex-1and so on. The observed Oct-4, SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81immunoreactivity of ovine AECs were predominant. RT-PCR experiments confirmed that the genes of Oct-4, Sox-2, Rex-1were expressed and Nanog was not expressed. The results indicated that the ovine AECs have the multi-directional differentiation potentiality of stem cell properties.
3. Directional induction and differentiation of ovine amnion epithelial cells in vitro
To check the multi-directional differentiation potentiality of ovine amnion epithelial cells in vitro, ovine AECs were induced to directional differentiate into nervous systemcells, osteoblast and adipocyte utilizing some additional factors. Cell immunofluorescence and RT-PCR technologies, alkaline phosphatase activities detection, alizarin bordeaux stain, oil red O dyeing were performed respectively to accredit induced and differentiated cells. The results showed:①the specific marker β-Ⅲ-tubulin in cellula nervosa and GFAP in nerve cement cells were observed positive immunofluorescence signals after28day in induced nerves direction; the genes of nestin, β-Ⅲ-tubulin and MAP-2were expressed.②alkaline phosphatase activities in bone formation induction and differentiation were elevate slightly after28day and begin to higher obviously than control group after35days. Moreover, the activities were to continue increase as cultural time prolong and the differences between induce and control group were evident; calcify nodus were visible in alizarin monosulfonate stain.③it could be observed lipid droplet formation by oil red O dyeing in cellula adiposa induction and differentiation on42d; alkaline phosphatase activities in foundation culture group were reach to maximum and higher conspicuously than each induced group. From above research to the morphous characteristics of differentiated cells, we may safely draw the suppose that ovine amnion epithelial cells have already induced and differentiated into positive pro-mature neuron cells expressed β-Ⅲ-tubulin, positive mature neuron cells expressed MAP-2, positive nerve cement cells expressed GFAP, osteoblast with calcify nodus and cellula adiposa with lipid droplet.
4. study of therapy efficacy applied ovine amnion epithelial cells in rabbit radius defected models
Injecting directly ovine amnion epithelial cells into ovine vivo to cure achilles tendon injury had reported and therapeutic efficacy was extremely excellent. To test the possibility of acquired ovine amnion epithelial cells differentiation in rabbit vivo and similar therapeutic efficacy with reported above, the13-centimetre long radius defected models were made artificially in30rabbits, divided into high dose group, low dose group and control group randomly. To carry out cellular transplant by intravenous injection according to setting dose after dealing with ovine aminion epithelial cells. Took the models for X-ray in2weeks,4weeks and8weeks before the ovine aminion epithelial cells transplantations, after operation and injection cells respectively and meanwhile observed histomorphology. The resultes hint:defect tissues were repaired in the high dose group at8weeks, observed from the X-ray and histological section of new bone, and the quality and quantities of trabecular bones in high dose group were better and higher than in the low dose group and it was the same situation between the low dose group and the control group. Accordingly, it was presume that ovine amnion epithelial cells in rabbit radius defected models in vivo were differentiated into bone and accelerated repaired speed and quality of bone coloboma.And the study indicated that it is feasible to apply ovine amnion epithelial cells to heal small bone defect.
In this study successfully gain ovine amnion epithelial cells possessed with stem cell characteristics are have the multi-directional differentiation potency in vivo and in vitro. And the results in this research supply with the theory knowledges of AECs in stem cell characteristics and differentiation in vivo and in vitro, and establish rationale and provide practice base for clinical exploratory development.
引文
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