T细胞因子4在毛囊毛乳头细胞中的表达及其功能研究
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摘要
一、研究背景与目的
位于毛囊基底部的特殊间质成分毛乳头细胞(dermal papilla cell,DPC)在毛囊发育和周期性再生调控中起主导作用。在胚胎期,DPC产生多种针对表皮的调节因子,促使表皮细胞增生分化形成毛囊。出生后毛囊的周期性再生过程中诱导上皮细胞增殖和分化的信号也来自DPC。诱导毛囊形成是DPC最为显著的功能特征,DPC功能的异常变化是导致毛囊周期失衡和脱发现象的主要起始因素。因此对DPC生物学功能变化的调控机制进行深入研究,对毛囊生物学和毛发疾病的研究都有重大的意义。相关研究先后鉴定出数十种与DPC相关的调控因子,这些调控因子在DPC和毛囊上皮细胞的相互作用中构成复杂的调控网络,但尚不能确定其中具有关键作用的因子或调控途径。
研究表明,细胞在不同的生物学功能状态中表达的基因不同,基因表达的有序性、选择性是细胞功能变化的内在根据。因此,通过分析不同状态下DPC基因表达的差异,可为揭示DPC生物学功能调控规律提供重要信息。获取差异表达的基因将有助于了解DPC在生理和病理条件下功能变化的分子机制,为毛囊发育和毛囊周期性生长调控研究提供新的视野。
在以往的研究中,本课题组使用抑制性消减杂交技术(SSH)结合SMARTTM cDNA合成技术对人活体组织中休止期毛囊DPC及生长期毛囊DPC mRNA的表达差异进行了研究。SSH方法通过两轮杂交和抑制性PCR,可对两个样本的基因表达进行有效对比。运用SMARTTM cDNA合成技术合成cDNA,使对活体组织毛乳头标本进行基因表达差异研究成为可能。最终我们成功建立了毛乳头差异表达cDNA文库,为进一步阐述DPC功能调控的分子机制奠定了基础。
从所建立的毛乳头差异表达cDNA文库中,我们首次发现了Wnt信号通路关键信号分子T细胞因子4(T cell factor4,TCF4)作为生长期毛囊DPC的上调表达基因,并使用反向Northern实验对该结果进行了验证。TCF4在DPC中差异表达为首次发现,生物学意义尚不明了。本课题拟研究DPC在凝集性生长和非凝集性生长状态下的TCF4基因表达差异,以及对TCF4基因在DPC生物学功能调控中的作用进行实验研究。
二、方法与结果
1.TCF4基因在毛囊DPC中的表达
首先应用原位杂交技术检测斑秃患者和正常人头皮组织的TCF4基因的表达;应用细胞免疫化学检测凝集性生长和非凝集性生长的人DPC的TCF4蛋白的表达;RT-PCR的方法从上述两种细胞的总RNA扩增TCF4基因。结果发现TCF4基因在正常头皮组织毛囊DPC表达,而在斑秃组织毛囊的DPC不表达;TCF4基因在凝集性生长期DPC中表达,而在非凝集性生长期DPC不表达。表明TCF4基因在生长期DPC中高水平表达。
2.pcDNA3.0-TCF4表达载体的构建及表达
为了研究TCF4基因对DPC增殖的影响,我们构建了pcDNA3.0-TCF4表达载体。首先从凝集性生长DPC中提取总RNA,RT-PCR获得带有酶切位点的TCF4基因克隆,亚克隆入pcDNA3.0载体中,并通过双酶切和测序进行鉴定。利用脂质体2000转染到DPC中进行稳定表达,检测转染前后TCF4表达的变化。以未转染的DPC作为对照组,分别用流式细胞仪检测DPC细胞周期的变化,Western blot检测DPC的肝细胞生长因子(hepatocyte growth factor,HGF)、干细胞生长因子(stem cell factor, SCF)的表达,MTT比色法检测细胞生长曲线,3H-TdR检测细胞增殖。结果表明,我们从DPC中获得TCF4基因克隆并且成功构建了真核表达载体。经过稳定转染,DPC中TCF4在mRNA和蛋白表达水平上调。与对照组相比,DPC的增殖能力和相关细胞因子的分泌能力得到明显提高。结果表明,TCF4基因可以促进DPC增殖和分泌细胞因子的功能。
3.RNA干扰抑制TCF4表达对DPC生物学功能的影响
为了进一步探讨TCF4的表达对DPC细胞生物学功能的影响,我们采用化学合成法合成3对TCF4 siRNA,并转染DPC。采用半定量RT-PCR及Western blot分别从mRNA和蛋白质水平检测DPC TCF4的表达情况。以未转染siRNA的DPC作为对照组,用流式细胞仪检测DPC细胞周期的变化,Western blot检测DPC的胰岛素样生长因子-1(insulin-like growth factor-1,IGF-1)和SCF的表达,MTT比色法检测细胞生长曲线,3H-TdR检测细胞增殖。结果表明与空白对照组相比,3组序列的mRNA和蛋白质表达均有明显降低,以序列2组下降明显。细胞增殖能力均显著下降(P<0.05),IGF-1、SCF表达明显降低,而对照组无显著性差异。结果表明TCF4 siRNA能显著下调DPC TCF4的表达,降低DPC的增殖能力,进一步提示TCF4在DPC生长调控中可能起到重要作用。
三、结论
1. TCF4基因在生长期DPC中高表达。
2. TCF4基因在DPC中过表达使其细胞周期、生长曲线明显改变,细胞增殖明显增强,并促进DPC分泌细胞因子。
3.通过RNA干扰降低TCF4基因的表达,可使DPC细胞增殖减慢,相关细胞因子的分泌受到抑制。
通过以上实验,为深入了解TCF4基因以及Wnt信号在毛囊周期性调控中的作用和机制奠定了基础。
Backgrounds and Objectives
Dermal papilla cells (DPC), located in basement of hair follicle, play an important role in morphology development and cycle regulation of hair follicle. During the embryo period, DPC secret various cytokines to promote proliferation of epidermal cells and formation of hair follicle. After birth, the main biological function of the DPC is to induce the hair follicle formation. The abnormality of the DPC function can cause the imbalance of follicle growth cycle and hair loss. It is meaningful for us to study the biological rule of DPC in hair follicle. Recent studies have found that DPC were related to several kinds of regulating factors, which constituted a complicated network. So far, we cannot identify the key factor in this network.
Studies have proved that cells in the different biological function status express different genes. Therefore, the analysis of the different genes expressed by DPC can reveal the molecule mechanism of DPC in different biological functions status, which provide new ways to study the regulation of hair follicle growth.
In previous work, we've identified the differential genes expressed by anagen dermal papilla and telogen dermal papilla by using suppression subtractive hybridization(SSH) and SMART~(TM) cDNA. SSH can be used to compare the different genes expressed by two samples by two rounds of hybridization and suppressive PCR. It is feasible to screen out the different expression genes in DPC through synthesizing cDNA by SMART~(TM) cDNA technology. Finally, we have constructed the cDNA library of DPC, which is the foundation for further studying the molecular mechanism of DPC in follicle growth cycle. It is the first time for us to find that T cell factor 4(TCF4) is differently expressed in DPC in different biological functions status. But its biological significance is unclear. In the cDNA library of DPC, we have found the expression of TCF4 gene was up-regulated in anagen dermal papilla, and the results have been confirmed by using reverse Northern. The aim of the study is to investigate the expression and function of TCF4 in DPC of hair follicle.
Methods and Results
1. The expression of TCF4 gene in DPC
Firstly, hybridization in situ was used to examine the expression of TCF4 gene expressed in alopecia areata(AA) and normal human scalp tissue. Secondly, immunochemistry was used to examine the expression of TCF4 protein in DPC with and without aggregative behavious. Finally, RT-PCR was used to amplify TCF4 gene from the total RNA of DPC. We found that TCF4 gene expressed in DPC of normal human scalp, and it was not found in DPC of scalp from alopecia patients. These results indicated that TCF4 gene highly expressed in anagen DPC.
2. The construction and expression of pcDNA3.0-TCF4 expression vector
In order to study the effect of TCF4 in the proliferation of DPC, we constructed the pcDNA3.0-TCF4 expression vector. Firstly, we extracted the total RNA from the aggregative DPC. TCF4 gene was gotten by RT-PCR , and was inserted into the eukaryotic expression vector pcDNA3.0. The sequence and reading frame were confirmed by two restriction enzymes and sequencing.The recombinant vector pcDNA3.0-TCF4 was stably transfected in DPC and the expressive changes of TCF4 gene were detected. DPC without transfection was used to be as the control. The cell cycle was detected by flow cytometry.The concentrations of hepatocyte growth factor (HGF) and insulin growth factor1 (IGF-1) were detected by Western blot.We examined the growth curve by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide(MTT) and detected the proliferation of DPC by 3H-TdR. The results showed that TCF4 gene was cloned from DPC and its eukaryotic expression vector was constructed successfully. The mRNA and protein levels of TCF4 were up-regulated respectively after the recombinant vector being transfected into DPC. The proliferation of DPC and secretion of cytokines were increased. Those suggested that TCF4 gene might promote the proliferation and secretion of DPC.
3.The effects of TCF4 siRNA in the biological functions of DPC
In order to study the role of TCF4 in the biological functions of DPC, we synthesized three pairs of TCF4 siRNA and transfected them into DPC.The mRNA and protein expression of TCF4 were analyzed by semi-quantified RT-PCR and Western blot, and DPC without transfecting was used to be as the control. Flow cytometry was used to detect the growth cycle of DPC. Western blot was used to detect the expression of the concentration of stem cell factor (SCF) and IGF-1.MTT and 3H-TdR were used to detect the proliferation capacity of DPC.The results showed that mRNA and protein expression were reduced respectively in siRNA group, but no change was found in control groups.The expressions of SCF, IGF-1 were decreased significantly and the proliferation capacities were inhibited in the RNA interference group. From our results, we can concluse that TCF4 siRNA can down-regulate the expression of TCF4 and lower the proliferation of DPC. So, TCF4 plays an important role in regulating and controlling the growth of DPC.
Conclusions
1. The expression of TCF4 gene is up-regulated in anagen DPC.
2.The overexpression of TCF4 in DPC chang cell cycle and growth curve,enhance the proliferation of DPC and promote the secretion of cytokines.
3.The expression of TCF4 gene is decreased by silencing the TCF4 gene, which step down the proliferation of DPC and inhibited the secretion of relevant cytokines.
The present experiment lay the foundation for further study the role of TCF4 gene and Wnt signal pathway in regulating and controlling the follicle cycle.
位于毛囊基底部的特殊间质成分毛乳头细胞(dermal papilla cell,DPC)在毛囊发育和周期性再生调控中起主导作用。在胚胎期,DPC产生多种针对表皮的调节因子,促使表皮细胞增生分化形成毛囊。出生后毛囊的周期性再生过程中诱导上皮细胞增殖和分化的信号也来自DPC。诱导毛囊形成是DPC最为显著的功能特征,DPC功能的异常变化是导致毛囊周期失衡和脱发现象的主要起始因素。因此对DPC生物学功能变化的调控机制进行深入研究,对毛囊生物学和毛发疾病的研究都有重大的意义。相关研究先后鉴定出数十种与DPC相关的调控因子,这些调控因子在DPC和毛囊上皮细胞的相互作用中构成复杂的调控网络,但尚不能确定其中具有关键作用的因子或调控途径。
研究表明,细胞在不同的生物学功能状态中表达的基因不同,基因表达的有序性、选择性是细胞功能变化的内在根据。因此,通过分析不同状态下DPC基因表达的差异,可为揭示DPC生物学功能调控规律提供重要信息。获取差异表达的基因将有助于了解DPC在生理和病理条件下功能变化的分子机制,为毛囊发育和毛囊周期性生长调控研究提供新的视野。
在以往的研究中,本课题组使用抑制性消减杂交技术(SSH)结合SMARTTM cDNA合成技术对人活体组织中休止期毛囊DPC及生长期毛囊DPC mRNA的表达差异进行了研究。SSH方法通过两轮杂交和抑制性PCR,可对两个样本的基因表达进行有效对比。运用SMARTTM cDNA合成技术合成cDNA,使对活体组织毛乳头标本进行基因表达差异研究成为可能。最终我们成功建立了毛乳头差异表达cDNA文库,为进一步阐述DPC功能调控的分子机制奠定了基础。
从所建立的毛乳头差异表达cDNA文库中,我们首次发现了Wnt信号通路关键信号分子T细胞因子4(T cell factor4,TCF4)作为生长期毛囊DPC的上调表达基因,并使用反向Northern实验对该结果进行了验证。TCF4在DPC中差异表达为首次发现,生物学意义尚不明了。本课题拟研究DPC在凝集性生长和非凝集性生长状态下的TCF4基因表达差异,以及对TCF4基因在DPC生物学功能调控中的作用进行实验研究。
二、方法与结果
1.TCF4基因在毛囊DPC中的表达
首先应用原位杂交技术检测斑秃患者和正常人头皮组织的TCF4基因的表达;应用细胞免疫化学检测凝集性生长和非凝集性生长的人DPC的TCF4蛋白的表达;RT-PCR的方法从上述两种细胞的总RNA扩增TCF4基因。结果发现TCF4基因在正常头皮组织毛囊DPC表达,而在斑秃组织毛囊的DPC不表达;TCF4基因在凝集性生长期DPC中表达,而在非凝集性生长期DPC不表达。表明TCF4基因在生长期DPC中高水平表达。
2.pcDNA3.0-TCF4表达载体的构建及表达
为了研究TCF4基因对DPC增殖的影响,我们构建了pcDNA3.0-TCF4表达载体。首先从凝集性生长DPC中提取总RNA,RT-PCR获得带有酶切位点的TCF4基因克隆,亚克隆入pcDNA3.0载体中,并通过双酶切和测序进行鉴定。利用脂质体2000转染到DPC中进行稳定表达,检测转染前后TCF4表达的变化。以未转染的DPC作为对照组,分别用流式细胞仪检测DPC细胞周期的变化,Western blot检测DPC的肝细胞生长因子(hepatocyte growth factor,HGF)、干细胞生长因子(stem cell factor, SCF)的表达,MTT比色法检测细胞生长曲线,3H-TdR检测细胞增殖。结果表明,我们从DPC中获得TCF4基因克隆并且成功构建了真核表达载体。经过稳定转染,DPC中TCF4在mRNA和蛋白表达水平上调。与对照组相比,DPC的增殖能力和相关细胞因子的分泌能力得到明显提高。结果表明,TCF4基因可以促进DPC增殖和分泌细胞因子的功能。
3.RNA干扰抑制TCF4表达对DPC生物学功能的影响
为了进一步探讨TCF4的表达对DPC细胞生物学功能的影响,我们采用化学合成法合成3对TCF4 siRNA,并转染DPC。采用半定量RT-PCR及Western blot分别从mRNA和蛋白质水平检测DPC TCF4的表达情况。以未转染siRNA的DPC作为对照组,用流式细胞仪检测DPC细胞周期的变化,Western blot检测DPC的胰岛素样生长因子-1(insulin-like growth factor-1,IGF-1)和SCF的表达,MTT比色法检测细胞生长曲线,3H-TdR检测细胞增殖。结果表明与空白对照组相比,3组序列的mRNA和蛋白质表达均有明显降低,以序列2组下降明显。细胞增殖能力均显著下降(P<0.05),IGF-1、SCF表达明显降低,而对照组无显著性差异。结果表明TCF4 siRNA能显著下调DPC TCF4的表达,降低DPC的增殖能力,进一步提示TCF4在DPC生长调控中可能起到重要作用。
三、结论
1. TCF4基因在生长期DPC中高表达。
2. TCF4基因在DPC中过表达使其细胞周期、生长曲线明显改变,细胞增殖明显增强,并促进DPC分泌细胞因子。
3.通过RNA干扰降低TCF4基因的表达,可使DPC细胞增殖减慢,相关细胞因子的分泌受到抑制。
通过以上实验,为深入了解TCF4基因以及Wnt信号在毛囊周期性调控中的作用和机制奠定了基础。
Backgrounds and Objectives
Dermal papilla cells (DPC), located in basement of hair follicle, play an important role in morphology development and cycle regulation of hair follicle. During the embryo period, DPC secret various cytokines to promote proliferation of epidermal cells and formation of hair follicle. After birth, the main biological function of the DPC is to induce the hair follicle formation. The abnormality of the DPC function can cause the imbalance of follicle growth cycle and hair loss. It is meaningful for us to study the biological rule of DPC in hair follicle. Recent studies have found that DPC were related to several kinds of regulating factors, which constituted a complicated network. So far, we cannot identify the key factor in this network.
Studies have proved that cells in the different biological function status express different genes. Therefore, the analysis of the different genes expressed by DPC can reveal the molecule mechanism of DPC in different biological functions status, which provide new ways to study the regulation of hair follicle growth.
In previous work, we've identified the differential genes expressed by anagen dermal papilla and telogen dermal papilla by using suppression subtractive hybridization(SSH) and SMART~(TM) cDNA. SSH can be used to compare the different genes expressed by two samples by two rounds of hybridization and suppressive PCR. It is feasible to screen out the different expression genes in DPC through synthesizing cDNA by SMART~(TM) cDNA technology. Finally, we have constructed the cDNA library of DPC, which is the foundation for further studying the molecular mechanism of DPC in follicle growth cycle. It is the first time for us to find that T cell factor 4(TCF4) is differently expressed in DPC in different biological functions status. But its biological significance is unclear. In the cDNA library of DPC, we have found the expression of TCF4 gene was up-regulated in anagen dermal papilla, and the results have been confirmed by using reverse Northern. The aim of the study is to investigate the expression and function of TCF4 in DPC of hair follicle.
Methods and Results
1. The expression of TCF4 gene in DPC
Firstly, hybridization in situ was used to examine the expression of TCF4 gene expressed in alopecia areata(AA) and normal human scalp tissue. Secondly, immunochemistry was used to examine the expression of TCF4 protein in DPC with and without aggregative behavious. Finally, RT-PCR was used to amplify TCF4 gene from the total RNA of DPC. We found that TCF4 gene expressed in DPC of normal human scalp, and it was not found in DPC of scalp from alopecia patients. These results indicated that TCF4 gene highly expressed in anagen DPC.
2. The construction and expression of pcDNA3.0-TCF4 expression vector
In order to study the effect of TCF4 in the proliferation of DPC, we constructed the pcDNA3.0-TCF4 expression vector. Firstly, we extracted the total RNA from the aggregative DPC. TCF4 gene was gotten by RT-PCR , and was inserted into the eukaryotic expression vector pcDNA3.0. The sequence and reading frame were confirmed by two restriction enzymes and sequencing.The recombinant vector pcDNA3.0-TCF4 was stably transfected in DPC and the expressive changes of TCF4 gene were detected. DPC without transfection was used to be as the control. The cell cycle was detected by flow cytometry.The concentrations of hepatocyte growth factor (HGF) and insulin growth factor1 (IGF-1) were detected by Western blot.We examined the growth curve by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide(MTT) and detected the proliferation of DPC by 3H-TdR. The results showed that TCF4 gene was cloned from DPC and its eukaryotic expression vector was constructed successfully. The mRNA and protein levels of TCF4 were up-regulated respectively after the recombinant vector being transfected into DPC. The proliferation of DPC and secretion of cytokines were increased. Those suggested that TCF4 gene might promote the proliferation and secretion of DPC.
3.The effects of TCF4 siRNA in the biological functions of DPC
In order to study the role of TCF4 in the biological functions of DPC, we synthesized three pairs of TCF4 siRNA and transfected them into DPC.The mRNA and protein expression of TCF4 were analyzed by semi-quantified RT-PCR and Western blot, and DPC without transfecting was used to be as the control. Flow cytometry was used to detect the growth cycle of DPC. Western blot was used to detect the expression of the concentration of stem cell factor (SCF) and IGF-1.MTT and 3H-TdR were used to detect the proliferation capacity of DPC.The results showed that mRNA and protein expression were reduced respectively in siRNA group, but no change was found in control groups.The expressions of SCF, IGF-1 were decreased significantly and the proliferation capacities were inhibited in the RNA interference group. From our results, we can concluse that TCF4 siRNA can down-regulate the expression of TCF4 and lower the proliferation of DPC. So, TCF4 plays an important role in regulating and controlling the growth of DPC.
Conclusions
1. The expression of TCF4 gene is up-regulated in anagen DPC.
2.The overexpression of TCF4 in DPC chang cell cycle and growth curve,enhance the proliferation of DPC and promote the secretion of cytokines.
3.The expression of TCF4 gene is decreased by silencing the TCF4 gene, which step down the proliferation of DPC and inhibited the secretion of relevant cytokines.
The present experiment lay the foundation for further study the role of TCF4 gene and Wnt signal pathway in regulating and controlling the follicle cycle.
引文
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