膀胱Cajal间质细胞（ICC）在膀胱起搏中的作用研究
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摘要
膀胱肌组织能够产生不受神经系统控制的自发性动作电位(如离体膀胱组织在多种神经阻滞剂混合物作用下仍可发生自发收缩,在体膀胱可以发生不受抑制的兴奋收缩等)[1],这提示我们特定情况下,膀胱可能被某种“潜在起搏点”所调控。
以往的观点认为这种自发性兴奋起搏来源于逼尿肌细胞,但更多的实验数据表明,逼尿肌细胞没有自发性兴奋的特点,无法担当膀胱起搏的任务[ 2]。所以,寻找和确认膀胱的起搏细胞成了亟待解决的问题。
对胃肠道的研究发现,胃肠道肌肉的蠕动是由分布于其间的ICC细胞所发动的。胃肠道的ICC细胞成群分布,常常交织成网状,与神经末梢,平滑肌有很多的结构联系[3],它们已被认为是胃肠道蠕动的起搏细胞。近年来,形态与胃肠道起搏细胞相似的ICC细胞在膀胱被发现,它被认为有类似的起搏功能。
目前对膀胱的ICC细胞所做的研究工作尚处于起步阶段,从取得的结果看,形态学研究较多,功能学研究较少,尤其对其是否是膀胱的起搏细胞阐释不清,对它在膀胱运动中的地位缺乏系统论证。
本实验目的在于考察膀胱的ICC细胞在膀胱运动中是否起到起搏作用。分为三个环节予以证明:1. ICC细胞具有成为起搏细胞的结构基础,利用形态学方法研究ICC细胞的分布特点以及ICC细胞与逼尿肌细胞之间的结构关系; 2. ICC细胞具有成为起搏细胞的功能特征,利用对ICC细胞上起搏通道HCN和ICC细胞与逼尿肌细胞信号通讯的研究,说明ICC细胞具有产生起搏电流和将兴奋传递给逼尿肌的能力;3. ICC细胞的正常功能受到抑制后,膀胱逼尿肌功能下降。应用ICC细胞特异性阻断剂Glivec,分别在细胞、组织、在体三个水平研究逼尿肌的功能的改变。另外,在完成对ICC细胞在膀胱运动中的起搏作用进行论证后,我们进一步对不稳定膀胱中ICC细胞的结构和功能改变做了初步探索,研究逼尿肌不稳定与ICC细胞改变间的关系。
主要的结果、结论如下:
1.建立了能有效观察膀胱ICC样细胞的免疫组织化学实验方法:采用改良的国外学者制备膀胱铺片方法,通过c-KIT免疫组织化学染色技术,证实在膀胱的粘膜下层和逼尿肌肌束边缘存在有ICC细胞。
2.发现了ICC细胞的结构分布特点:对ICC细胞的免疫荧光观察发现ICC细胞呈现明显的网络状分布,与胃肠道ICC网络相似。
3. ICC细胞与逼尿肌细胞之间结构上存在密切联系:免疫荧光双标发现,ICC细胞与逼尿肌细胞相邻,且有相互交错分布现象。透射电镜发现,ICC细胞与逼尿肌细胞之间具有细胞间电信号传递的结构基础——缝隙连接。这样,ICC细胞具有了成为膀胱起搏的结构特征。
4.发现了ICC细胞上有可产生起搏电流的HCN阳离子通道:采用c-Kit和HCN抗原的免疫荧光双标法,证明了c-Kit阳性的ICC细胞上具有HCN离子通道抗原的表达,这样ICC细胞上就具有可产生起搏电流的功能单位的存在。
5. ICC细胞与逼尿肌细胞之间可以发生信号传递:荧光漂白实验发现,ICC细胞可将荧光染料有效传递给相邻的被漂白的逼尿肌细胞,这说明ICC细胞与逼尿肌细胞之间可以存在信号通讯。这也是ICC细胞可以将兴奋信号传递给逼尿肌细胞的功能基础。
6.建立了特异性阻断ICC细胞功能的实验模式:利用对细胞游离钙的检测发现,c-Kit阻断剂Glivec主要影响ICC细胞的游离钙波动而对逼尿肌细胞没有明显影响,即Glivec作用靶点在ICC细胞上。这给我们提供了一个阻断实验的模式,即选择性阻断ICC功能,观察在ICC功能缺失的情况下,逼尿肌细胞功能的变化,从而考察ICC细胞在膀胱起搏中的作用。
7.在细胞、组织、在体水平特异阻断ICC细胞后逼尿肌发生功能改变:细胞水平阻断使ICC细胞游离钙波动、ICC细胞与逼尿肌细胞之间的通讯受到明显抑制;而在组织和在体水平的实验均发现,肌收缩的振幅(收缩力)明显缩窄。这说明ICC细胞在膀胱起搏中发挥着重要的作用。
8.不稳定膀胱中的ICC细胞网络结构和HCN阳离子通道的表达发生了明显改变:不稳定膀胱中的ICC细胞网络结构形态得到强化,而HCN阳离子通道的表达是明显增加的,这说明ICC的改变有可能是膀胱功能改变的原因。给我们提供了逼尿肌不稳定机制的一种全新解释方式。
Spontaneous action potential can be recorded from muscular tissue of bladder, even if its nerval control is removed. That indicates that in some circumstance, spontaneous excitation and contraction of bladder could be induced by some‘pacemaker cells’which remained unknown to us till now.
Years ago, it was regarded that that‘pacemaking’was from cells in detrusor but outcomes of a series of experiments showed that detrusor smooth muscle cells could not act as‘pacemaker’due to the lack of their ability to evoke spontaneous excitation. Since that case, it was our goal to find which is the pacemaker of bladder and to indentify it.
Study from gastrointestinal tract(GI) discovered that enterocinesia was induced by interstitial cells of Cajal(ICC) in it, so ICCs were regarded as pacemaker cells in GI. ICCs in GI, divided into different groups and reticulate, had quite a few structural junction not only to nerve terminal but also to smooth muscle cells.It was not long before the ICC-like cells was find in bladder, and the role of them was also thought to be similar to their counterpart in GI.
From all accounts, study on ICC in bladder as pacemaker cell is still in primary phase. Evidences should be found to prove the hypothesis.
The aim of the study is to investigate whether or not ICC in bladder is the pacemaker cell and we are going to pursue our goal from three directions: First, ICC as pacemaker should have a specilized structure. Characteristic of its distribution and structural connection between ICC and detrusor smooth muscle cell will be analysised in morphology.Second, ICC as pacemaker should have specilized function, that is,ICC could generate pacemaking current and transmit the current to neighboring detrusor smooth muscle cells. Third, detrusor function could be down-regulated when function of ICC was inhibited by blocking agent Glivec. Changes of detrusor function would be detected on the level of cell, tissue, and in vivo after blockade. Moreover, we made a intitial study on the structural and functional changes of ICC in instable bladder when the demonstration of ICC as pacemaker was accomplished.
Results and conclusions:
1. We established the effective method to investigate the morphology of ICC in the bladder: ICCs were identified to exist in suburothlium layer and the border of detrusor smooth muscle in bladder through KIT immunohistochemistry on the reformed stretch prepared bladder.
2. We found the characteristic of ICC’s distribution: ICCs exist as a network just like ICC in GI, which we found by immunofluorescence(IF).
3. There was tight relationship between ICC and detrusor smooth muscle cell: ICCs were close to smooth muscle cells and they were intercrossed to each other when double-labeled IF was applied for analysis.Moreover,Gap junction was detected by transmission electron microscope(TEM).
4. Hyperpolarization-activated cyclic nucleotide gate(HCN) ion channel, which was specified in generating pacemaking current, was found on the membrane of ICC: we used double-labeled IF by c-Kit and HCN antigen to detect it, so the capcity of ICC to generate pacemaking current was found.
5. Signal transmission was found from ICC to detrusor smooth muscle cell: We found the cellar signal could be transmitted efficiently from ICC to detrusor smooth muscle cells using Fluorescence Recovery After Photobleaching (FRAP).That might be the functional basis for ICC to be pacemaker cell to initiate the action potential of detrusor smooth muscle cells.
6. A mode for ICC’s functional inhibition was established: The effects of blocking agent Glivec were mainly on the calcium influx of ICC which provided us a new mode to investigate the function of smooth muscle cells with ICC’s function decreased.
7. Changes of detrusor function were detected on the level of cell, tissue, and in in vivo. Calcium influx and signal transmission from ICC to detrusor were inhibited significantly and contractile amplitude of detrusor was also decreased significantly in muscle strip and bladder as a whole. That indicated that ICC would play a crucial important role in the movements of bladder.
8. Changes on ICC network and expression of HCN were found in instable detruor: Network in ICC was strengthened while the protein expression of HCN was increased significantly, which implied that changes of ICC may be the cause for functional abnormality of detrusor.
以往的观点认为这种自发性兴奋起搏来源于逼尿肌细胞,但更多的实验数据表明,逼尿肌细胞没有自发性兴奋的特点,无法担当膀胱起搏的任务[ 2]。所以,寻找和确认膀胱的起搏细胞成了亟待解决的问题。
对胃肠道的研究发现,胃肠道肌肉的蠕动是由分布于其间的ICC细胞所发动的。胃肠道的ICC细胞成群分布,常常交织成网状,与神经末梢,平滑肌有很多的结构联系[3],它们已被认为是胃肠道蠕动的起搏细胞。近年来,形态与胃肠道起搏细胞相似的ICC细胞在膀胱被发现,它被认为有类似的起搏功能。
目前对膀胱的ICC细胞所做的研究工作尚处于起步阶段,从取得的结果看,形态学研究较多,功能学研究较少,尤其对其是否是膀胱的起搏细胞阐释不清,对它在膀胱运动中的地位缺乏系统论证。
本实验目的在于考察膀胱的ICC细胞在膀胱运动中是否起到起搏作用。分为三个环节予以证明:1. ICC细胞具有成为起搏细胞的结构基础,利用形态学方法研究ICC细胞的分布特点以及ICC细胞与逼尿肌细胞之间的结构关系; 2. ICC细胞具有成为起搏细胞的功能特征,利用对ICC细胞上起搏通道HCN和ICC细胞与逼尿肌细胞信号通讯的研究,说明ICC细胞具有产生起搏电流和将兴奋传递给逼尿肌的能力;3. ICC细胞的正常功能受到抑制后,膀胱逼尿肌功能下降。应用ICC细胞特异性阻断剂Glivec,分别在细胞、组织、在体三个水平研究逼尿肌的功能的改变。另外,在完成对ICC细胞在膀胱运动中的起搏作用进行论证后,我们进一步对不稳定膀胱中ICC细胞的结构和功能改变做了初步探索,研究逼尿肌不稳定与ICC细胞改变间的关系。
主要的结果、结论如下:
1.建立了能有效观察膀胱ICC样细胞的免疫组织化学实验方法:采用改良的国外学者制备膀胱铺片方法,通过c-KIT免疫组织化学染色技术,证实在膀胱的粘膜下层和逼尿肌肌束边缘存在有ICC细胞。
2.发现了ICC细胞的结构分布特点:对ICC细胞的免疫荧光观察发现ICC细胞呈现明显的网络状分布,与胃肠道ICC网络相似。
3. ICC细胞与逼尿肌细胞之间结构上存在密切联系:免疫荧光双标发现,ICC细胞与逼尿肌细胞相邻,且有相互交错分布现象。透射电镜发现,ICC细胞与逼尿肌细胞之间具有细胞间电信号传递的结构基础——缝隙连接。这样,ICC细胞具有了成为膀胱起搏的结构特征。
4.发现了ICC细胞上有可产生起搏电流的HCN阳离子通道:采用c-Kit和HCN抗原的免疫荧光双标法,证明了c-Kit阳性的ICC细胞上具有HCN离子通道抗原的表达,这样ICC细胞上就具有可产生起搏电流的功能单位的存在。
5. ICC细胞与逼尿肌细胞之间可以发生信号传递:荧光漂白实验发现,ICC细胞可将荧光染料有效传递给相邻的被漂白的逼尿肌细胞,这说明ICC细胞与逼尿肌细胞之间可以存在信号通讯。这也是ICC细胞可以将兴奋信号传递给逼尿肌细胞的功能基础。
6.建立了特异性阻断ICC细胞功能的实验模式:利用对细胞游离钙的检测发现,c-Kit阻断剂Glivec主要影响ICC细胞的游离钙波动而对逼尿肌细胞没有明显影响,即Glivec作用靶点在ICC细胞上。这给我们提供了一个阻断实验的模式,即选择性阻断ICC功能,观察在ICC功能缺失的情况下,逼尿肌细胞功能的变化,从而考察ICC细胞在膀胱起搏中的作用。
7.在细胞、组织、在体水平特异阻断ICC细胞后逼尿肌发生功能改变:细胞水平阻断使ICC细胞游离钙波动、ICC细胞与逼尿肌细胞之间的通讯受到明显抑制;而在组织和在体水平的实验均发现,肌收缩的振幅(收缩力)明显缩窄。这说明ICC细胞在膀胱起搏中发挥着重要的作用。
8.不稳定膀胱中的ICC细胞网络结构和HCN阳离子通道的表达发生了明显改变:不稳定膀胱中的ICC细胞网络结构形态得到强化,而HCN阳离子通道的表达是明显增加的,这说明ICC的改变有可能是膀胱功能改变的原因。给我们提供了逼尿肌不稳定机制的一种全新解释方式。
Spontaneous action potential can be recorded from muscular tissue of bladder, even if its nerval control is removed. That indicates that in some circumstance, spontaneous excitation and contraction of bladder could be induced by some‘pacemaker cells’which remained unknown to us till now.
Years ago, it was regarded that that‘pacemaking’was from cells in detrusor but outcomes of a series of experiments showed that detrusor smooth muscle cells could not act as‘pacemaker’due to the lack of their ability to evoke spontaneous excitation. Since that case, it was our goal to find which is the pacemaker of bladder and to indentify it.
Study from gastrointestinal tract(GI) discovered that enterocinesia was induced by interstitial cells of Cajal(ICC) in it, so ICCs were regarded as pacemaker cells in GI. ICCs in GI, divided into different groups and reticulate, had quite a few structural junction not only to nerve terminal but also to smooth muscle cells.It was not long before the ICC-like cells was find in bladder, and the role of them was also thought to be similar to their counterpart in GI.
From all accounts, study on ICC in bladder as pacemaker cell is still in primary phase. Evidences should be found to prove the hypothesis.
The aim of the study is to investigate whether or not ICC in bladder is the pacemaker cell and we are going to pursue our goal from three directions: First, ICC as pacemaker should have a specilized structure. Characteristic of its distribution and structural connection between ICC and detrusor smooth muscle cell will be analysised in morphology.Second, ICC as pacemaker should have specilized function, that is,ICC could generate pacemaking current and transmit the current to neighboring detrusor smooth muscle cells. Third, detrusor function could be down-regulated when function of ICC was inhibited by blocking agent Glivec. Changes of detrusor function would be detected on the level of cell, tissue, and in vivo after blockade. Moreover, we made a intitial study on the structural and functional changes of ICC in instable bladder when the demonstration of ICC as pacemaker was accomplished.
Results and conclusions:
1. We established the effective method to investigate the morphology of ICC in the bladder: ICCs were identified to exist in suburothlium layer and the border of detrusor smooth muscle in bladder through KIT immunohistochemistry on the reformed stretch prepared bladder.
2. We found the characteristic of ICC’s distribution: ICCs exist as a network just like ICC in GI, which we found by immunofluorescence(IF).
3. There was tight relationship between ICC and detrusor smooth muscle cell: ICCs were close to smooth muscle cells and they were intercrossed to each other when double-labeled IF was applied for analysis.Moreover,Gap junction was detected by transmission electron microscope(TEM).
4. Hyperpolarization-activated cyclic nucleotide gate(HCN) ion channel, which was specified in generating pacemaking current, was found on the membrane of ICC: we used double-labeled IF by c-Kit and HCN antigen to detect it, so the capcity of ICC to generate pacemaking current was found.
5. Signal transmission was found from ICC to detrusor smooth muscle cell: We found the cellar signal could be transmitted efficiently from ICC to detrusor smooth muscle cells using Fluorescence Recovery After Photobleaching (FRAP).That might be the functional basis for ICC to be pacemaker cell to initiate the action potential of detrusor smooth muscle cells.
6. A mode for ICC’s functional inhibition was established: The effects of blocking agent Glivec were mainly on the calcium influx of ICC which provided us a new mode to investigate the function of smooth muscle cells with ICC’s function decreased.
7. Changes of detrusor function were detected on the level of cell, tissue, and in in vivo. Calcium influx and signal transmission from ICC to detrusor were inhibited significantly and contractile amplitude of detrusor was also decreased significantly in muscle strip and bladder as a whole. That indicated that ICC would play a crucial important role in the movements of bladder.
8. Changes on ICC network and expression of HCN were found in instable detruor: Network in ICC was strengthened while the protein expression of HCN was increased significantly, which implied that changes of ICC may be the cause for functional abnormality of detrusor.
引文
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