机械牵张对豚鼠膀胱ICC细胞兴奋性的影响及其与逼尿肌不稳定的关系
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摘要
背景及目的:储/排尿是膀胱的主要生理功能。这一功能受到来自中枢神经系统的支配和控制,神经因素长期以来被认为是膀胱功能调节最经典甚至是惟一的调控方式。但是有研究表明膀胱逼尿肌在失去神经控制的状态下,仍然存在自发性的收缩,目前越来越多的证据显示膀胱源性因素也参与了膀胱功能的调节。这些因素包括膀胱上皮细胞的分泌功能、逼尿肌细胞之间的缝隙连接和信号传递以及膀胱壁内的一些特殊的细胞群等等。这些膀胱自身的调控因素在膀胱逼尿肌兴奋的起源和调控机制尚待进一步阐明。神经因素之外的膀胱自身调控因素如何参与膀胱的兴奋性控制,他们与经典的神经调控机制之间的关系毫无疑问地成为了膀胱功能调节崭新的研究方向。
既然膀胱具有自发的兴奋性,而同样具有自发性兴奋的器官如心脏和胃肠道等都有一个共同的特点,自发的兴奋性与某些特殊分化的细胞群有密切的关系。因此很多研究人员都自然而然地联想到膀胱中是否存在这样一群类似的细胞。新近的报道以及我们的研究中发现:膀胱中的确存在一种特殊的间质细胞,这种细胞和胃肠道卡哈尔间质细胞(Interstitial cells of Cajal,ICC)类似,有特异性的c-kit酪氨酸激酶受体的表面标志。很多研究都业已证实胃肠道的ICC细胞参与了胃肠道蠕动功能的调节,而在某些由于ICC细胞缺失或功能失调导致的先天性胃肠道功能紊乱性疾病中同时也伴有膀胱功能障碍。因此我们推测ICC细胞可能参与了膀胱功能的调节,并且作为一种重要的膀胱源性因素,影响了膀胱的自发性兴奋收缩以及膀胱功能的调控。ICC细胞作为胃肠道中的“起搏细胞”,在调节胃肠道动力的病理生理学机制方面起到重要的作用。目前的研究表明,ICC细胞是一种具有多种功能的特殊间质细胞,它们的主要功能是产生和传播胃肠道基本电节律(Basic electrical rhythm ,BER)、整合神经调控以及感受胃肠道的机械牵张刺激。近年来的研究表明,在包括人在内的多种属的泌尿系统中,也存在着这样一些特殊的间质细胞,它们可分布在输尿管、膀胱、尿道、前列腺、阴茎海绵体,但是对这些特殊的细胞的功能知之甚少,命名也尚不统一,它们曾被称作如膀胱间质细胞、非典型平滑肌细胞、ICC样间质细胞、类ICC细胞等等。这些细胞的广泛分布和潜在的功能开启了泌尿系统相关研究的一个新领域。虽然这类间质细胞和胃肠道ICC细胞有类似的形态学特征和某些生理学功能(如自发兴奋性等),但很多研究也表明其与胃肠道ICC有明显的差别,胃肠道ICC细胞的功能亦尚未一一在膀胱ICC细胞中得到印证。为了规范名称便于交流,2007年的第五届国际Cajal间质细胞论坛建议将泌尿系这一类与胃肠道ICC有相似形态学特征和免疫学标志的间质细胞命名为泌尿系ICC细胞,本文中对于该类细胞的命名也借鉴了上述标准。在以往的研究中,已经明确的观察到ICC细胞在泌尿道的分布以及形态学特征,甚至从组织中将他们分离出来进行培养和研究他们的免疫学、生理学特性,但是到目前为止,泌尿系ICC细胞究竟如何参与和调节泌尿系统的功能仍然没有定论。
细胞的生物机械环境对于细胞的正常生长发育,相互作用及其特殊功能的发挥都有重要的影响,在众多的机械刺激当中,机械牵张刺激是最为常见的。膀胱在生理状态下,感受不断产生的尿液对膀胱壁的充盈刺激是调节膀胱排空的重要因素。目前的研究表明:在体条件下,当膀胱内容量充盈到一定程度时,即产生足够的牵张刺激,使逼尿肌兴奋性增高,诱发其收缩,从而启动膀胱的排空;而在离体条件下,膀胱逼尿肌条受到牵张刺激时逼尿肌细胞可产生自发性的兴奋,启动肌条的节律性收缩,这种收缩在膀胱失去神经支配和多种神经受抑制剂(包括河豚毒素)作用下仍然存在。而在某些病理状态下,如逼尿肌不稳定中,上述牵张诱导的肌条活动表现为同样张力条件下不稳定逼尿肌较正常逼尿肌收缩频率增高。因此机械牵张在启动膀胱源性逼尿肌收缩和控制逼尿肌兴奋性中有重要作用。
我室以往的研究表明:正常豚鼠膀胱中存在c-kit阳性的ICC细胞,可主要分布于膀胱粘膜下、逼尿肌肌束之间以及逼尿肌肌束内部。膀胱ICC细胞可产生自发性起搏电位If,可能与逼尿肌的自发性收缩关系密切;膀胱不同部位的ICC细胞有着不同的分布密度,三角区的膀胱ICC细胞密度最高,而与之相对应的部位逼尿肌条的自发性收缩频率更高,提示膀胱中可能存在兴奋的最高控制点,即起搏点,而膀胱ICC细胞可能和起搏功能有密切关系;另外我们还发现ICC细胞可以对ATP、卡巴胆碱等神经递质或类似物产生兴奋样冲动,膀胱内灌注ATP可诱发大鼠盆神经放电,用c-kit特异性抑制剂甲磺酸依马替尼阻断ICC细胞功能后,盆神经放电频率明显降低,提示ICC细胞极有可能参与了ATP介导的膀胱感觉传入,ICC细胞可能作为神经末梢调控逼尿肌细胞收缩“中转站”的结构基础发挥了重要的中介作用。而膀胱ICC细胞的潜在起搏功能和神经传递功能都来自基于胃肠道ICC细胞功能的延伸和推测,因此我们有理由相信膀胱ICC细胞可能和胃肠道ICC细胞一样,也可通过感受机械牵张刺激参与了膀胱逼尿肌收缩功能的调控。而这种特殊的牵张感受功能对我们理解膀胱源性的逼尿肌自发性兴奋从而进一步认识储尿排尿生理和病理状态下的膀胱功能异常都有重要的意义。
综上所述,膀胱逼尿肌具有自发性兴奋,机械牵张刺激可诱导膀胱逼尿肌发生周期性的收缩,而膀胱中的ICC细胞是不是这种自发性兴奋的结构基础?膀胱ICC细胞是否具有牵张敏感特性?在膀胱功能异常的情况下ICC细胞的结构和功能会不会发生变化?对这些问题进行深入的探索具有重要的科学研究意义,并将为逼尿肌兴奋性调控相关研究开创新的领域,为膀胱功能障碍性疾病的发病机制研究提供一个全新的切入点。
本课题通过体内慢性梗阻和体外培养细胞的机械牵张模型研究ICC细胞的形态、数量以及兴奋性的变化,探讨膀胱ICC细胞的机械牵张敏感性及其在逼尿肌不稳定中的可能机制。
我们拟从以下几个方面进行研究:第一:通过膀胱颈部分梗阻(partial bladder outlet obstruction, PBOO)建立豚鼠逼尿肌不稳定动物模型,并比较梗阻后膀胱ICC细胞的形态、数量及分布的变化,研究ICC细胞在膀胱流出道梗阻状态下的适应性改变;第二:观察PBOO膀胱和正常膀胱内ICC细胞的自发钙活动的变化,探讨ICC细胞在PBOO后的功能改变以及在逼尿肌不稳定(detrusor overactivity, DO)发病机制中的可能作用;第三:构建体外培养细胞机械牵张装置,通过对体外培养的膀胱ICC细胞施加静态牵张力的作用,观察ICC细胞内牵张诱导钙瞬变(stretch-induced calcium transient, SICT)的特征;第四:通过施加一定的钙离子阻断因素,包括清除细胞外钙离子、RYR或IP3敏感钙库抑制等探讨ICC细胞SICT的来源和初步作用机制。
方法:
1.本研究以2-3月龄豚鼠为研究对象,尿道近端结扎法制作膀胱流出道部分梗阻模型,并设假手术组为对照,6周后行充盈性膀胱测压,根据测压结果将动物分为梗阻后逼尿肌不稳定组(DO组)、梗阻后逼尿肌稳定组(DS组)和对照组。各组分别行c-kit免疫荧光组织染色,激光共聚焦观察ICC细胞的形态和分布情况;
2.流式细胞仪检测各组c-kit阳性细胞数量的变化;为排除肥大细胞的干扰(因为膀胱中的肥大细胞也可表现为c-kit染色阳性)以验证流式细胞仪的结果,在激光共聚焦显微镜下对各组膀胱组织标本行ICC细胞计数;
3.利用StageFlexer硅酮膜、聚乙烯齿梳、3140密封胶以及普通细胞培养皿等材料制作体外水平机械牵张装置,并与低渗溶液诱导细胞膨胀进行比较;
4.胶原酶消化膀胱组织,体外培养ICC细胞72h并通过c-kit免疫荧光细胞染色进行鉴定;
5.活细胞钙荧光指示剂Fluo-4AM负载急性分离贴壁的细胞,激光共聚焦动态观察DO组、DS组和对照组膀胱ICC细胞自发钙活动的变化情况;
6.将正常膀胱ICC细胞培养于体外水平机械牵张装置中72h牢固贴壁后,通过梯度机械牵张刺激观察ICC细胞在机械牵张负荷下的SICT变化情况;
7.利用无钙HBSS缓冲液、RYR钙库特异性阻断剂钌红(Ruthenium red,RU)或IP3敏感钙库特异性阻滞剂2-氨基乙氧基苯硼酸(2-Aminoethoxydiphenyl borate,2-APB)处理体外培养的ICC细胞,探讨胞外钙离子内流以及胞内钙库释放在ICC细胞自发性钙活动以及SICT产生机制中的作用。
结果:
1.通过免疫荧光组织染色我们发现正常膀胱和DS膀胱中粘膜下层c-kit阳性细胞呈单层连续分布,在平滑肌束之间散在分布,相互间缺乏联系;PBOO术后出现DO组膀胱ICC细胞在粘膜下ICC细胞多层分布,肌束间ICC细胞互相之间连接呈网络状;
2.流式细胞仪检测发现DO组膀胱中c-kit阳性细胞数量较对照组显著增多,而DS组和正常对照组间无显著差异;激光共聚焦显微镜下行ICC细胞计数的结果表明PBOO后膀胱ICC细胞数量较对照组显著增加,而DO组膀胱ICC细胞数量与DS组相比亦有明显增加;
3.成功构建体外水平静态机械牵张培养装置,该装置可稳定将培养于牵张膜上的细胞机械拉伸10%-30%,并可在应力状态下动态观察,而低渗细胞膨胀实验虽然也可以达到增加细胞体积的作用但是存在改变细胞外生存环境,导致细胞膜不均匀膨胀的缺点,因此在后续的实验中采用前一种机械牵张模式;
4.体外稳定培养膀胱ICC细胞,并通过c-kit免疫细胞染色鉴定在体外培养状态下具有长梭形突起典型特征的细胞为ICC细胞;
5.急性分离贴壁1h后的ICC细胞可观察到自发性的钙波,而DO膀胱中的ICC自发性的钙波和正常组及DS组相比有高频率、低振幅的特点;
6.培养于牵张膜上的ICC细胞在牵张20%、30%状态下兴奋性增高,荧光钙染色可观察到兴奋性的钙波—SICT,平滑肌细胞也可出现类似的钙波,但对于相同的机械牵张刺激,平滑肌的反应时间显著长于ICC细胞的反应时间,ICC细胞在机械牵张诱导下产生的SICT可通过细胞膜向邻近的平滑肌细胞传递;
7.细胞无钙状态和胞内钙库的阻断均可显著抑制ICC细胞自发性钙活动;
8.细胞外无钙状态和RU(10μM)均可抑制机械牵张诱导ICC细胞产生钙波的振幅,而2-APB(10μM)则可将其完全阻断。
结论:
1. PBOO后豚鼠膀胱内ICC细胞的形态、数量、分布以及自发性钙活动的特征均发生了改变,并且和DO的发生有直接关系,提示ICC细胞的一系列适应性变化有可能是导致DO的病理基础;
2.机械牵张能诱导ICC细胞的兴奋状态改变,提示ICC细胞有牵张敏感的特性,并且对相同的机械牵张刺激ICC细胞比平滑肌细胞更为敏感,钙波可从ICC细胞传递至平滑肌细胞。ICC细胞的牵张感受功能可能与膀胱源性逼尿肌收缩有密切的关系;
3.胞外钙离子内流和胞内钙库释放均参与了ICC细胞自发性兴奋和SICT的形成,而IP3敏感的钙库在SICT的产生过程中发挥了更为重要的作用。
Background and Objective: Bladder function regulation of urine storage and emptying involves complicated mechanisms. Many researches indicated that besides neural modulation, myogenic factors in bladder take part in the process of detrusor contractions. Detrusor strips show spontaneous contractions under static mechanical stretch, which are independent with neural regulation. Many studies suggested some myogenic changes lead to bladder dysfunction, such as overactive bladder. Since then, lots of theories about bladder myogenic factors have been presented to explain bladder function regulation such as secretion of urothelium, gap junctions and some special cell population. However, the exact mechanisms of those myogenic factors are not fully understood. In recent years, researchers found some special interstitial cells in bladder and believe those cells are important myogenic factors that take part in bladder modulation. Those interstitial cells have the same receptor tyrosine kinase c-kit molecular marker as interstitial cells of Cajal (ICC) in gastrointestinal tract and some scientist named those cells as bladder ICC. Previous researches of bladder ICC about their potential pacemaker function and relationship with nerve brought new understandings and recognitions of physiology and pathophysiology underlining bladder function regulation.
Interstitial cells of Cajal in gut have potential pace-making property. They have spontaneous excitability and generate periodic“slow waves”to aid local coordination to sense excitatory and inhibitory neural inputs and spread those signal to the adjacent myocytes and they can sense mechanical stimulations and integrate gut motility. McCloskey firstly identified c-kit positive interstitial cells in guinea pig bladder in 2002. They also widely distribute in urinary tract, including renal pelvic, ureter, bladder, urethral and even in cavernous body. Those cells share the same molecular marker with gut ICC, but their morphological properties and potential functions may not assemble with their analogue in gastrointestinal tract. The 5th International Symposium on Interstitial Cells of Cajal (Ireland, 2007) recommended that all such cells in the urinary tract be classified as ICC and we adopted this nomenclature in the present paper. ICC in bladder have close connection with detrusor myocytes and show intimate relationship with nerve fibers. Those specific characters indicate that bladder ICC may play a similar role as gut ICC. Although there are little direct evidence of ICC in bladder is a pacemaker, ICC networking is a potential candidate to modulate bladder sensation and coordinate autonomous activities in bladder wall.
Several studies have demonstrated that ICC in gut can respond the mechanical stimulation and convert this stimulus into electrical signals and consequently modulate intestinal peristalsis. Since ICC has also been identified in the urinary bladder for years, and they were presumed to relate with spontaneous phasic activity of the detrusor muscle and maintaining local tension in storage phase, we speculate those functions may associate with mechanical stretch stimulation. However, the correlation between bladder ICC and mechanical stretch has not been defined yet.
In our previous studies, c-kit positive ICC in guinea pig bladder have been demonstrated to have spontaneous depolarization potentials(If), and have close relationship with detrusors spontaneous contractions; ICC in bladder have different distributive density; bladder trigone have higher density of ICC and smooth muscle strips derived from that region of bladder have higher spontaneous contraction frequency. We also found that ICC can sense and respond to neurotransmitters such as ATP, carbacol, et al. The effects of Glevic on rat pelvic nerve afferent discharge evoked by ATP indicated that bladder ICC play very important role in bladder sensation and neurotransmission. Since the potential pacemaker and neurotransmmition function have beem demonstrated in bladder ICC, we speculated that bladder ICC have similar functions of mechanical sensitivity and take part in the the regulation of detrusor contractions. Moreover, the special function of bladder ICC in mechanical sensitivities may contribute to the normal bladder regulation and mechanisms underline bladder dysfunction.
In summary, bladder detrusor have spontaneous excitability and present periodical contraction under static mechanical stretch. Whether bladder ICC is the origin of the spontaneous excitability? Whether bladder ICC have mechanical sensitivity and whether the changes of ICC in structure and function contribute to bladder dysfunction? Answering those questions and exploring bladder ICC provide a new approach to further understand of bladder regulation and pathogenesis of bladder dysfunction.
In this study, we tried to investigate the variation of morphology, distribution and excitability of bladder ICC in chronical bladder obstructive animal models in vivo and detected the mechanical sensitiveity of cultured ICC and its preliminary pharmacological properties in vitro.
Our studies were carried out as following steps: first, we constructed partial bladder outlet obstruction (PBOO) models and investigated the morphological and quantitative changes of bladder ICC in PBOO bladders to elucidate the adaptive variation of bladder ICC underline long-term mechanical stretch; Second, at the base of the results of the first part, we detected the spontaneous [Ca2+]i transient properties of ICC after PBOO in vitro to explore the possible mechanisms underline detrusor overactivity (DO); Third, ICC were cultured in vitro in the static uniaxial mechanical stretch device and applied step-wise static stretch on cultured ICC. Stretch induced [Ca2+]i transient properties were detected. We also investigated the preliminary mechanisms of those [Ca2+]i transient with calcium influx and intracellular calcium stores inhibitors application.
Materials and methods:
1. Female guinea pigs of 2～3 months old were used in the study. Proximal urethra was partial ligated to produce the models of partial bladder outlet obstruction (PBOO), sham operated animals were set as control. Intravesical pressure was measured 6 weeks later. Animals were divided into DO group, DS group and control group based on the urodynamic results. Immunohistochemical studies under confocal microscopy were performed in whole mounted preparations and cryosections to identified the morphological and distributional properties of c-kit positive ICC in bladders;
2. The quantitative evaluation of c-kit positive cells in bladders of each group was performed with FCM analysis as well as manually counting of c-kit positive ICC under confocal microscopy;
3. Static mechanical stretch device was constructed with StageFlexer silicone membrane and polyethylene toothcombs ect. Mechanical stretch was also obtained from hypotonic distention; those two methods were compared in the effeciency of stretch and cell morphology;
4. Urinary bladder tissues were dispersed with colleagenase and cultured in vitro and c-kit positive ICC were identified with immunofluorescent staining;
5. Spontaneous [Ca2+]i transient properties of ICC were identified with living cell calcium indicator Fluo-4AM.
6. After 3-4 days cultured on the mechanical stretch silicone mambranes, step-wise mechanical stretch was applied to the membrane and the cells cultured onto it, meanwhile, [Ca2+]i transient induced by mechanical stretch (SICT) of ICC were detected under confocal microscopy.
7. The calcium transient properties of cultured cells under mechanical stretch were also been measured after exposed respectively to ruthenium red (a ryanodine sensitive intracellular Ca2+ stores inhibitor), 2-APB (an IP3 sensitive intracellular Ca2+ stores inhibitor) and replacing extracellular solution by no calcium HBS to investigate the composition of SICT in cultured ICC.
Results:
1. C-kit positive ICC mainly located in suburothelium and intermuscular layers. In control and DS bladders, we found those intramuscular c-kit positive cells were discrete and did not contact with each other. Stellate-shaped c-kit positive cells in DO bladders presented many cytoplasmic branches emanating from them. Those lateral branches connected with each other to construct a reticular network between smooth muscle bundles
2. C-kit positive cells in DO bladders were significant increased comparing to the DS and control bladders.
3. Static mechanical stretch device for in vitro cultured cells was successfully constructed. Mechanical stretch could be applied approximate 10-30% step-wisely and extension was subjected uniformly to the silicone membrane, and the cells cultured on it. Hypotonic distension could also expand the cell volume to obtain mechanical stretch in vitro. However, the nonuniform swelling and extracellular environment changing underline hypotonic restrict its application.
4. Successfully cultured bladder ICC in vitro. Those fusiform cells with dendritic branches were identified as ICC with c-kit immunocytochemistry experiment.
5. Freshly isolated ICC from DO bladders showed spontaneous calcium waves with higher frequency and lower amplitude comparing to those from DS and control bladder.
6. Strech-induced [Ca2+]i transient could be detected in cultured bladder ICC when 20-30% extension was applied to the cultured cells via lengthening the silicone membrane. The similar calcium augment were also detected in the cultured smooth muscle cells with longer responding time comparing to ICC. SICT generated in ICC could transfer to adjacent smooth muscle cells throough cell membrane connection.
7. The amplitude of SICT was significantly reduced when removing the extracellular Ca2+ or exposed to ruthenium red . 2-APB nearly abolished the augment of [Ca2+]i response to mechanical stretch application.
Conclusion:
1. Long-term obstruction following PBOO caused morphological changes and increasing quantity of ICC, which may play a role in the pathogenesis of DO. Freshly dispersed ICC from DO bladders showed spontaneous calcium waves with high frequency and lower amplitude comparing to those from DS and control bladder, which indicated that ICC have different excitability in DO bladders.
2. Cultured bladder ICC showed mechanical sensitivity and presented enhanced [Ca2+]i augment under stretch load. ICC were more sensitive than SMC to mechanical stretch and the calicium waves could transfer from ICC to adjacent SMC. Mechanosensitive role of ICC provide a novel mechanism underling myogenic contraction.
3. IP3 sensitive Ca2+ stores release compose the major part of initiation of [Ca2+]i augment in responding to mechanical stretch.
既然膀胱具有自发的兴奋性,而同样具有自发性兴奋的器官如心脏和胃肠道等都有一个共同的特点,自发的兴奋性与某些特殊分化的细胞群有密切的关系。因此很多研究人员都自然而然地联想到膀胱中是否存在这样一群类似的细胞。新近的报道以及我们的研究中发现:膀胱中的确存在一种特殊的间质细胞,这种细胞和胃肠道卡哈尔间质细胞(Interstitial cells of Cajal,ICC)类似,有特异性的c-kit酪氨酸激酶受体的表面标志。很多研究都业已证实胃肠道的ICC细胞参与了胃肠道蠕动功能的调节,而在某些由于ICC细胞缺失或功能失调导致的先天性胃肠道功能紊乱性疾病中同时也伴有膀胱功能障碍。因此我们推测ICC细胞可能参与了膀胱功能的调节,并且作为一种重要的膀胱源性因素,影响了膀胱的自发性兴奋收缩以及膀胱功能的调控。ICC细胞作为胃肠道中的“起搏细胞”,在调节胃肠道动力的病理生理学机制方面起到重要的作用。目前的研究表明,ICC细胞是一种具有多种功能的特殊间质细胞,它们的主要功能是产生和传播胃肠道基本电节律(Basic electrical rhythm ,BER)、整合神经调控以及感受胃肠道的机械牵张刺激。近年来的研究表明,在包括人在内的多种属的泌尿系统中,也存在着这样一些特殊的间质细胞,它们可分布在输尿管、膀胱、尿道、前列腺、阴茎海绵体,但是对这些特殊的细胞的功能知之甚少,命名也尚不统一,它们曾被称作如膀胱间质细胞、非典型平滑肌细胞、ICC样间质细胞、类ICC细胞等等。这些细胞的广泛分布和潜在的功能开启了泌尿系统相关研究的一个新领域。虽然这类间质细胞和胃肠道ICC细胞有类似的形态学特征和某些生理学功能(如自发兴奋性等),但很多研究也表明其与胃肠道ICC有明显的差别,胃肠道ICC细胞的功能亦尚未一一在膀胱ICC细胞中得到印证。为了规范名称便于交流,2007年的第五届国际Cajal间质细胞论坛建议将泌尿系这一类与胃肠道ICC有相似形态学特征和免疫学标志的间质细胞命名为泌尿系ICC细胞,本文中对于该类细胞的命名也借鉴了上述标准。在以往的研究中,已经明确的观察到ICC细胞在泌尿道的分布以及形态学特征,甚至从组织中将他们分离出来进行培养和研究他们的免疫学、生理学特性,但是到目前为止,泌尿系ICC细胞究竟如何参与和调节泌尿系统的功能仍然没有定论。
细胞的生物机械环境对于细胞的正常生长发育,相互作用及其特殊功能的发挥都有重要的影响,在众多的机械刺激当中,机械牵张刺激是最为常见的。膀胱在生理状态下,感受不断产生的尿液对膀胱壁的充盈刺激是调节膀胱排空的重要因素。目前的研究表明:在体条件下,当膀胱内容量充盈到一定程度时,即产生足够的牵张刺激,使逼尿肌兴奋性增高,诱发其收缩,从而启动膀胱的排空;而在离体条件下,膀胱逼尿肌条受到牵张刺激时逼尿肌细胞可产生自发性的兴奋,启动肌条的节律性收缩,这种收缩在膀胱失去神经支配和多种神经受抑制剂(包括河豚毒素)作用下仍然存在。而在某些病理状态下,如逼尿肌不稳定中,上述牵张诱导的肌条活动表现为同样张力条件下不稳定逼尿肌较正常逼尿肌收缩频率增高。因此机械牵张在启动膀胱源性逼尿肌收缩和控制逼尿肌兴奋性中有重要作用。
我室以往的研究表明:正常豚鼠膀胱中存在c-kit阳性的ICC细胞,可主要分布于膀胱粘膜下、逼尿肌肌束之间以及逼尿肌肌束内部。膀胱ICC细胞可产生自发性起搏电位If,可能与逼尿肌的自发性收缩关系密切;膀胱不同部位的ICC细胞有着不同的分布密度,三角区的膀胱ICC细胞密度最高,而与之相对应的部位逼尿肌条的自发性收缩频率更高,提示膀胱中可能存在兴奋的最高控制点,即起搏点,而膀胱ICC细胞可能和起搏功能有密切关系;另外我们还发现ICC细胞可以对ATP、卡巴胆碱等神经递质或类似物产生兴奋样冲动,膀胱内灌注ATP可诱发大鼠盆神经放电,用c-kit特异性抑制剂甲磺酸依马替尼阻断ICC细胞功能后,盆神经放电频率明显降低,提示ICC细胞极有可能参与了ATP介导的膀胱感觉传入,ICC细胞可能作为神经末梢调控逼尿肌细胞收缩“中转站”的结构基础发挥了重要的中介作用。而膀胱ICC细胞的潜在起搏功能和神经传递功能都来自基于胃肠道ICC细胞功能的延伸和推测,因此我们有理由相信膀胱ICC细胞可能和胃肠道ICC细胞一样,也可通过感受机械牵张刺激参与了膀胱逼尿肌收缩功能的调控。而这种特殊的牵张感受功能对我们理解膀胱源性的逼尿肌自发性兴奋从而进一步认识储尿排尿生理和病理状态下的膀胱功能异常都有重要的意义。
综上所述,膀胱逼尿肌具有自发性兴奋,机械牵张刺激可诱导膀胱逼尿肌发生周期性的收缩,而膀胱中的ICC细胞是不是这种自发性兴奋的结构基础?膀胱ICC细胞是否具有牵张敏感特性?在膀胱功能异常的情况下ICC细胞的结构和功能会不会发生变化?对这些问题进行深入的探索具有重要的科学研究意义,并将为逼尿肌兴奋性调控相关研究开创新的领域,为膀胱功能障碍性疾病的发病机制研究提供一个全新的切入点。
本课题通过体内慢性梗阻和体外培养细胞的机械牵张模型研究ICC细胞的形态、数量以及兴奋性的变化,探讨膀胱ICC细胞的机械牵张敏感性及其在逼尿肌不稳定中的可能机制。
我们拟从以下几个方面进行研究:第一:通过膀胱颈部分梗阻(partial bladder outlet obstruction, PBOO)建立豚鼠逼尿肌不稳定动物模型,并比较梗阻后膀胱ICC细胞的形态、数量及分布的变化,研究ICC细胞在膀胱流出道梗阻状态下的适应性改变;第二:观察PBOO膀胱和正常膀胱内ICC细胞的自发钙活动的变化,探讨ICC细胞在PBOO后的功能改变以及在逼尿肌不稳定(detrusor overactivity, DO)发病机制中的可能作用;第三:构建体外培养细胞机械牵张装置,通过对体外培养的膀胱ICC细胞施加静态牵张力的作用,观察ICC细胞内牵张诱导钙瞬变(stretch-induced calcium transient, SICT)的特征;第四:通过施加一定的钙离子阻断因素,包括清除细胞外钙离子、RYR或IP3敏感钙库抑制等探讨ICC细胞SICT的来源和初步作用机制。
方法:
1.本研究以2-3月龄豚鼠为研究对象,尿道近端结扎法制作膀胱流出道部分梗阻模型,并设假手术组为对照,6周后行充盈性膀胱测压,根据测压结果将动物分为梗阻后逼尿肌不稳定组(DO组)、梗阻后逼尿肌稳定组(DS组)和对照组。各组分别行c-kit免疫荧光组织染色,激光共聚焦观察ICC细胞的形态和分布情况;
2.流式细胞仪检测各组c-kit阳性细胞数量的变化;为排除肥大细胞的干扰(因为膀胱中的肥大细胞也可表现为c-kit染色阳性)以验证流式细胞仪的结果,在激光共聚焦显微镜下对各组膀胱组织标本行ICC细胞计数;
3.利用StageFlexer硅酮膜、聚乙烯齿梳、3140密封胶以及普通细胞培养皿等材料制作体外水平机械牵张装置,并与低渗溶液诱导细胞膨胀进行比较;
4.胶原酶消化膀胱组织,体外培养ICC细胞72h并通过c-kit免疫荧光细胞染色进行鉴定;
5.活细胞钙荧光指示剂Fluo-4AM负载急性分离贴壁的细胞,激光共聚焦动态观察DO组、DS组和对照组膀胱ICC细胞自发钙活动的变化情况;
6.将正常膀胱ICC细胞培养于体外水平机械牵张装置中72h牢固贴壁后,通过梯度机械牵张刺激观察ICC细胞在机械牵张负荷下的SICT变化情况;
7.利用无钙HBSS缓冲液、RYR钙库特异性阻断剂钌红(Ruthenium red,RU)或IP3敏感钙库特异性阻滞剂2-氨基乙氧基苯硼酸(2-Aminoethoxydiphenyl borate,2-APB)处理体外培养的ICC细胞,探讨胞外钙离子内流以及胞内钙库释放在ICC细胞自发性钙活动以及SICT产生机制中的作用。
结果:
1.通过免疫荧光组织染色我们发现正常膀胱和DS膀胱中粘膜下层c-kit阳性细胞呈单层连续分布,在平滑肌束之间散在分布,相互间缺乏联系;PBOO术后出现DO组膀胱ICC细胞在粘膜下ICC细胞多层分布,肌束间ICC细胞互相之间连接呈网络状;
2.流式细胞仪检测发现DO组膀胱中c-kit阳性细胞数量较对照组显著增多,而DS组和正常对照组间无显著差异;激光共聚焦显微镜下行ICC细胞计数的结果表明PBOO后膀胱ICC细胞数量较对照组显著增加,而DO组膀胱ICC细胞数量与DS组相比亦有明显增加;
3.成功构建体外水平静态机械牵张培养装置,该装置可稳定将培养于牵张膜上的细胞机械拉伸10%-30%,并可在应力状态下动态观察,而低渗细胞膨胀实验虽然也可以达到增加细胞体积的作用但是存在改变细胞外生存环境,导致细胞膜不均匀膨胀的缺点,因此在后续的实验中采用前一种机械牵张模式;
4.体外稳定培养膀胱ICC细胞,并通过c-kit免疫细胞染色鉴定在体外培养状态下具有长梭形突起典型特征的细胞为ICC细胞;
5.急性分离贴壁1h后的ICC细胞可观察到自发性的钙波,而DO膀胱中的ICC自发性的钙波和正常组及DS组相比有高频率、低振幅的特点;
6.培养于牵张膜上的ICC细胞在牵张20%、30%状态下兴奋性增高,荧光钙染色可观察到兴奋性的钙波—SICT,平滑肌细胞也可出现类似的钙波,但对于相同的机械牵张刺激,平滑肌的反应时间显著长于ICC细胞的反应时间,ICC细胞在机械牵张诱导下产生的SICT可通过细胞膜向邻近的平滑肌细胞传递;
7.细胞无钙状态和胞内钙库的阻断均可显著抑制ICC细胞自发性钙活动;
8.细胞外无钙状态和RU(10μM)均可抑制机械牵张诱导ICC细胞产生钙波的振幅,而2-APB(10μM)则可将其完全阻断。
结论:
1. PBOO后豚鼠膀胱内ICC细胞的形态、数量、分布以及自发性钙活动的特征均发生了改变,并且和DO的发生有直接关系,提示ICC细胞的一系列适应性变化有可能是导致DO的病理基础;
2.机械牵张能诱导ICC细胞的兴奋状态改变,提示ICC细胞有牵张敏感的特性,并且对相同的机械牵张刺激ICC细胞比平滑肌细胞更为敏感,钙波可从ICC细胞传递至平滑肌细胞。ICC细胞的牵张感受功能可能与膀胱源性逼尿肌收缩有密切的关系;
3.胞外钙离子内流和胞内钙库释放均参与了ICC细胞自发性兴奋和SICT的形成,而IP3敏感的钙库在SICT的产生过程中发挥了更为重要的作用。
Background and Objective: Bladder function regulation of urine storage and emptying involves complicated mechanisms. Many researches indicated that besides neural modulation, myogenic factors in bladder take part in the process of detrusor contractions. Detrusor strips show spontaneous contractions under static mechanical stretch, which are independent with neural regulation. Many studies suggested some myogenic changes lead to bladder dysfunction, such as overactive bladder. Since then, lots of theories about bladder myogenic factors have been presented to explain bladder function regulation such as secretion of urothelium, gap junctions and some special cell population. However, the exact mechanisms of those myogenic factors are not fully understood. In recent years, researchers found some special interstitial cells in bladder and believe those cells are important myogenic factors that take part in bladder modulation. Those interstitial cells have the same receptor tyrosine kinase c-kit molecular marker as interstitial cells of Cajal (ICC) in gastrointestinal tract and some scientist named those cells as bladder ICC. Previous researches of bladder ICC about their potential pacemaker function and relationship with nerve brought new understandings and recognitions of physiology and pathophysiology underlining bladder function regulation.
Interstitial cells of Cajal in gut have potential pace-making property. They have spontaneous excitability and generate periodic“slow waves”to aid local coordination to sense excitatory and inhibitory neural inputs and spread those signal to the adjacent myocytes and they can sense mechanical stimulations and integrate gut motility. McCloskey firstly identified c-kit positive interstitial cells in guinea pig bladder in 2002. They also widely distribute in urinary tract, including renal pelvic, ureter, bladder, urethral and even in cavernous body. Those cells share the same molecular marker with gut ICC, but their morphological properties and potential functions may not assemble with their analogue in gastrointestinal tract. The 5th International Symposium on Interstitial Cells of Cajal (Ireland, 2007) recommended that all such cells in the urinary tract be classified as ICC and we adopted this nomenclature in the present paper. ICC in bladder have close connection with detrusor myocytes and show intimate relationship with nerve fibers. Those specific characters indicate that bladder ICC may play a similar role as gut ICC. Although there are little direct evidence of ICC in bladder is a pacemaker, ICC networking is a potential candidate to modulate bladder sensation and coordinate autonomous activities in bladder wall.
Several studies have demonstrated that ICC in gut can respond the mechanical stimulation and convert this stimulus into electrical signals and consequently modulate intestinal peristalsis. Since ICC has also been identified in the urinary bladder for years, and they were presumed to relate with spontaneous phasic activity of the detrusor muscle and maintaining local tension in storage phase, we speculate those functions may associate with mechanical stretch stimulation. However, the correlation between bladder ICC and mechanical stretch has not been defined yet.
In our previous studies, c-kit positive ICC in guinea pig bladder have been demonstrated to have spontaneous depolarization potentials(If), and have close relationship with detrusors spontaneous contractions; ICC in bladder have different distributive density; bladder trigone have higher density of ICC and smooth muscle strips derived from that region of bladder have higher spontaneous contraction frequency. We also found that ICC can sense and respond to neurotransmitters such as ATP, carbacol, et al. The effects of Glevic on rat pelvic nerve afferent discharge evoked by ATP indicated that bladder ICC play very important role in bladder sensation and neurotransmission. Since the potential pacemaker and neurotransmmition function have beem demonstrated in bladder ICC, we speculated that bladder ICC have similar functions of mechanical sensitivity and take part in the the regulation of detrusor contractions. Moreover, the special function of bladder ICC in mechanical sensitivities may contribute to the normal bladder regulation and mechanisms underline bladder dysfunction.
In summary, bladder detrusor have spontaneous excitability and present periodical contraction under static mechanical stretch. Whether bladder ICC is the origin of the spontaneous excitability? Whether bladder ICC have mechanical sensitivity and whether the changes of ICC in structure and function contribute to bladder dysfunction? Answering those questions and exploring bladder ICC provide a new approach to further understand of bladder regulation and pathogenesis of bladder dysfunction.
In this study, we tried to investigate the variation of morphology, distribution and excitability of bladder ICC in chronical bladder obstructive animal models in vivo and detected the mechanical sensitiveity of cultured ICC and its preliminary pharmacological properties in vitro.
Our studies were carried out as following steps: first, we constructed partial bladder outlet obstruction (PBOO) models and investigated the morphological and quantitative changes of bladder ICC in PBOO bladders to elucidate the adaptive variation of bladder ICC underline long-term mechanical stretch; Second, at the base of the results of the first part, we detected the spontaneous [Ca2+]i transient properties of ICC after PBOO in vitro to explore the possible mechanisms underline detrusor overactivity (DO); Third, ICC were cultured in vitro in the static uniaxial mechanical stretch device and applied step-wise static stretch on cultured ICC. Stretch induced [Ca2+]i transient properties were detected. We also investigated the preliminary mechanisms of those [Ca2+]i transient with calcium influx and intracellular calcium stores inhibitors application.
Materials and methods:
1. Female guinea pigs of 2～3 months old were used in the study. Proximal urethra was partial ligated to produce the models of partial bladder outlet obstruction (PBOO), sham operated animals were set as control. Intravesical pressure was measured 6 weeks later. Animals were divided into DO group, DS group and control group based on the urodynamic results. Immunohistochemical studies under confocal microscopy were performed in whole mounted preparations and cryosections to identified the morphological and distributional properties of c-kit positive ICC in bladders;
2. The quantitative evaluation of c-kit positive cells in bladders of each group was performed with FCM analysis as well as manually counting of c-kit positive ICC under confocal microscopy;
3. Static mechanical stretch device was constructed with StageFlexer silicone membrane and polyethylene toothcombs ect. Mechanical stretch was also obtained from hypotonic distention; those two methods were compared in the effeciency of stretch and cell morphology;
4. Urinary bladder tissues were dispersed with colleagenase and cultured in vitro and c-kit positive ICC were identified with immunofluorescent staining;
5. Spontaneous [Ca2+]i transient properties of ICC were identified with living cell calcium indicator Fluo-4AM.
6. After 3-4 days cultured on the mechanical stretch silicone mambranes, step-wise mechanical stretch was applied to the membrane and the cells cultured onto it, meanwhile, [Ca2+]i transient induced by mechanical stretch (SICT) of ICC were detected under confocal microscopy.
7. The calcium transient properties of cultured cells under mechanical stretch were also been measured after exposed respectively to ruthenium red (a ryanodine sensitive intracellular Ca2+ stores inhibitor), 2-APB (an IP3 sensitive intracellular Ca2+ stores inhibitor) and replacing extracellular solution by no calcium HBS to investigate the composition of SICT in cultured ICC.
Results:
1. C-kit positive ICC mainly located in suburothelium and intermuscular layers. In control and DS bladders, we found those intramuscular c-kit positive cells were discrete and did not contact with each other. Stellate-shaped c-kit positive cells in DO bladders presented many cytoplasmic branches emanating from them. Those lateral branches connected with each other to construct a reticular network between smooth muscle bundles
2. C-kit positive cells in DO bladders were significant increased comparing to the DS and control bladders.
3. Static mechanical stretch device for in vitro cultured cells was successfully constructed. Mechanical stretch could be applied approximate 10-30% step-wisely and extension was subjected uniformly to the silicone membrane, and the cells cultured on it. Hypotonic distension could also expand the cell volume to obtain mechanical stretch in vitro. However, the nonuniform swelling and extracellular environment changing underline hypotonic restrict its application.
4. Successfully cultured bladder ICC in vitro. Those fusiform cells with dendritic branches were identified as ICC with c-kit immunocytochemistry experiment.
5. Freshly isolated ICC from DO bladders showed spontaneous calcium waves with higher frequency and lower amplitude comparing to those from DS and control bladder.
6. Strech-induced [Ca2+]i transient could be detected in cultured bladder ICC when 20-30% extension was applied to the cultured cells via lengthening the silicone membrane. The similar calcium augment were also detected in the cultured smooth muscle cells with longer responding time comparing to ICC. SICT generated in ICC could transfer to adjacent smooth muscle cells throough cell membrane connection.
7. The amplitude of SICT was significantly reduced when removing the extracellular Ca2+ or exposed to ruthenium red . 2-APB nearly abolished the augment of [Ca2+]i response to mechanical stretch application.
Conclusion:
1. Long-term obstruction following PBOO caused morphological changes and increasing quantity of ICC, which may play a role in the pathogenesis of DO. Freshly dispersed ICC from DO bladders showed spontaneous calcium waves with high frequency and lower amplitude comparing to those from DS and control bladder, which indicated that ICC have different excitability in DO bladders.
2. Cultured bladder ICC showed mechanical sensitivity and presented enhanced [Ca2+]i augment under stretch load. ICC were more sensitive than SMC to mechanical stretch and the calicium waves could transfer from ICC to adjacent SMC. Mechanosensitive role of ICC provide a novel mechanism underling myogenic contraction.
3. IP3 sensitive Ca2+ stores release compose the major part of initiation of [Ca2+]i augment in responding to mechanical stretch.
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