Hans Journal of Surgery
Vol. 08  No. 02 ( 2019 ), Article ID: 29718 , 8 pages
10.12677/HJS.2019.82009

Research Progress of Molecular Regulation and Clinical Diseases of Interstitial Cells of Cajal

Gang Zhao*, Qifan Lu

East Hospital of Tongji University, Shanghai

Received: Mar. 25th, 2019; accepted: Apr. 9th, 2019; published: Apr. 16th, 2019

ABSTRACT

Interstitial cells of Cajal (iccs) are such a kind of cells mainly found in the stomach, gallbladder, bladder and oviduct that work as the pacemaker and signal transduction cells. Through current research, it is found that there are a large number of molecular regulatory mechanisms related to the regulation of the number, function and phenotypic differentiation of iccs, including anoctamin 1 (Ano1), C-kit, stem cell factor (SCF), lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α). At the same time, there are a large number of reports that iccs are inseparable from the development of various clinical diseases, including gallstones, chronic pseudo-intestinal obstruction, and tubal ectopic pregnancy. However, the relationship between the molecular regulation mechanism of iccs and clinical diseases is not yet clear. This article will review the origin, classification, related molecular regulation mechanisms and related diseases of iccs.

Keywords:Interstitial Cells of Cajal, Molecular Regulation, Clinical Diseases, Gallbladder Function

Cajal间质细胞相关分子调控及临床疾病的 研究进展

赵刚*,陆启帆

上海市东方医院(同济大学附属东方医院),上海

收稿日期:2019年3月25日;录用日期:2019年4月9日;发布日期:2019年4月16日

摘 要

Cajal间质细胞(Interstitial cells of Cajal, iccs)是一类主要存在于人消化系统并呈以网络状分布于胃、胆囊、膀胱、输卵管等部位的平滑肌层内间质细胞,属胃肠道慢波电位起搏细胞和信号传导细胞。通过目前的研究发现,存在有大量与调控iccs的数量、功能、表型分化相关的分子调控机制,包括氯离子通道蛋白(Anoctamin 1, Ano1)、酪氨酸激酶膜受体蛋白(c-kit)、重组干细胞因子(Stem cell factor, SCF)、脂多糖(Lipopolysaccharides, LPS)与肿瘤坏死因子-α (Tumor Necrosis Factor-α, TNF-α)等。同时也有大量报道指出,iccs与多种临床疾病的发生发展密不可分,包括胆囊结石、慢性假性肠梗阻、输卵管异位妊娠等。但目前iccs的分子调控机制与临床疾病之间的关系尚未十分明确。本文就iccs的起源、分类、相关分子调控机制及相关疾病等作一综述。

关键词 :Cajal间质细胞,分子调控,临床疾病,胆囊功能

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

Cajal间质细胞(iccs)是1893由西班牙神经解剖学家Cajal发现并进行描述的细胞 [1] 。近年研究表明,iccs主要存在于人类消化系统 [2] [3] 并呈网络状广泛分布在胃、胆囊、小肠、结肠等组织的平滑肌层内;属胃肠道慢波电位起搏细胞和信号传导细胞,主要功能是产生和调控胃肠道基本电节律、参与神经信号转导、维持消化道正常功能 [4] [5] 。目前国内外的最新研究发现,包括Ano1、SCF及TUG1等多种iccs相关的分子调控机制与众多临床疾病的发生发展密不可分。本文就iccs的主要特点、生理功能及与之相关的临床疾病研究进展做一综述。

2. iccs主要特征

2.1. iccs特异性标记物

在iccs早期研究中,常用甲基蓝、嗜银染色、碱性蕊香红-123等方法对iccs进行染色并做形态、分布观察 [2] 。但这些染色方法因缺乏特异性被限制了应用。Al-Shboul OA [6] 在2013年发现了一种iccs基因表达产物c-kit。该c-kit是一种原癌基因,位于5号染色体W位点上,分子量约145 kDa,由975个氨基酸组成 [7] 。c-kit免疫组化染色可显示消化道仅有iccs和肥大细胞表达阳性 [8] [9] ;而iccs分布在消化道平滑肌层内,肥大细胞位于黏膜及其下层、胞体圆而较小、无突触且数量较少、仅占c-kit阳性细胞8%。故通过细胞形态和分布特点,可快速鉴别这两类细胞 [10] [11] 。目前认为,c-kit是iccs的特异标记物 [12] ,c-kit免疫组化染色是鉴定iccs的可靠方法 [13] 。

2.2. iccs分布

iccs分布于消化道多个区域,主要位于胃肠道粘膜下层的纵行肌、环形肌、环形肌层深肌丛以及环形肌层与纵行肌层肌间神经丛周围,与神经元末梢及神经束相伴随,通过缝隙连接形成iccs网络并广泛与末梢神经元及平滑肌细胞相联 [14] 。在胃内,iccs多分布于胃体胃窦环形肌、纵行肌内并形成网络结构 [15] 。在小肠内,iccs主要分布于平滑肌层间,深肌层iccs可穿入环形肌最内层和黏膜下层 [16] 。在胆道系统,iccs主要分布于胆囊、胆囊管、胆总管和Oddi’s括约肌;人类胆囊iccs呈网络状分布于平滑肌层内,与神经束伴随,分布密度从高到低依次为胆囊体、颈、底部 [17] ;在肝外胆道,iccs主要分布在胆总管下端、Oddi’s括约肌外侧壁和十二指肠乳头括约肌壁内,并在壶腹部形成一个iccs环,但肝内胆道未发现iccs存在 [18] 。

2.3. iccs分类

Thuneberg L等 [19] 于1982年根据分布部位将iccs分为四类:ICC-I:位于环形肌、纵行肌间,与肌间神经丛发生密切联系;ICC-II:位于黏膜下层,沿环形肌内形成网络;ICC-III:位于肌源神经丛;ICC-IV:位于环形肌外层,沿肌梭分布。之后,又有多位学者对其进行了多种分类。最新的分类标准主要以Sanders K M [20] 分类作为参照,分别是:ICC-SM (黏膜下ICC):位于黏膜、黏膜下层与结缔组织、环形肌内层之间;ICC-MY (肌间丛ICC):位于环形肌和纵行肌束间;ICC-DMP (深肌丛ICC):位于环形肌和深部肌丛内;ICC-IM (肌内ICC):存在于环形肌和纵行肌束内。

2.4. iccs与相关分子调控机制

目前发现有多种与iccs功能及数目有关的分子调控机制及相关蛋白,包括钙激活氯离子通道蛋白(Ano1)、酪氨酸激酶膜受体蛋白(c-kit)、重组干细胞因子(SCF)等。

2.4.1. Ano1

Malysz J [21] 等的一项研究表明,Ano1作为一种钙激活氯离子通道蛋白,其在肌间丛ICC (ICC-MY)中表达并对正常胃肠运动起重要作用;在动物实验中,当部分敲除成年小鼠Ano1基因时,ICC-MY的钙瞬变和及慢波持续时间与对照组相比均有所减少;完全敲除Ano1则会导致慢波减少和非同步钙瞬变发生,并影响正常胃肠道运动功能。Cobine CA等 [22] 的实验则表明,当敲除成年小鼠Ano1基因或用Ano1抑制剂使Ano1失活,ICC-MY钙瞬变会失去正常节律,影响胃肠道平滑肌的节律性收缩。Qian A等 [23] 通过数学模型模拟Ano1表达对慢波周期影响的研究表明,随Ano1表达量逐步下调,慢波周期逐步减少并最终影响胃肠道正常节律。

2.4.2. SCF与C-kit

Tong W等 [24] 将小鼠空肠体外培养并阻断c-kit信号通路,可致iccs向平滑肌样细胞表型转变,同时肠道慢波消失;但第7天加用SCF进行体外培养后,肌条慢波逐渐恢复,与未用SCF相比肌间神经丛中c-kit阳性标记细胞增加,c-kit mRNA及蛋白表达上调。由此表明,由SCF激活的c-kit信号通路是控制iccs存活和增殖的关键途径;通过局部使用SCF可促进c-kit信号途径阻断导致的iccs数量减少和空肠电节律恢复。

2.4.3. 脂多糖(LPS)与肿瘤坏死因子-α (TNF-α)

胃肠道炎症可由炎性细胞因子如白细胞介素、化学炎症介质和来自革兰氏阴性菌的脂多糖(LPS)等引起,而后者是胃肠道炎症的主要致病因素,实验亦证实LPS是导致胃肠动力障碍的重要因素之一。Wei J [25] 的最新研究表明,先天性巨结肠(Hirschsprung)患者体内iccs功能标记物c-kit显著降低,iccs另一标记物CD34未改变。对小鼠腹腔注射LPS后,肠道c-kit蛋白和mRNA表达显著降低的同时CD34表达没影响,意味iccs表型发生改变。Zuo DC [26] 等研究则发现,LPS通过toll样受体4 (TLR-4)介导的信号通路激活核因子κB (NF-κB)途径及活性氧物质(ROS)信号级联,并激活p38丝裂原活化蛋白激酶(MAPK)产生白细胞介素、前列腺素(PGs)、诱导型NO合酶(i NOS)等,最终导致iccs起搏器活性改变。而Keyu R [27] 等人则在小鼠的溃疡性结肠炎模型中发现TNF-α通过激活iccs中的NF-κB途径下调SCF的表达。这提示肠道炎症疾病的发生发展可能与iccs减少及功能缺失相关。

2.4.4. STIM1、Orai1与SOCE

主要在内质网膜–质膜连接处产生的钙池操纵的钙内流(store-operated calcium entry, SOCE)是存在于众多细胞内的一种钙信号产生机制,其受到内质网膜上的钙离子感受器蛋白(Stromal Interaction Molecule 1, STIM1)和质膜上的Orai1钙离子通道共同介导 [28] 。Haifeng Z [29] 等人的研究则发现干扰STIM-Orai相互作用的抑制肽阻断了iccs中的自发瞬时内向电流(STIC)和慢波电流,而在正常肌肉中iccs与起搏器活动相关的Ca2+瞬变的成像显示Orai拮抗剂阻断了iccs中的Ca2+瞬变。这些数据表明,通过STIM-Orai相互作用的Ca2+恢复是维持iccs起搏器活动所必需的。

2.4.5. 长链非编码RNA TUG1

长链非编码RNA(long non-coding RNA, lncRNA)参与多种重要细胞过程的调节,而其中的lncRNA牛磺酸上调基因1 (TUG1)涉及许多疾病的发病机制。来自Zhao K [30] 等人的研究发现经过TNF-α处理可抑制iccs活性,诱导iccs凋亡,促进iccs炎症反应。TUG1在TNF-α处理的iccs中表达下调。而当TUG1过度表达时则可以保护iccs免受TNF-α诱导的细胞凋亡和促炎细胞因子的表达。TUG1通过下调microRNA-127 (miR-127)然后使NF-κB和Notch通路失活来减弱TNF-α在iccs中的细胞凋亡和炎症反应。

3. iccs与临床疾病

3.1. iccs与胆囊疾病

在胆道系统中,iccs数量减少及功能缺失可能与胆道动力性疾病发病关系密切 [31] 。Pasternak A等 [32] 对30例胆结石和25例无胆石患者的胆囊进行石蜡切片并进行染色比较后发现,胆结石患者胆囊固有肌层iccs密度显著低于对照组。胆石症患者iccs减少可能会影响胆囊运动,导致胆囊动力受损、收缩性减退。Fan Y等 [33] 研究表明,伴有iccs受损的胆囊肌条慢波幅度和频率显着降低,胆囊肌条对CCK-8收缩反应也有所降低。胆囊iccs可产生慢波电位,参与调节CCK-8诱导的胆囊平滑肌运动。在胆固醇结石形成过程中,iccs密度明显降低,损害胆囊运动性;而iccs密度降低可能与胆固醇结石形成过程中c-kit和SCF表达降低相关。Huang Z P等 [34] 在豚鼠上进行的一项实验则发现,在急性胆囊炎期间,iccs数量减少。炎症缓解后iccs密度增加。此外,急性胆囊炎期间SCF和c-kit蛋白的mRNA表达水平降低,炎症缓解后SCF和c-kit蛋白和mRNA表达水平升高。急性胆囊炎时iccs凋亡增加,急性胆囊炎消退后iccs凋亡减少。在急性胆囊炎中,iccs损伤可能与胆囊运动障碍有关。

3.2. iccs与胃肠道疾病

人胃肠道iccs减少、信号通路受阻、功能缺失可能与慢性假性肠梗阻 (chronic intestinal pseudo-obstruction, CIPO)、糖尿病胃轻瘫(diabetic gastroparesis, DGP)、慢性传输性便秘(slow transit constipation, STC)等一系列胃肠道疾病的发生发展相关。CIPO是一种有肠梗阻临床表现但无机械性梗阻的无肠腔阻塞综合征。Amiot A [35] 通过免疫组化发现,48% (10/21) CIPO患者iccs数量显著降低,这可能与CIPO发病有关。DGP是糖尿病患者中较常见的一种胃肠植物神经功能紊乱,Park KS [36] 比较26名对照组和35名糖尿病患者的免疫荧光染色显示,糖尿病患者胃中iccs数随糖尿病持续时间延长而降低,c-Kit阳性免疫反应亦降低。

STC是指结肠功能紊乱、肠道内容物传输缓慢引起的便秘,其病因在于结肠运动障碍、无法有效推进内容物或结肠收缩无力。Tong WD [37] 研究表明,STC结肠中c-kit mRNA和蛋白表达相较对照组显著降低,提示c-kit信号通路受到阻断,并可能导致STC发病过程中iccs减少;而iccs作为胃肠道慢波起搏细胞,其数量减少与结肠传输减弱有密切联系。此外,Bettolli M [38] 还观察到,阑尾炎晚期炎症阶段c-kit免疫反应性(c-kit IR)显著降低,并与炎症严重程度相关。电子显微镜检查证实阑尾炎急性炎症期iccs和神经纤维网络中超微结构受损,急性炎症消退后iccs恢复正常超微结构和c-Kit IR。这提示iccs功能受损及数量减少可能在阑尾炎发生发展中起到重要作用。

3.3. iccs与泌尿生殖系统疾病

由于iccs存在于人泌尿道内,泌尿道中iccs数量过多、密度过大等可能与逼尿肌不稳定(Detrusor instability, DI)、糖尿病性膀胱病(Diabetic cystopathy, DCP)等泌尿道疾病有关。DI主要表现为患者膀胱逼尿肌兴奋性收缩性增高。研究表明,DI患者及小鼠膀胱中均有iccs密度增加 [39] ;豚鼠使用c-kit受体阻滞剂后,可通过膀胱iccs上c-kit受体抑制豚鼠和过度活跃的人逼尿肌,降低膀胱逼尿肌兴奋性及收缩性 [40] ;膀胱出口阻塞及缺血缺氧、异常pH条件下膀胱壁中神经紊乱或受损时,膀胱内压显著增加而膀胱壁随iccs数量、分布和超微结构特征改变而重塑,特别在穹顶壁,穹顶壁iccs充当起搏器细胞故导致DI [41] 。DCP是糖尿病常见并发症,常表现为膀胱排空不良、容量增加和感觉降低三联征,膀胱从过度活跃到收缩不良,严重影响生活质量。Xu J [42] 实验表明,DCP大鼠膀胱c-Kit、SCF蛋白增加,而用木犀草素与索利那新口服后DCP大鼠膀胱过度活动改善,c-Kit、SCF表达降低,可能是木犀草素抑制SCF/c-kit信号通路之故。另外,已发现肾盂输尿管连接部梗阻(Ureteropelvic junction obstruction, UPJO) [43] 、巨膀胱–微小结肠–小肠蠕动功能障碍综合症(Megacystis-microcolon-intestinal hypoperistalsis syndrome, MMIHS) [44] 、膀胱出口梗阻(Bladder outlet obstruction, BOO) [45] 等几种泌尿功能受损疾病中iccs分布异常。这表明,泌尿系统肌层中iccs数量变化及功能失调可能与泌尿功能障碍有关。

iccs由于还分布于女性输卵管,被称为cajal样输卵管间质细胞(t-ICC),故t-ICC起搏细胞改变可能在输卵管异位妊娠(Tubal ectopic pregnancy, tEP)和输卵管因子不孕(Tubal factor infertility, TFI)中起一定作用。tEP是指孕卵在正常着床过程中因各种原因导致孕卵无法正常运行,使之在输卵管内停留、着床、发育障碍,导致输卵管妊娠流产或破裂 [46] ,tEP也是TFI的常见原因。Yang X J [47] 对10例未破裂tEP和10例对照受试者输卵管全层峡部节段标本通过蜡包埋、c-kit/CD117免疫组化染色分析t-ICC网络分布和面积密度的回顾性对照研究表明,t-ICC主要在固有层和平滑肌层,与对照组相比,tEP组t-ICC失去网络完整性、变得稀疏且难以被观察到,t-ICC面积密度也显著下降(76 ± 7.4 vs. 156 ± 18.3 mm, P < 0.001)。Dixon RE [48] 的实验表明,感染沙眼衣原体的小鼠表现输卵管扩张、积水和自发收缩活动丧失,形态学检查示t-ICC网络中断,电生理学记录示t-ICC内在起搏器活动丧失而基底平滑肌膜电位无变化,这提示t-ICC网络中断及起搏器活动丧失导致输卵管假性梗阻和卵母细胞推进性收缩丧失,伴随输卵管分泌物滞留,可能促进了TFI发展。

4. 展望

综上所述,iccs的数量、分布及功能异常与多种疾病的发生发展密切相关。国内外的多项研究发现,与iccs相关的多种分子调控机制可能与多种临床疾病相关,在明确相关的调控机制后将会为下一步的疾病治疗提供更加明确的作用靶点和治疗思路。但在iccs相关研究方面仍有很多问题有待于进一步探讨和解决,如通过scf/c-kit与iccs相关性恢复或重建病变器官中iccs功能数量,通过降低胆囊胆固醇增加胆囊壁iccs数量改善胆囊收缩功能、防治胆囊结石生成,还有哪些器官是否存在iccs其作用如何,有无特异性更高的标记物,有关scf/c-kit或新iccs信号通路的机制,等等。相信随着对iccs研究的不断深入,相关疾病的发生发展、机制和iccs干预靶点会进一步明确,并展示光明的前景。

文章引用

赵刚,陆启帆. Cajal间质细胞相关分子调控及临床疾病的研究进展
Research Progress of Molecular Regulation and Clinical Diseases of Interstitial Cells of Cajal[J]. 外科, 2019, 08(02): 51-58. https://doi.org/10.12677/HJS.2019.82009

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NOTES

*通讯作者。

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