摘要
Cajal细胞(Interstitial cells of Cajal, ICCs)是一种特殊的间质细胞,以细胞网络的形式分布于整个胃肠道。它能自发性产生电慢波、整合并放大胆碱能和硝基能神经递质的传递,同时也是胃肠道张力感受器,在调节胃肠道平滑肌运动中具有重要作用。近年临床研究发现ICCs与一些新生儿胃肠运动功能障碍性疾病:如婴儿肥厚性幽门狭窄(Infantile hypert- rophic pyloric stenosis, IHPS)、先天性巨结肠(Hirschsprung’s disease, HD)、新生儿假性肠梗阻(neonatal pseudo-obstruction)及胃肠术后一过性肠麻痹等密切相关。尽管上述疾病的发病机制目前仍不十分清楚,但是均有相似的病理改变,即消化管壁内ICCs不同程度的减少,甚至缺如,同时ICCs彼此间及其与平滑肌细胞间不能形成完整的细胞网络,说明ICCs发育过程的延迟或异常可能是胃肠运动障碍性疾病的重要原因。因此,探讨新生小鼠消化管壁内ICCs的发育规律,将对阐明胃肠运动功能障碍性疾病的发病机制提供实验基础,并为治疗提供一定的指导作用。
结肠壁内的ICCs根据分布的位置而分为四个不同的亚群:1)分布在肌间神经丛周围的ICCs(ICC-MY);2)环形平滑肌和纵形平滑肌内的ICCs(ICC-IM);3)浆膜下ICCs(ICC-SS)和4)粘膜下层靠近环肌面的ICCs(ICC-SM)。不同亚群的ICCs的功能存在差别,如ICC-SM是结肠的起搏细胞,ICC-IM介导兴奋性和抑制性神经递质的传递,而ICC-SS可能具有感受张力变化的作用。而且不同亚群的ICCs的发育过程也存在较大差异。因此,首先了解新生小鼠结肠不同亚群ICCs的发育过程是十分必要的。此外,在我们前期的实验结果显示,小鼠小肠ICCs从出生到成年细胞数量增加了近30倍,而且增加的细胞可能是由胰岛素样生长因子受体1(insulin-like growth factor 1 receptor, IGF-1R)阳性的ICCs前体细胞的增殖而来。那么结肠内的ICCs是否有增殖?是否也存在前体细胞?也是我们关注的问题。
ICCs持续表达由原癌基因c-kit编码的III型受体酪氨酸激酶受体Kit蛋白,它能够与平滑肌细胞Sl基因编码的干细胞因子(stem cell factor,SCF)结合,对ICCs的发育、存活、增殖和表型维持有重要的调控作用。在c-Kit突变的W/W~V小鼠、W/W~ S大鼠,或者Sl基因突变的Sl/Sl~d小鼠动物模型中;或者在胚胎晚期或生后早期,用Kit中和性抗体或Kit受体阻断剂阻断Kit受体功能;以及在体外培养体系中加入Kit中和性抗体或去除外源性SCF,都将导致胃肠壁内ICCs发育受阻,其数量明显减少,细胞网络被破坏,并伴有胃潴留、反流性食道炎、十二指肠内容物逆流等胃肠功能障碍的症状。我们前期对成年小鼠和豚鼠研究表明: Kit信号通路对小肠壁内ICCs的存活和自主节律性运动都具有重要作用。近年来的研究认为,出生后小鼠胃肠壁内同样存在ICCs前体细胞,但是不具有产生慢波的能力。在病理因素导致ICCs数量减少时,这些前体细胞在胰岛素(insulin)/胰岛素生长因子-I(insulin growth factor,IGF-I)信号和Kit/SCF信号的共同作用下,大量增殖再分化为成熟的,能产生自发性电活动的ICCs。那么Kit信号是否对结肠各亚型ICCs的发育和存活是否具有调控作用?各亚型ICCs的反应是否相同?Kit信号通路和IGF-1R信号通路对ICCs的增殖有何调控作用?这些问题也是我们关注的问题。
本实验分为以下三个部分:
第一部分:新生小鼠结肠ICCs的发育
通过Kit蛋白免疫荧光染色特异性标记结肠ICCs,阐明不同部位不同亚型的结肠ICCs在生后(P0)到成年(P56)的过程中,细胞位置、形态、密度和总数的变化。主要结果如下:
1. ICC-MY,ICC-IM,ICC-SS是出生0天即形成,ICC-SM是生后6天才出现于近端结肠,提示不同亚型的ICCs的发育过程有一定的时间差异。
2. ICC-SM在P6出现于近端结肠,P8才见于远端结肠,提示同一亚型的ICCs在结肠不同部位的发育,存在时间顺序性。且ICC-MY在近端结肠的发育早于中间段,远端结肠的发育最晚。提示结肠ICCs是从头端向尾端的方向发育成熟的。
3.出生后,随着结肠的长度、直径及表面积不断增加,各亚型ICCs的总数均不断增加。
上述结果表明新生小鼠结肠ICCs逐渐发育成熟且数量不断增加,各亚型ICCs的发育存在一定的时间和空间顺序性,表现为结肠靠近头端的ICCs先发育,而各亚群中ICC-SM发育最迟。
第二部分:新生小鼠结肠ICCs的增殖特点
本研究通过BrdU标记和追踪增殖细胞,并结合抗核增殖抗原Ki67标记以及多重免疫荧光染色的实验方法,探讨出生后结肠ICCs的增殖潜能和规律。主要结果如下:
1. ICC-MY,ICC-IM和ICC-SS具有增殖能力,在新生早期最旺盛,但随年龄的增长,增殖能力逐渐降低。
2.新生小鼠结肠中存在Kit~+/IGF-IR~+/Ki67~+细胞,这些ICCs前体细胞,可能是增殖ICCs的主要来源。
3. ICC-SM具有与其他亚群ICCs不同的增殖模式,其数目的增加可能是由Kit~-的前体细胞增殖随后开始表达Kit蛋白并分化为成熟的ICCs。
上述结果表明结肠成体ICC-IM,ICC-MY,ICC-SS均具有增殖的潜能,在结肠生后发育过程中大量增加的细胞,可能是来源于Kit~+/IGF-IR~+前体细胞。Kit阳性的ICC-SM不具有增殖能力,其数量的增加的过程可能是Kit~-的前体细胞增殖后再分化为Kit~+的ICC。
第三部分:Kit信号通路对新生小鼠结肠ICCs发育和增殖的调控
利用Imatinib灌胃构建Kit信号通路被抑制的动物模型,BrdU腹腔注射,结合多重免疫荧光组织化学,激光共聚焦显微镜,western印迹的研究方法,探讨Kit信号通路和IGF-IR信号通路对小肠和结肠ICCs存活和增殖的调控机制,以及ICCs增殖的模式。主要结果如下:
1. Imatinib能够有效在体抑制Kit信号通路的激活。
2. Kit信号通路抑制后,除ICC-SM外的各亚群ICCs细胞数量明显减少,细胞网络不完整,说明Kit信号通路参与调节新生期小鼠肠道ICCs的存活,但是ICC-SM对该信号不敏感。
3.阻断Kit信号通路,Kit~+ICCs和/或前体细胞的增殖完全停止,而抑制IGF-IR信号通路,增殖ICCs的细胞数量减少,证明ICCs的增殖依赖于Kit信号通路,而IGF-1R对ICCs增殖也具有一定的调控作用。
4.停止Imatinib处理后,ICCs细胞数量迅速恢复正常,而增殖的Kit~+ICCs的数量较少且出现较晚。提示Kit阴性的ICCs前体细胞的增殖可能是大量增加的ICCs来源之一。
上述结果表明新生期小鼠结肠的存活、增殖都依赖于Kit信号通路。当某些病理因素导致ICCs丢失时,Kit阴性的ICCs前体细胞可大量增殖分化为成熟的ICCs,维持肠道正常的生理功能。IGF-IR信号通路参与调节ICCs的增殖。
综上所述,本研究初步证明出生后随结肠结构的不断完善ICCs亦可进一步发育。新生小鼠结肠ICCs具有增殖能力,且随年龄的增长逐渐降低消失。而增殖ICCs的主要来源可能是Kit~+/CD44~+/CD34~+/IGF-IR~+的ICCs前体细胞。Kit信号通路对ICCs的存活和增殖具有重要的调控作用,但是ICC-SM对Kit信号通路不敏感。
Interstitial cells of Cajal (ICCs) are a kind of speical interstial cells, and distribute throughout the entire gastrointestinal tract. They play a very important role in the regulation of gastrointestinal(GI) motility by generating and propagating spontaneous electric slow-wave activity and mediating nitrergic and cholinergic neurotransmission. ICCs can also mediate responses to stretch and serve as mechanosensors. Recent clinical studies have indicated that ICCs are associated with many GI motility disorders such as Infantile hypert- rophic pyloric stenosis(IHPS), Hirschsprung’s disease(HD), neonatal pseudo-obstruction and temporary post-operational entero-paralysis. Although the etiological factor and pathogenesis of these diseases have not been kown, they all showed up reduction of ICCs in numbers and impaired of the cell network, which indicated that the prolonged or abnormal of development of ICCs must be one of the reasons for GI motility dysfunctions. Clarification of the development of ICCs will help us to understand the etiology and pathophysiology of disorders characterized by a deficiency of ICCs, and provides us with new insight into the treatment of relevant disease.
ICC in the colon of adult animals are divided into four subtypes according to their distinct locations and morphologic features: 1) At the level of Auerbach’s plexus (ICC-MY) ; 2) At the border between circular muscle layer and submucosa (ICC-SM); 3) Within the longitudinal and circular smooth muscle layers (ICC-IM) and 4) In the connective tissue beneath serosa (ICC-SS). Different subtype of ICCs has different function and developmental process, for instance ICC-SM are pacemaker cells but ICC-SS act as mechanosensors of the colon, so it is necessary to understand the developmental process of all subtypes of ICCs. Moreover, our previous study has indicated that the number of ICCs in mouse small intestine increased 30 folds from newborns to adults, and these increased cells might derived from proliferation of insulin-like growth factor 1 receptor(IGF-1R)positive ICCs. Whether proliferation is also involved in the colon? Are there being local progenitors? Both are our concerned questions.
ICCs express typeⅢtyrosine kinase receptor Kit protein, the gene product of c-kit proto-oncogene. Stem cell factor(SCF)is the natural ligand for Kit protein, which can activate the receptor and then regulates the development, survival, proliferation and phenotypic maintained of ICCs. Development of ICCs will be affected under conditions of c-kit mutation in the W/W~V mice and W/W~ S rats models and Sl/Sl~d mice models harbored Sl mutant; or neutralization antibody ACK2 and inhibitor of Kit receptor block Kit signaling in late embryo stage and early neonatal stage; or add neutralization antibody ACK2 and remove exogenous SCF from the cultural system. The number of ICCs decrease sharply and accompany with a set of symptoms of GI motility dysfunction such as gastric retention, reflux esophagitis, regurgitation of duodemun content. Our recent studies on mice and Guinea-pigs have also indicated that Kit signaling palyed an important role in survival and motor function maintained of mature ICCs. Recently, researchers have found that there are ICCs progenitors without ability of generating spontaneous electric slow-wave in postnatal mouse GI. When the number of ICCs decreased under some pathological factors, insulin/IGF-IR signaling and Kit/SCF signaling would stimulate proliferate of these progenitors and differentiate into mature ICCs. Whether Kit signaling can regulate the development and survival of different subtype of colonic ICCs? Response of these ICCs? How to regulate the proliferation of ICCs by Kit /SCF signaling and insulin/IGF-IR signaling? It is eager to elucidate these questions.
This investigation is divided into three parts:
Part 1: Development of neonatal mouse colon.
In order to investigate the alterations of distribution, morphology and cell numbers of ICC in each segment of mouse colon over the period extending from neonatal (P0) to adult life (P56), immunofluorescent staining of Kit protein was utilized. The results are as followings:
1. ICC-MY were prominent at birth while ICC-IM and ICC-SS began to appear, and ICC-SM emerged at P6, indicated that time difference was existed between ICCs subtypes during the developmental process.
2. ICC-SM emerged at P6 in the proximal colon and subsequently in the distal colon at P8, and ICC in the oral end of colon revealed a better development in morphology and a higher density than that in the anal side. Which indicated that a proximal to distal and transural gradient of ICC distribution in the postnatal development of colon.
3. The estimated total cell numbers of ICCs increased from birth to adulthood along with the lengthening and extending of mouse colon.
Part 2: The proliferation of ICCs in neonatal mouse colon.
BrdU incorporation and anti-Ki67 multi-immunofluorescent staining were utilized to investigate the proliferative potential and characteristics of ICCs in postnatal mouse colon. The results are as followings:
1. ICC-MY, ICC-IM and ICC-SS had proliferative potential, and presented an age-dependent characteristics.
2. There were some Kit/IGF-IR/Ki67 multi-labeled ICCs progenitors in neonatal mouse colon, which might be the source of increased ICCs.
3. The proliferative characteristics of ICC-SM is different from other subtypes, the increased of estimated total cell numbers might rely on proliferation of Kit negative progenitors and subsequently differentiate into mature ICCs.
Part 3: Kit signaling regulates the development and proliferation of ICCs in neonatal mouse colon.
Mice with Imatinib administration or PPP intraperitoneal injection were used as animal models, immunofluorescent staining and Western blot methods were utilized to investigate the alteration of survival and proliferation of colonic ICCs at neonatal stage after blockade of Kit signaling and IGF-I signaling. Further realized the proliferative mode of postnatal mouse colon. The results are as followings:
1. Imatinib was a potent inhibitor of Kit signaling in vivo.
2. Each subtype of ICCs except ICC-SM reduced in numbers and incompleted of cell network after blockade of Kit signaling, indicated that Kit signaling was essential for survival of neonatal ICCs except ICC-SM.
3. The proliferation of Kit positive ICCs or/and progenitors was inhibited completely by blocking Kit signaling. However, only a half of proliferative ICCs were disappeared after blockade of IGF-IR signaling. Which demonstrated that proliferation of ICCs depent on Kit signaling but was regulated by IGF-IR signaling in part.
4. Number of ICCs could recover up to normal rapidly but few of proliferative Kit positive ICCs emerged at later stage followed the withdrawal of Imatinib. So we presumed that Kit negative progenitors might be one of the sources of increased ICCs.
The third part revealed that Kit signaling played a key role in survival and proliferation of ICCs in neonatal mouse colon. Kit negative progenitors could be expanded substantially when reduction of Kit positive ICCs under some pathology factors in order to maintain the normal physiology function of GI. IGF-IR signaling participated in regulating proliferation of ICCs.
To sum up, this study demonstrated that the further development of ICCs along with the constant improvement of colonic structure from newborn to adult. Proliferative potential of ICC-MY, ICC-IM and ICC-SS characterized by age-dependence. Primary source of proliferative ICCs might be Kit~+/CD44~+/CD34~+/IGF-IR~+ multi-positive progenitors. Kit singnaling regulated survival and proliferation of ICCs except for ICC-SM.
引文
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