肠道结构的完整性是其发挥吸收功能和屏障功能的基础。小肠上皮作为机体代谢和更新最旺盛的组织,其功能的实现依赖于独特的组织结构——隐窝绒毛轴[1]。肠道干细胞驱动的上皮更新,是其结构形成的动力所在,也是肠道损伤修复的必要途径[2]。干细胞定向分化为各种功能细胞,共同维护肠道健康。肠道干细胞的增殖和分化受Wnt/β-连环蛋白(β-catenin)、Notch和骨形态发生蛋白(BMP)等信号通路共同调控,维持肠道上皮更新或再生应答[3]。当Wnt/β-catenin处于“关闭”状态时,Notch信号会促使肠道干细胞向吸收型细胞分化,而抑制其向分泌型细胞分化,当Wnt/β-catenin信号处于“启动”状态时,Notch信号协同促进肠道干细胞自更新[4]。而BMP信号与Wnt/β-catenin信号拮抗,防止Wnt/β-catenin的过度激活[5]。Wnt/β-catenin信号通路对肠上皮的更新和再生至关重要,其失调会引起肠道稳态失衡和功能减弱,甚至导致肠道肿瘤的发生[6]。因此,本文就Wnt/β-catenin信号控制肠道干细胞增殖和分化命运决定,以及参与调控肠上皮更新与损伤后修复等方面做一综述,以期为肠道健康管理的调控提供新思路。
1 肠道干细胞驱动肠上皮更新和再生隐窝-绒毛轴是小肠上皮的基本组成单元,隐窝是肠道干细胞及其后代组成的增殖区,绒毛是各种功能细胞组成的分化区[7]。肠道干细胞包括由富含亮氨酸重复的G蛋白偶联受体(leucine rich repeat containing G protein coupled receptor 5,Lgr5)标记的隐窝基底位置(crypt base columnar,CBC)活跃型肠道干细胞以及B细胞特异性白血病病毒插入位点(B cell specific moloney murine leukemia virus insertion site 1,Bmi1)标记的“+4”位置沉默型肠道干细胞[8-9]。研究表明,Lgr5+干细胞(具有Lgr5标记的肠道干细胞)处于活跃的有丝分裂状态,是肠上皮更新永久的驱动力;而Bmi1+干细胞(具有Bmi1标记的肠道干细胞)在正常状态下处于静息状态,对肠上皮更新没有实质性作用,但在肠上皮损伤后被激活,转化为Lgr5+干细胞,负责肠上皮损伤后的修复[10]。
肠道干细胞进行非对称分裂,产生1个原代干细胞和1个瞬时扩增细胞(transient amplification cell,TA细胞)[11-12]。原代干细胞实现自我更新,而TA细胞则快速迁移至隐窝绒毛轴的交界处,分化为4种主要的功能细胞,其中吸收细胞占上皮细胞的90%以上,完成营养素的感应、转运和吸收,是维持肠道自身和机体营养代谢的基础;杯状细胞(分泌黏蛋白,形成黏液层)约占5%,与紧密连接一起构筑肠道屏障;肠内分泌细胞约占1%,分泌胆囊收缩素(cholecystokinin,CCK)、血管活性肠肽(vasoactive intestinal peptide,VIP)和胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)等胃肠激素,调控采食和营养物质的消化吸收;潘氏细胞(分泌防御素和溶菌酶),每个隐窝有10~15个,维持肠道干细胞活性,这些功能细胞共同维护肠道这个“生态系统”的良性循环。除此之外,肠道干细胞还会分化成一些罕见的细胞类型,如簇状细胞,但其功能仍不为人所知[13-15]。肠道干细胞驱动的小肠上皮更新如图 1所示。
经典的Wnt信号通路以细胞核内β-catenin积聚转录为特征,因此又称为Wnt/β-catenin信号通路[16]。Wnt/β-catenin信号通路在进化过程中高度保守,并且与其他信号通路(如Notch、BMP等)存在复杂的相互作用,以驱动肠道干细胞有序的自我更新和分化,保障隐窝增殖、维持肠道稳态[17]。Wnt/β-catenin信号组分包括:Wnts配体、卷曲受体蛋白(frizzleds,Fzds)、β-catenin降解复合体、β-catenin、转录因子淋巴样增强因子/T细胞因子(lymphoid enhancer factor/T cell factor proteins,LEF/TCFs)和各种靶基因等[18]。肠道干细胞微环境中的Wnts主要由潘氏细胞和间充质细胞分泌[19],其通过与Fzds及其辅助受体低密度脂蛋白受体相关蛋白(low-density lipoprotein receptor-related protein,LRPs)(如LRP5和LRP6),将信号传递给蓬乱蛋白(dishevelled,Dvl);活化的Dvl降低由大肠腺瘤息肉蛋白(adenomatous polyposis coli,APC)、轴蛋白(axis inhibition protein,Axin)、糖原合成酶激酶3β(glycogen synthase kinase 3β,GSK3β)、蛋白磷酸酶2A(phosphoprotein phosphatase 2A,PP2A)和酪蛋白激酶-1(casein kinase-1,CK-1)组成的β-catenin降解复合物活性,抑制其对β-catenin的磷酸化,从而使得胞质内的β-catenin稳定累积并向核内转移,最终与LEF/TCFs结合,取代靶基因启动子中的转录抑制因子,调节下游靶基因的转录,刺激1个或多个细胞内的信号级联反应。Wnt的靶基因包括c-Myc、Cyclin D1和Lgr5等,其中c-Myc、Cyclin D1能促进肠上皮细胞增殖,Lgr5能增强肠道干细胞活性。相反,当无Wnt配体时,β-catenin被降解复合物磷酸化,进而被泛素蛋白酶体识别和降解[20-23]。
此外,间充质细胞和潘氏细胞还可分泌R-脊椎蛋白(R-spondins,Rspos),调节Wnt/β-catenin信号,促进肠道发育和再生[24]。Rspos包含4个分泌生长因子(Rspo1~4),是刺激肠道干细胞增殖和分化的必需成分。离体培养下,Rspos可支持肠道干细胞的存活、扩增和出芽,缺少Rspo1会导致隐窝和肠道干细胞凋亡[25]。Rspos增强Wnt/β-catenin信号主要是通过Rspos与泛素连接酶、Lgr家族因子形成三元复合物,诱导E3泛素连接酶/环指蛋白43(zinc and ring finger 3/ring finger 43,ZNRF3/RNF43)的自动泛素化和清除,从而抑制ZNRF3/RNF43活性,使Wnt受体在细胞膜积聚,提高其与Wnts结合的敏感性;当Rspos处于非活化状态下,ZNRF3/RNF43通过泛素依赖性蛋白降解途径诱导Fzds和LRPs降解[26-27]。
Wnt/β-catenin信号还存在2类胞外拮抗剂,一类是与Fzds竞争性结合Wnt配体,从而发挥抑制作用,这类拮抗剂包括分泌型卷曲相关蛋白(secreted Frizzled-related protein,sFRP)和Wnt抑制因子(Wnt inhibitory factor,WIF);另一类是与Wnt配体竞争性结合Wnt受体发挥抑制作用[28-29],包括Wnt抑制因子(dickkopf,Dkk)家族成员。Wnt/β-catenin信号通路作用机制如图 2所示。
Wnt/β-catenin信号富集于隐窝微环境,并沿着小肠隐窝-绒毛轴逐渐递减[30]。Wnt活性降低会导致TA细胞的减少和隐窝结构的消失,相反,Wnt活性过高能够引起TA细胞过度增殖、分化和隐窝区域的扩大。因此,Wnt信号维持在一个正常水平是小肠上皮有序更新的基础[31]。
3.1 Wnt配体Wnt配体由350~400个氨基酸组成的分泌型糖蛋白,其序列高度保守,在特定位置被脂质化和糖基化修饰,在内质网中合成后并转运到高尔基体,最后通过不同的亚细胞结构释放[32-33]。目前已知共有19种Wnt配体(Wnt1、Wnt2、Wnt2b/13、Wnt3、Wnt3a、Wnt4、Wnt5a、Wnt5b、Wnt6、Wnt7a、Wnt7b、Wnt8a、Wnt8b、Wnt9a、Wnt9b、Wnt10a、Wnt10b、Wnt11和Wnt16)参与Wnt/β-catenin信号通路[34]。Wnts能够与受体富含半胱氨酸的结构域(cysteine-rich domains,CRD)结合发挥作用,但当受体的CRD发生突变时,Wnt/β-catenin信号通路依旧可以正常运行,说明除了CRD,受体的其他部分也会与Wnts作用。然而,Wnts与受体之间的特异性机制还未被全部解析清楚[35-36]。
Wnts是干细胞微环境的必需组分,高水平的Wnts信号会提高肠道干细胞的干性,低水平的Wnts倾向于肠上皮细胞的分化[37]。Kabiri等[38]认为,当肠上皮失去分泌Wnts能力时,间充质细胞分泌的Wnts足以维持肠道干细胞的功能,即肠上皮分泌的Wnts可能存在冗余。而Zou等[39]则发现,当肠道受到轮状病毒感染后,即使只有肠上皮细胞产生Wnt3和Wnt9b,肠上皮的结构依旧可以维持。因此,间充质细胞或肠上皮细胞分泌Wnts是否存在冗余,还需进一步研究证实。
Porcupine蛋白属于膜结合O-酰基转移酶(membrane-bound O-acyltransferase,MBOAT)家族的一员,是合成Wnt配体的必需成分[40]。当敲除小鼠的Porcupine基因后,十二指肠部位的隐窝几乎完全消失,肠绒毛变细甚至断裂,TA细胞停止增殖分化[41]。相反,对“老化”的肠道干细胞补充Wnt3a能明显提高类肠团的出芽率以及靶基因无刚毛鳞甲复合体样蛋白2(Ascl2)mRNA的丰度,即干细胞恢复到“年轻”状态,提示Wnts一定程度上能够可以延缓干细胞功能的衰退[42]。同样,Wnt5a分泌量的降低会抑制上皮细胞的分化[43-44],这些研究均表明,Wnt配体对肠道干细胞驱动的肠上皮更新是不可或缺的。
3.2 Wnt主效应因子及靶基因Wnt主效应因子及其靶基因参与肠上皮稳态的维持[45]。研究表明,β-catenin特异性敲除会导致小鼠隐窝萎缩,凋亡细胞数量增加,杯状细胞数量减少[46]。Young[47]在干细胞培养体系中添加Ascl2蛋白,会增加小鼠类肠团Lgr5+干细胞、具有溴素蛋白(olfactomedin 4,Olfm4)标记的Olfm4+干细胞、具有Ki67标记的Ki67+干细胞数量。T细胞因子4(TCF4)与β-catenin一样,也是Wnt/β-catenin信号的主要效应因子,系统性敲除TCF4可导致Lgr5+干细胞的快速丢失[48]。Janeckova等[49]则发现,TCF4基因突变的小鼠,其肠上皮杯状细胞能正常发育,但不存在分泌细胞。相反,c-Myc过度表达的小鼠,其杯状细胞丢失严重。此外,Wnt的靶基因EphB2和EphB3的缺失会也会导致肠道干细胞增殖和分化细胞的混乱,且在敲除EphB3基因的小鼠肠道内,潘氏细胞不再沿着隐窝方向移动,而是向绒毛等四处游移[50],肠道有序结构被破坏。同样,通过腺病毒转染肠上皮或通过基因编辑使Dkk1过表达时,也可观察到Lgr5+干细胞凋亡速度加快[48]。这些结果进一步说明Wnt/β-catenin信号对肠道干细胞的发育和维持是必要的。
4 Wnt/β-catenin信号驱动肠上皮再生小肠上皮的再生依赖于肠道干细胞的快速应答,损伤时,由临近的隐窝干细胞扩增补充,通过Lgr5+干细胞驱动,快速完成修复[51]。研究表明,当小肠上皮暴露于单一应激源时,会刺激Lgr5的表达,而当其遭受多种应激源时,Lgr5表达量反而会下降,说明Lgr5+肠道干细胞对外部刺激较为敏感,轻微的损伤会加速Lgr5+干细胞的增殖分化,从而修复小肠上皮损伤,而持续或强烈的刺激则会导致Lgr5+干细胞大量丢失,小肠上皮再生能力下降,绒毛严重萎缩[52]。由于Wnt/β-catenin信号调控Lgr5的表达,Wnt/β-catenin信号的适当上调可增加Lgr5+干细胞的活性,促进隐窝绒毛轴的重建。
Liu等[53]发现,沙门氏菌感染导致肠道中Wnt11蛋白的表达升高,且Wnt11过表达后,能够显著抑制沙门氏菌在上皮细胞的定植,减轻肠道炎症反应,不仅如此,Wnt3a和Wnt2b同样具有此功效。Wnts发挥抗炎作用的原因可能是其通过增加Wnt/β-catenin活性,激活肠道干细胞群,从而促进小肠上皮功能细胞的生成,上调凝集素和溶菌酶的分泌,从而增强宿主的防御功能[54-55];Saha等[56]分离电离辐射后的Porcn-/-(特异性敲除Porcn基因)小鼠隐窝进行体外培养发现,添加Wnt6能显著增加类肠团出芽效率。同样,静脉注射Wnt3a和Rspo1也能增强辐射后肠道干细胞的增殖和分化活性,改善肠道形态结构和功能[57-59]。本实验室研究发现,呕吐毒素[60]、高温[61]或耐热肠毒素[62]均可下调肠上皮细胞系Wnt/β-catenin信号通路,降低Lgr5表达,抑制细胞增殖,诱导细胞凋亡,损伤肠道屏障功能,而添加Rspo1能逆转这一过程。
5 小结综上所述,Wnt/β-catenin信号控制肠道干细胞的增殖和分化命运,它不仅是肠道上皮细胞有序结构和肠道稳态维持的控制器,也是肠道损伤修复过程中所必需的信号分子,可通过增加肠道干细胞活性,促进肠上皮再生,从而缓解或修复肠道损伤。目前人们对于Wnt/β-catenin介导的复杂调节途径的认识仍然有限,尤其是Wnts配体之间的关系以及它们在新型饲料添加剂和药物开发领域中的潜在作用还有待挖掘。此外,Wnt/β-catenin信号与其他参与调节肠上皮更新或再生过程的信号之间的关联性也需要进一步的探究。随着人和各种动物肠道干细胞培养体系的相继建立,对Wnt/β-catenin信号调控肠上皮生长或损伤修复的机制及与其他信号的串扰作用将会越来越清晰,以此为畜牧生产中调控动物肠道发育的生产应用,以及在药理学方面对肠炎等疾病的治疗提供理论依据。
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