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Article(id=1212692429791216370, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212692423956939344, articleNumber=1001-2494(2024)17-1558-07, orderNo=null, doi=10.11669/cpj.2024.17.002, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1716652800000, receivedDateStr=2024-05-26, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1767058005997, onlineDateStr=2025-12-30, pubDate=1725724800000, pubDateStr=2024-09-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1767058005997, onlineIssueDateStr=2025-12-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1767058005997, creator=13701087609, updateTime=1767058005997, updator=13701087609, issue=Issue{id=1212692423956939344, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='17', pageStart='1553', pageEnd='1664', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1767058004596, creator=13701087609, updateTime=1767058886858, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1212696124457140722, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212692423956939344, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1212696124457140723, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212692423956939344, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1558, endPage=1564, ext={EN=ArticleExt(id=1212692430076429058, articleId=1212692429791216370, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Research Progress in the Use of Cell Line and Organoid Models for Studying Inflammatory Bowel Disease, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

It is important to select a suitable in vitro experimental model to study the pathology and pharmacological mechanisms of inflammatory bowel disease (IBD), thereby developing advanced therapeutic drugs. Immortalized cell lines, as a classic in vitro model, offer several advantages in the research and drug evaluation of IBD, such as high efficiency, low cost, simple operation and intuitive experimental results. However, these models cannot recapitulate the multicellular composition and intercellular interaction of intestinal tissue in vivo and may lose genetic characteristics after multiple passages in vitro. The development of organoids and organs-on-a-chip has promoted the technological innovation of in vitro models by significantly improving our capability to simulate the architecture and function of IBD. The enhanced reproducibility of the organoid model to the microenvironment of the source tissue also confers improved predictive capability for patient treatment response. This paper reviews the current research status of these models by discussing their characteristics, advantages, disadvantages, and their applications in evaluation of IBD therapeutic drugs and development of advanced therapeutic drugs, as well as in the exploration of pharmacological mechanisms.

, correspAuthors=Qingwei ZHAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Pan LIU, Xueling LIU, Qingwei ZHAO), CN=ArticleExt(id=1212692431024341816, articleId=1212692429791216370, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=体外细胞和类器官模型在炎症性肠病研究中的应用, columnId=1212692426674848354, journalTitle=中国药学杂志, columnName=炎症性肠病研究专栏, runingTitle=null, highlight=null, articleAbstract=

选择与研究目的契合的体外实验模型对于炎症性肠病病理研究、治疗药物开发以及药理机制探索具有重要意义。永生化细胞系作为经典的体外模型,虽然在炎症性肠病研究及药物评价中具有高效、低成本、操作简便及实验结果直观等优势,但此类模型对体内肠组织中多细胞组成及其相互作用还原程度有限,且经历体外多次传代后可能无法保留部分遗传特征。类器官和类器官芯片技术的兴起推动了体外模型的技术革新,极大地增强了模拟炎症性肠病体内组织结构与功能的能力,类器官模型对来源组织微环境较好的重现能力也使其能更好预测患者的治疗反应。本文概述了上述模型的研究现状,讨论了各模型的优劣势,并总结了各模型在评价炎症性肠病治疗药物中的应用,以期为后续治疗药物研发和药理机制探索提供合适的研究模型。

, correspAuthors=赵青威, authorNote=null, correspAuthorsNote=
* 赵青威,女,博士,主任药师,博士生导师 研究方向:临床药学 Tel:(0571)87236595
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刘盼,女,硕士研究生 研究方向:临床药学、药物评价

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模型 细胞类型 结构复杂性 病理相关性 特征模拟 患者特异性 可及性 花费 医学伦理 适用场景
永生化细胞系 Caco-2 低 低 肠上皮炎症反应,肠上皮物理屏障 否 易 低 不涉及 大规模药筛、药理机制探索
HT-29 低 低 肠上皮黏液屏障,肠上皮炎症反应 否 易 低 不涉及 大规模药筛、药理机制探索
T84 低 低 肠上皮物理屏障 否 易 低 不涉及 大规模药筛、药理机制探索
共培养细胞模型 Caco-2与THP-1 中 中 巨噬细胞与肠上皮细胞相互作用引发的炎症反应、肠屏障完整性变化 否 中 中 不涉及 免疫细胞在IBD中的作用、药理机制探索
Caco-2,HT-29和THP-1 中 中 巨噬细胞与多种肠上皮细胞相互作用引发的炎症反应、肠屏障完整性变化 否 中 中 不涉及 免疫细胞在IBD中的作用、药理机制探索
类器官 肠组织 中-高 高 多种不同细胞类型相互作用引发炎症反应、肠屏障变化 是 难 高 涉及 个体化用药、药理机制探索、药物评价
类器官芯片 肠组织+细胞
系/原代细胞		 高 高 肠道结构与功能微环境模拟 是 难 高 涉及 肠炎复杂动态相互作用关系、药物评价、药理机制探索
), ArticleFig(id=1212786698673635611, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692429791216370, language=CN, label=表1, caption=

炎症性肠病(IBD)不同体外模型的特点

, figureFileSmall=null, figureFileBig=null, tableContent=
模型 细胞类型 结构复杂性 病理相关性 特征模拟 患者特异性 可及性 花费 医学伦理 适用场景
永生化细胞系 Caco-2 低 低 肠上皮炎症反应,肠上皮物理屏障 否 易 低 不涉及 大规模药筛、药理机制探索
HT-29 低 低 肠上皮黏液屏障,肠上皮炎症反应 否 易 低 不涉及 大规模药筛、药理机制探索
T84 低 低 肠上皮物理屏障 否 易 低 不涉及 大规模药筛、药理机制探索
共培养细胞模型 Caco-2与THP-1 中 中 巨噬细胞与肠上皮细胞相互作用引发的炎症反应、肠屏障完整性变化 否 中 中 不涉及 免疫细胞在IBD中的作用、药理机制探索
Caco-2,HT-29和THP-1 中 中 巨噬细胞与多种肠上皮细胞相互作用引发的炎症反应、肠屏障完整性变化 否 中 中 不涉及 免疫细胞在IBD中的作用、药理机制探索
类器官 肠组织 中-高 高 多种不同细胞类型相互作用引发炎症反应、肠屏障变化 是 难 高 涉及 个体化用药、药理机制探索、药物评价
类器官芯片 肠组织+细胞
系/原代细胞		 高 高 肠道结构与功能微环境模拟 是 难 高 涉及 肠炎复杂动态相互作用关系、药物评价、药理机制探索
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体外细胞和类器官模型在炎症性肠病研究中的应用
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刘盼 1, 2 , 刘雪玲 2 , 赵青威 2, *
中国药学杂志 | 炎症性肠病研究专栏 2024,59(17): 1558-1564
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中国药学杂志 | 炎症性肠病研究专栏 2024, 59(17): 1558-1564
体外细胞和类器官模型在炎症性肠病研究中的应用
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刘盼1, 2, 刘雪玲2, 赵青威2, *
作者信息
  • 1 温州医科大学药学院, 浙江 温州 325035
  • 2 浙江大学医学院附属第一医院临床药学部, 浙江省药物临床研究与评价技术重点实验室, 浙江省中药临床评价与转化研究中医药重点实验室, 杭州 310003

    • 刘盼,女,硕士研究生 研究方向:临床药学、药物评价

通讯作者:

* 赵青威,女,博士,主任药师,博士生导师 研究方向:临床药学 Tel:(0571)87236595
Research Progress in the Use of Cell Line and Organoid Models for Studying Inflammatory Bowel Disease
Pan LIU1, 2, Xueling LIU2, Qingwei ZHAO2, *
Affiliations
  • 1 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
  • 2 Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
出版时间: 2024-09-08 doi: 10.11669/cpj.2024.17.002
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选择与研究目的契合的体外实验模型对于炎症性肠病病理研究、治疗药物开发以及药理机制探索具有重要意义。永生化细胞系作为经典的体外模型,虽然在炎症性肠病研究及药物评价中具有高效、低成本、操作简便及实验结果直观等优势,但此类模型对体内肠组织中多细胞组成及其相互作用还原程度有限,且经历体外多次传代后可能无法保留部分遗传特征。类器官和类器官芯片技术的兴起推动了体外模型的技术革新,极大地增强了模拟炎症性肠病体内组织结构与功能的能力,类器官模型对来源组织微环境较好的重现能力也使其能更好预测患者的治疗反应。本文概述了上述模型的研究现状,讨论了各模型的优劣势,并总结了各模型在评价炎症性肠病治疗药物中的应用,以期为后续治疗药物研发和药理机制探索提供合适的研究模型。

炎症性肠病  /  细胞模型  /  类器官  /  类器官芯片

It is important to select a suitable in vitro experimental model to study the pathology and pharmacological mechanisms of inflammatory bowel disease (IBD), thereby developing advanced therapeutic drugs. Immortalized cell lines, as a classic in vitro model, offer several advantages in the research and drug evaluation of IBD, such as high efficiency, low cost, simple operation and intuitive experimental results. However, these models cannot recapitulate the multicellular composition and intercellular interaction of intestinal tissue in vivo and may lose genetic characteristics after multiple passages in vitro. The development of organoids and organs-on-a-chip has promoted the technological innovation of in vitro models by significantly improving our capability to simulate the architecture and function of IBD. The enhanced reproducibility of the organoid model to the microenvironment of the source tissue also confers improved predictive capability for patient treatment response. This paper reviews the current research status of these models by discussing their characteristics, advantages, disadvantages, and their applications in evaluation of IBD therapeutic drugs and development of advanced therapeutic drugs, as well as in the exploration of pharmacological mechanisms.

inflammatory bowel disease  /  cell model  /  organoid  /  organs-on-a-chip
刘盼, 刘雪玲, 赵青威. 体外细胞和类器官模型在炎症性肠病研究中的应用. 中国药学杂志, 2024 , 59 (17) : 1558 -1564 . DOI: 10.11669/cpj.2024.17.002
Pan LIU, Xueling LIU, Qingwei ZHAO. Research Progress in the Use of Cell Line and Organoid Models for Studying Inflammatory Bowel Disease[J]. Chinese Pharmaceutical Journal, 2024 , 59 (17) : 1558 -1564 . DOI: 10.11669/cpj.2024.17.002
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炎症性肠病(inflammatory bowel disease, IBD)是以慢性炎症为主要特征的一类肠道疾病,严重影响人类健康及生活质量[1]。在人体肠道组织内,包括上皮细胞、免疫细胞在内的各类细胞协同作用共同维持肠道屏障完整性并调节免疫平衡。在IBD病理状态下,不同种类细胞比例失衡、细胞功能受损、细胞间相互作用改变,导致肠道屏障破坏、局部免疫调节失衡,从而诱发或扩大炎症反应。IBD病因不明、进展机制复杂,且受遗传、免疫系统、肠道微生物等多种因素影响[2-3]。现有治疗方式主要侧重于缓解、控制IBD的炎症过程,氨基酸水杨酸制剂、免疫调节剂、糖皮质激素、生物制剂、靶向小分子制剂及中药制剂等在IBD的治疗中展现出一定的疗效。但鉴于IBD病情变化大,不同患者对相同药物或药物组合的治疗反应差异大,且部分患者对现有疗法耐受,亟待在进一步解析IBD病理机制的基础上,开发新的治疗药物或药物治疗策略[4]。
体内外实验模型是疾病机制研究和药物评价的重要工具。动物模型作为研究IBD的传统模型,能为IBD的研究提供整体性生物背景以及系统性的见解,但实验动物模型的人源化程度、动物伦理问题以及高成本限制了其在大规模药物筛选和药理机制探索上的应用[5]。与此相比,基于细胞的体外评价模型能更直观地展现IBD病理特征,且具有高效、低成本、可大规模操作等优势[6]。近年来,随着细胞培养技术和组织工程领域的发展,多种基于细胞的IBD模型被开发出来,这些模型能较好地还原IBD体内病理状况,更简便地用于治疗药物评估及机制探索[7-8](表1)。
1 细胞模型在IBD病理研究及药物评价中的应用
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肠道组织内存在高度多样性和复杂性的不同种类细胞,各类型细胞在IBD中发挥不同功能,且细胞间互作能影响IBD发生发展。不同种类的永生化细胞系因与肠道内细胞在结构与功能上的相似性被用于IBD研究,细胞系在实验可控性、成本、建模速度等方面具有显著优势,常被作为实验模型用于病理机制研究、大规模药物筛选和药理机制探索[6]。本文列出了目前用于模拟IBD特征的细胞模型和在药物评价中的应用。
1.1 刺激因子作用下模拟IBD病理特征的永生化细胞系模型构建
1.1.1 Caco-2细胞系
Caco-2细胞是在体外培养过程中能够分化形成与肠道上皮相似的紧密连接结构与微绒毛特征,且具有与肠上皮相似的吸收、转运和屏障功能,是模拟肠上皮的一类经典细胞模型[9]。研究表明,IBD能分泌大量细胞因子、化学趋化因子和生长因子等,不同类型的分泌因子在IBD不同阶段功能各异。例如,在急性发作期,促炎因子如白细胞介素-6(interleukin-6, IL-6)水平升高,驱动炎症过程[10],而在缓解期,抗炎因子如白细胞介素-10(interleukin-10, IL-10)则更为活跃,帮助抑制炎症并促进组织修复[11]。
不同条件的刺激作用下,Caco-2细胞能分泌不同的炎性因子,一定程度上模拟IBD不同状态下的炎症反应。例如,肿瘤坏死因子-α(tumor necrosis factor-alpha, TNF-α)作用于Caco-2细胞后能上调促炎介质和细胞因子应答蛋白环氧合酶-2(cyclooxygenase-2, cox-2)和炎性因子IL-6 mRNA的表达水平[12-13],也能上调炎性因子白细胞介素-8(interleukin-8, IL-8)mRNA的表达水平[14]。也有研究发现脂多糖(lipopolysaccharide, LPS)能上调Caco-2细胞中炎性因子白细胞介素-1β(interleukin-1β, IL-1β)和IL-6 mRNA的表达水平[15]。除对IBD炎症反应的还原外,Caco-2细胞系也能模拟IBD物理屏障受损。TNF-α能降低Caco-2细胞跨上皮电阻(transepithelial electrical resistance, TEER),增加细胞旁通透性,引起肠道物理屏障功能受损[16]。LPS能下调Caco-2细胞内紧密连接蛋白occludin和ZO-1的表达[15]。由此可见,不同刺激因子作用于Caco-2细胞系能诱导不同炎症因子分泌、不同程度的肠道物理屏障功能受损。总之,基于Caco-2细胞系的IBD模型能模拟IBD的炎症反应与肠屏障受损状态,根据IBD不同的药物开发需求,可以选择合适的刺激条件作用于Caco-2细胞开展药物评价相关实验。
1.1.2 HT-29细胞系
与Caco-2细胞系相比,HT-29细胞系在分化程度上较为原始,在特定条件刺激下能分化为吸收细胞或杯状细胞等多种黏液分泌细胞类型,在模拟肠道黏液分泌方面表现出更显著的特征[17],也常被用于IBD研究[18-20]。
葡聚糖硫酸钠(dextran sulfate sodium, DSS)常被用于构建化学诱导型肠炎模型,向培养基添加2% DSS,HT-29细胞分泌黏蛋白MUC2在HT-29细胞中的表达量显著下降[21]。Wei等[22]通过该模型发现黏膜屏障蛋白MarvelD3的上调能稳定肠道屏障,缓解DSS诱导的结肠炎,发挥肠道保护作用。除用于黏液层屏障作用研究外,HT-29细胞也被用于肠炎相关炎症反应和物理屏障作用研究。研究人员发现,经干扰素-γ(interferon-γ, IFN-γ)预处理并用LPS刺激HT-29细胞后,炎症因子IL-6、IL-1β和TNF-α的水平显著升高,紧密连接蛋白claudin-1和occludin的表达水平相应降低[23]。TNF-α处理后cox-2的表达和趋化因子CXCL-1表达均发生上调[24]。
HT-29细胞系因其保留的肠道上皮细胞特性,在体外模拟IBD黏蛋白MUC2的变化和维持肠道屏障等方面应用发挥了重要作用,这为揭示IBD的病理机制及潜在治疗提供了一个有价值的细胞模型。
1.1.3 T84细胞系
T84细胞系因其出色的增殖能力和分化成吸收性上皮单层的能力,在维持结肠上皮细胞的吸收、屏障和转运功能方面展现出较高的体内一致性和可重复性,这些特性使得T84细胞成为探究肠上皮屏障功能及其调控机制的理想模型[25]。Grosheva等[26]发现LPS作用于T84细胞后会导致紧密连接蛋白结构扭曲度显著增加、肠道屏障功能削弱,增加肠道通透性,进而引发肠道炎症。进一步的研究表明,特定病原体的引入可导致T84细胞层的TEER降低,细通透性增加,上皮屏障的完整性被破坏。例如,齿龈卟啉单胞菌能降低T84细胞层的TEER,破坏细胞上皮屏障完整性[27]。从克罗恩病(Crohn's disease, CD)患者体内分离的原型AIEC大肠埃希菌-LF82(adherent-invasive Escherichia coli LF82)作用于T84上皮细胞后,可观察到IL-8 mRNA的表达水平显著增加,TEER的显著降低以及线粒体分裂过程异常[28]。在类似的研究中,研究人员[29]通过使用IFN-γ来降低T84细胞TEER,增加上皮层通透性,从而模拟炎症条件下的肠道环境。
1.2 共培养细胞模型
IBD患者肠黏膜内除多种上皮细胞外也存在多类免疫细胞,这些细胞在控制炎症反应和维持肠道屏障中扮演关键角色[30-31]。前文提及的细胞系培养方法简便,但此类模型往往无法复现肠炎病理条件下不同种类细胞间相互作用,在免疫反应与肠道屏障功能方面的模拟上存在局限。与单细胞系培养相比,引入免疫细胞与上皮细胞共培养的模型有助于更全面地重现和解析肠道炎症环境对屏障功能的影响。
此外,THP-1、MUTZ-3和U937等人单核细胞白血病细胞系能在体外分化成具有不同免疫功能的细胞,如THP-1和U937可分化为具有吞噬功能的巨噬细胞,MUTZ-3用于生成树突细胞。当使用磷酸酯(phorbol 12-myristate 12-acetate, PMA)诱导THP-1细胞分化并与Caco-2细胞共培养时,IFN-γ和LPS刺激后的Caco-2细胞内TEER暂时性下降,IL-6、白细胞介素-4(interleukin-4, IL-4)、TNF-α等炎症因子的释放增加,表明肠道功能受损[32],这为理解IBD中炎症过程提供了重要信息。Kämpfer等[33]则通过将Caco-2和HT29-MTX细胞联合分化后的THP-1细胞的巨噬细胞构建出一种共培养模型,观察到刺激后肠细胞TEER降低、肠道渗透性增加,且炎症因子释放量上升,再次凸显了免疫细胞在肠道炎症反应中的作用和共培养模型的研究优势。共培养模型相较于单细胞系培养模型,能更好地再现肠道微环境,更全面揭示免疫细胞调节炎症因子的表达和信号转导通路方式以及不同种类细胞对肠道屏障的完整性和功能的影响,这对于理解IBD的病理机制和新型治疗策略开发具有重要意义。
1.3 细胞模型在IBD治疗药物评价中的应用
不同的细胞模型已经广泛应用于揭示IBD的病理机制、评价各类活性物质和药物对此疾病的影响和治疗潜力。
1.3.1 细胞模型在大分子药物评价中的应用
在IBD的体外模型研究中,向LS174T细胞添加TNF-α以模拟患者炎症的肠道环境。研究人员将抗TNF-α单克隆抗体——英夫利西单抗(Infliximab)应用于该细胞模型,观察到英夫利西单抗能有效减轻肠道上皮细胞的炎症反应。研究结果显示,在炎症肠道上皮细胞中,泛素D(ubiquitin D,UBD)的表达增加是由Notch信号和TNF-α协同作用所导致的,揭示了肠炎环境中细胞信号途径的交互作用[34]。
1.3.2 细胞模型在小分子药物评价中的应用
Gerner等[35]培养IBD患者炎症组织中分离的黏膜下单核细胞,并在该细胞模型上比较了地塞米松、英夫利西单抗和烟酰胺磷酸核糖转移酶(nicotinamide phosphoribosyltransferase,NAMPT)抑制剂FK866对IBD的抗炎效果,结果发现FK866在降低IL-1β、IL-6、TNF-α等炎症因子的产生方面最为有效,展现了在体外抑制炎症反应能力上的优势。
“1.1.1”项提及Caco-2细胞在TNF-α的作用下能模拟IBD中上皮屏障功能障碍的病理状态。利用该模型,研究发现西罗莫司(又称雷贝卡霉素)能通过增加紧密连接蛋白claudin-5的表达、抑制肌动蛋白轻链激酶(myosin light chain kinase, MLCK)的活性,来保护肠上皮屏障功能。该研究进一步发现,雷贝卡霉素可能通过激活细胞周期检查点激酶1(checkpoint kinase 1, Chk1)抑制MLCK mRNA表达,进而防止肌动蛋白轻链(myosin light chain, MLC)的磷酸化,从而维护紧密连接结构的完整性[14]。
广谱JAK激酶抑制剂托法替尼(tofacitinib)在IFN-γ处理的T84细胞模型上显示出肠上皮屏障保护作用。研究发现,托法替尼预处理能够有效防止由IFN-γ引起T84细胞的TEER降低,并通过调节紧密连接蛋白的表达和定位来发挥作用。即便在IFN-γ处理后,托法替尼也能促进TEER的部分恢复,揭示其在预防及修复屏障功能损伤方面的双重作用,为IBD治疗提供了新的研究方向[29]。
1.3.3 细胞模型在活性物质评价中的应用
T84细胞系被用于评估不同生物活性分子对肠道上皮紧密连接蛋白的影响。有研究发现牛磺酸等分子能有效保护紧密连接蛋白免受炎症介质的破坏,研究指出,特定的炎症介质如TNF-α和LPS能显著破坏T84细胞中的紧密连接结构,增加肠道通透性,这为治疗IBD提供了潜在的药物候选[26]。研究人员利用DSS诱导HT29细胞来研究壳聚糖低聚糖(chitosan oligosaccharides,COS)对肠道黏液层的影响,发现COS处理DSS刺激的HT-29细胞后MUC2表达显著上调,DSS诱导的黏液层损伤减轻[21]。
也有研究团队利用Caco-2细胞模型挖掘出牛蒡苷元发挥肠保护作用机制,发现该药能激活雌激素受体β(estrogen receptor β, Erβ),进而维持肠上皮完整性[36]。另一研究团队发现,白芍药素对于LPS刺激的Caco-2细胞具有抗炎效果,可能是针对IBD的潜在治疗剂,通过这个细胞模型研究进一步发现白芍药素通过激活Nrf2/HO-1信号通路,抑制LPS刺激的Caco-2细胞中的NF-κB信号,以此来达到对细胞屏障功能的保护作用,从而发挥抗炎作用[37]。
这些研究结果不仅验证了体外细胞模型在药物评价和疾病机制研究中的价值,也为IBD的新疗法提供了理论依据。
2 IBD类器官模型的开发及应用
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尽管永生化细胞系为研究肠上皮的功能提供了基础的细胞生物学信息和药物筛选的初步平台,但它们通常缺乏肠道本身的三维结构和多细胞类型的复杂互作,这在一定程度上限制了其在模拟真实肠道生理状态方面的有效性。在模拟IBD时,这种二维单层细胞模型无法充分再现炎症环境下细胞间的动态互动和信号通路的全貌。类器官作为一种三维细胞培养技术,能够在体外形成类似原发组织的微结构和功能,提供多细胞、多层次交互的复杂环境,不仅能够模拟细胞系所不能达到的细胞极性、细胞外基质互作和细胞间通讯,而且能更好地复现IBD过程中的病理变化[38]。
2.1 IBD类器官模型的构建
人源肠道类器官能够在体外模拟人类肠道的结构和功能。这些微型三维结构由来源于人类肠道上皮的干细胞培养而成,能够再现肠道的多种细胞类型,包括吸收性肠细胞、杯状细胞和潘氏细胞及肠道其他内分泌细胞[39]。肠道类器官的培养从单个干细胞开始,这些干细胞在特定的培养条件下可以无限扩增,并能分化成肠道上皮的所有主要细胞类型。随着培养时间的延长,这些细胞会自组织成具有完整肠道上皮结构的球形或囊状体,内含有中空的腔室,模拟了肠道的内腔[40]。肠道类器官模型的一个关键优势在于其能够再现人类肠道对疾病的响应,包括IBD、肠道感染和肠癌等。通过使用患者特定的干细胞来源,可以生成具有特定遗传背景的肠道类器官[41]。
研究人员利用肠道类器官这一新型体外模型,比较了非炎症性肠病对照组与IBD患者来源的肠道类器官的形态学和功能性表型。与健康对照组相比,IBD类器官展示了明显的形态学和炎症改变,如器官形态的缩小、芽形成能力的下降以及炎症因子分泌的增加。此外,在IBD类器官中,紧密连接蛋白的表达也有显著下降,揭示了这些细胞模型在疾病状态下上皮屏障功能的损伤[7]。
在UC患者的肠道组织及相应的类器官中,研究发现高度一致的基因表达谱,表明肠道类器官能够准确反映患者肠道的病理状态。研究进一步指出,在UC患者结肠上皮中,可能由于干细胞区域印记的改变,导致了疾病持续性的永久性变化[42]。
与此同时,研究人员还比较了从CD患者肠隐窝中分离出的肠类器官与健康个体的肠类器官。在CD患者来源的类器官中,紧密连接蛋白、黏附连接蛋白和桥粒蛋白的表达均有明显降低,这一发现意味着即使在无额外炎症因子刺激的情况下,这些变化也能够在体外持续存在,暗示了肠类器官模型在反映肠道上皮屏障功能变化方面的可靠性[43]。
这些发现证实了肠道类器官在研究IBD及其病理机制中的重要应用价值,它们为探索疾病的发生、发展及潜在治疗方法提供了一个生物学上和技术上先进的研究工具。
2.2 类器官模型在IBD机制探索及药物评价中的应用
通过从分离的结肠隐窝建立肠道类器官模型,研究人员能够在体外模拟和研究人体内的生物过程。
类器官模型能在一定程度上还原IBD病理状态下的细胞生物学过程,是研究IBD病理机制及相关药物药理机制的有力工具。研究发现[7],由IBD患者的患病组织构建的类器官,不仅保留了患者特有的病理特征,还能在体外环境中展现出与体内相似的炎症反应。此外,这些类器官模型可用于评估潜在治疗药物的有效性和安全性,从而推动个性化医疗的发展。在类器官模型上进一步研究发现,Notch信号和TNF-α的协同作用是影响肠道上皮细胞炎症反应的重要因素。英夫利西单抗是临床常用的IBD治疗药物,但其药理机制尚不明确。类器官模型与IBD患者在肠道炎症反应及其病理机制的相似性,使其成为研究英夫利西单抗的重要模型。研究发现[34],英夫利西单抗作用于IBD患者衍生的类器官能下调UBD表达,进一步研究发现,TNF-α刺激能激活Notch信号,Notch胞内区域(Notch intracellular domain, NICD)蛋白稳定性增加,促使其下游NF-κB结合UBD基因的启动子区域和5'UTR,显著增加UBD的表达,而英夫利西单抗能下调UBD表达,调控肠道上皮细胞的炎症反应,发挥抗炎作用。英夫利西单抗治疗IBD药理机制的探明,将有助于该药物在临床上的精准应用,也能助力新型IBD药物的研发。
使用C57BL/6J野生型和IL-10基因敲除的小鼠肠道组织构建的肠炎类器官,能模拟IBD的病理条件。美沙拉嗪,也称为5-氨基水杨酸,是临床上常用的一类IBD治疗药物,能通过阻止炎症介质的产生来抑制炎症反应。硫唑嘌呤也是一种常用于治疗IBD的免疫抑制剂。研究发现美沙拉嗪和硫唑嘌呤能够恢复TNF-α处理的野生型类器官中E-钙黏蛋白的表达,改善肠道屏障功能。此外,美沙拉嗪还能恢复野生型类器官中因TNF-α处理而降低的脱脂素2表达。基于这个类器官模型,研究团队探索美沙拉嗪和硫唑嘌呤可以通过重组细胞间连接蛋白,降低由炎症介质引起的细胞间通透性[44]。
类器官模型也能是研究肠道微生物的有效工具。构建来源于核糖体蛋白NLR家族成员X1(NLR family member X1, NLRX1)缺失小鼠和野生型小鼠的肠道类器官,利用该模型发现,NLRX1基因的丧失导致小鼠对结肠炎症的敏感性增加。进一步分析表明,在NLRX1缺失小鼠的肠道类器官中,某些促炎细菌类群(如Veillonella和Clostridiales)的丰度显著增加。此外,当外源性补充谷氨酰胺或通过药物干预改变谷氨酰胺代谢途径来调节肠道菌群的组成和功能时,发现这些措施能够缓解NLRX1缺失小鼠中的肠道炎症。这表明微生物组成的差异可能在肠道炎症性疾病的发病机制中起重要作用[45]。
3 IBD类器官芯片的开发及应用
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类器官技术在模拟人体肠道结构及功能方面取得了突破性进展,并为IBD的研究提供了创新平台,但其模拟系统仍有一定的局限性。当前的类器官模型未能充分再现血液循环和肠内容物流动的动态变化,这一不足制约了其在复杂动态相互作用研究中的应用。而且,类器官模型通常未能整合肠道免疫细胞、微生物群落等对于IBD至关重要的关键微环境元素。肠道类器官芯片通过在微流控芯片中整合类器官技术,模拟人体肠道的微环境,复制如流体剪切力和营养梯度等肠道的物理和生化环境,模拟血流和肠道内容物的流动[8]。此外,肠道类器官芯片能够整合包括上皮细胞、免疫细胞以及微生物等不同类型的肠道微环境组分,实现人类上皮细胞与微生物在代表性肠道环境下的共培养,再现体内转录、代谢和免疫反应[46-47]。
3.1 IBD类器官芯片模型的构建
在IBD的体外研究中,Gijzen等[48]开发了一种新型的“肠道芯片”平台,该平台包含了40个独立的极化3D灌注上皮管状结构,能够有效地模拟肠道的结构和功能。研究团队在该系统中添加了可以被激活的免疫细胞THP-1和MUTZ-3,并通过添加TNF-α和IL-1β来模拟炎症条件,通过测量TEER观察到屏障功能的损伤,同时监测到炎症因子IL-8的显著增加,证实了肠道炎症的发生。
另一个研究利用Caco-2细胞与微血管/淋巴管内皮细胞在肠道芯片中构建了肠上皮的结构,并发现在LPS刺激下,虽然上皮层的防御屏障仍然保持完整,但是当与人类外周血单核细胞结合使用时,不仅TEER值下降,而且激发了包括IL-1β、IL-6、IL-8和TNF-α在内的炎症性细胞因子的产生,并增强了细胞间黏附分子-1(intercellular cell adhesion molecule-1, ICAM-1)的表达,揭示了肠道炎症模型中的细胞间相互作用和信号传递[49]。
通过微流控通道模拟的肠道类器官模型,研究团队在肠腔侧播种人类肠上皮细胞,血管腔室侧播种免疫细胞,模拟肠道壁的细胞组成。在这一模型中,通过向肠腔侧添加DSS,模拟炎症条件下上皮屏障的损伤和黏液的变化,并观察到DSS处理可以显著损害上皮屏障的完整性,同时刺激下的炎症因子和免疫细胞的产生也得到了证实[50]。
这些研究进一步证实了肠道芯片和微流控通道等体外模型在IBD研究中的应用价值,为探讨疾病的起源、发展以及潜在治疗方法上提供了重要研究工具。
3.2 IBD类器官芯片评估潜在治疗药物
在IBD中,肠类器官芯片技术不仅能够用于模拟疾病的病理过程,还能用于筛选和评估潜在的治疗药物。IBD类器官芯片提供了更接近人体病理生理状态的实验条件,使得研究结果更具有生物相关性和预测价值[50]。
壳聚糖寡糖是一种天然多糖,Jing等[51]通过在芯片上共培养人类肠上皮细胞、血管内皮细胞和免疫细胞来构建IBD类器官芯片模型,进而添加壳聚糖寡糖进行治疗研究。在构建的模型中,壳聚糖寡糖能够有效减轻DSS和大肠杆菌E. coli 11775引起的肠炎模型中的肠上皮损伤,通过促进黏液层的形成,增强紧密连接蛋白的表达以降低炎症反应,表明其是一种潜在的治疗IBD的药物。
使用OrganoPlate平台建立Caco-2细胞的3D肠道管道,添加IL-1β、TNF-α或IFN-γ诱导为IBD状态。研究团队观察到将小分子化合物TPCA-1应用于这个3D管道后,TPCA-1通过选择性抑制IκB激酶β阻断NF-κB途径的激活,从而减少炎症细胞因子的产生,达到抗炎的效果。这不仅表明TPCA-1对于IBD中肠道屏障损伤和炎症反应有预防效果,同时也验证了3D肠道芯片模型在药物效果评估中的适用性[52]。
4 结语与展望
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人体肠道是一个具有多层结构的复杂器官,不同类型的细胞发挥不同作用,彼此之间相互作用,形成肠道复杂细胞体系。在IBD发生发展阶段,炎症级联反应启动并分泌大量化合物,使得肠道中细胞行为更为复杂,这给深入研究IBD带来挑战。
近年来,细胞培养技术飞速发展,类器官及类器官芯片等体外模型不断涌现,在模拟IBD独特的结构特征及炎症状态方面展现优势。本文综述了IBD各类体外模型,不同模型能不同程度地复制IBD重要特征,是研究IBD发生发展机制、研发IBD治疗药物及探索药理作用机制的重要工具。永生化细胞系是一种简化的、广泛应用的体外模型,不同刺激因子作用于细胞系不同时间后展现IBD不同特征,为研究IBD提供了一种直接、可重复且成本效益高的方法。但是,永生化细胞系作为IBD体外模型过于简化,无法完全复制体内环境,实验条件下观察到的细胞反应可能与IBD体内病理状态存在差异。类器官培养技术近年来发展迅速,类器官模型能更好还原IBD患者病理特征,但是,与永生化细胞系相比,类器官及类器官芯片模型相对不成熟,需要对其进行彻底表征,这将有助于进一步解析IBD。综上,永生化细胞系、类器官、类器官芯片等体外模型,能不同程度地模拟IBD特征、复杂性质以及患者个体化特征,在研究IBD病理及药物研发方面显示出巨大潜力。
基金
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  • 浙江省重点研发计划资助(2021C01180)
文献
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参考文献 引证文献
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2024年第59卷第17期
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doi: 10.11669/cpj.2024.17.002
  • 接收时间：2024-05-26
  • 首发时间：2025-12-30
  • 出版时间：2024-09-08
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  • 收稿日期：2024-05-26
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浙江省重点研发计划资助(2021C01180)
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    1 温州医科大学药学院, 浙江 温州 325035
    2 浙江大学医学院附属第一医院临床药学部, 浙江省药物临床研究与评价技术重点实验室, 浙江省中药临床评价与转化研究中医药重点实验室, 杭州 310003

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* 赵青威,女,博士,主任药师,博士生导师 研究方向:临床药学 Tel:(0571)87236595
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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