Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection.
Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection.
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DOI：
10.1136/gutjnl-2017-314540
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发表时间：
2019-03
期刊：
影响因子：
24.5
通讯作者：
Meyer TF
中科院分区：
文献类型：
--
作者：
Boccellato F;Woelffling S;Imai-Matsushima A;Sanchez G;Goosmann C;Schmid M;Berger H;Morey P;Denecke C;Ordemann J;Meyer TF
幽门螺杆菌导致胃粘膜终身定植，导致慢性炎症，增加胃癌的风险。这种感染的发病机制的研究将大大受益于一个真实的人在体外模型。来自手术标本的胃窦来源的胃腺通过短暂的气液界面培养阶段建立极化的上皮单层，以研究与H。幽门和邻近的基质。由此产生的“粘液样培养物”，如此命名是因为它们概括了胃粘膜的关键特征，代表了可以传代数月的正常干细胞驱动的培养物。这些高度极化的柱状上皮层包括各种胃窦细胞类型，并在顶面分泌粘液。默认情况下，它们向小凹、产生MUC5AC的表型分化，而Wnt信号转导刺激产生MUC6的细胞增殖并保留腺体基底的干性。来自固有层的基质细胞分泌Wnt抑制剂，拮抗干细胞生态位信号传导并诱导分化。感染H. pylori感染时，优先在未分化的基底细胞表型中诱导强烈的炎症反应。培养物感染数周会产生活菌灶和持续的炎症状态，而分泌的粘液会建立一个只有少数细菌能够克服的屏障。胃粘膜样细胞培养忠实地再现了正常人胃上皮细胞的特征，为研究H。pylori与上皮表面的相互作用以及与基底外侧间质区室的相互作用。我们的观察为炎症和防御的调节回路提供了惊人的见解。
Helicobacter pylori causes life-long colonisation of the gastric mucosa, leading to chronic inflammation with increased risk of gastric cancer. Research on the pathogenesis of this infection would strongly benefit from an authentic human in vitro model. Antrum-derived gastric glands from surgery specimens served to establish polarised epithelial monolayers via a transient air–liquid interface culture stage to study cross-talk with H. pylori and the adjacent stroma. The resulting ‘mucosoid cultures’, so named because they recapitulate key characteristics of the gastric mucosa, represent normal stem cell-driven cultures that can be passaged for months. These highly polarised columnar epithelial layers encompass the various gastric antral cell types and secrete mucus at the apical surface. By default, they differentiate towards a foveolar, MUC5AC-producing phenotype, whereas Wnt signalling stimulates proliferation of MUC6-producing cells and preserves stemness—reminiscent of the gland base. Stromal cells from the lamina propria secrete Wnt inhibitors, antagonising stem-cell niche signalling and inducing differentiation. On infection with H. pylori, a strong inflammatory response is induced preferentially in the undifferentiated basal cell phenotype. Infection of cultures for several weeks produces foci of viable bacteria and a persistent inflammatory condition, while the secreted mucus establishes a barrier that only few bacteria manage to overcome. Gastric mucosoid cultures faithfully reproduce the features of normal human gastric epithelium, enabling new approaches for investigating the interaction of H. pylori with the epithelial surface and the cross-talk with the basolateral stromal compartment. Our observations provide striking insights in the regulatory circuits of inflammation and defence.
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影响因子：
10.5
作者：
de Lau W;Peng WC;Gros P;Clevers H
通讯作者：
Clevers H
影响因子：
6.4
作者：
Howitt MR;Lee JY;Lertsethtakarn P;Vogelmann R;Joubert LM;Ottemann KM;Amieva MR
通讯作者：
Amieva MR
宿主尿素的化学检测和破坏使幽门螺杆菌可以定位上皮。
影响因子：
30.3
作者：
Huang JY;Sweeney EG;Sigal M;Zhang HC;Remington SJ;Cantrell MA;Kuo CJ;Guillemin K;Amieva MR
通讯作者：
Amieva MR
影响因子：
7.3
作者：
Bansil R;Celli JP;Hardcastle JM;Turner BS
通讯作者：
Turner BS
影响因子：
6
作者：
Katano, Takahito;Ootani, Akifumi;Joh, Takashi
通讯作者：
Joh, Takashi