Modelling human development and disease in pluripotent stem-cell-derived gastric organoids.
Modelling human development and disease in pluripotent stem-cell-derived gastric organoids.
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DOI：
10.1038/nature13863
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发表时间：
2014-12-18
期刊：
影响因子：
64.8
通讯作者：
Wells, James M.
中科院分区：
文献类型：
--
作者：
McCracken, Kyle W.;Cata, Emily M.;Crawford, Calyn M.;Sinagoga, Katie L.;Schumacher, Michael;Rockich, Briana E.;Tsai, Yu-Hwai;Mayhew, Christopher N.;Spence, Jason R.;Zavros, Yana;Wells, James M.
胃病，包括消化性溃疡疾病和胃癌，影响着世界上10%的人口，主要是由于慢性幽门螺杆菌感染。成人胃的胚胎发育和构筑的物种差异使得动物模型不太适合研究人类胃的器官发生和发病机制，而且还没有正常人类胃粘膜的实验模型。在这里，我们报道了通过人多能干细胞(HPSCs)的定向分化，在体外培养三维人胃组织的方法。我们发现，在时间上操纵成纤维细胞生长因子、WNT、BMP、维甲酸和EGF信号通路以及三维生长足以产生人胃有机化合物(HGO)。HGO的发育经历了分子和形态发生阶段，这与小鼠胃腔的发育阶段几乎相同。有机化合物形成原始的胃腺体和小凹结构域，含有LGR5表达细胞的增殖区，表面和胃窦粘液细胞，以及各种胃内分泌细胞。我们使用hGO培养来识别新的信号机制，这些机制调控转录因子NEUROG3上游的早期内胚层模式和胃内分泌细胞分化。利用hGOS模拟人类疾病的发病机制，我们发现，幽门螺杆菌感染导致毒力因子CagA与c-Met受体迅速结合，激活信号转导，并诱导上皮细胞增殖。总之，这些研究描述了一种新颖而强大的体外系统，用于阐明人类胃发育和疾病的潜在机制。
Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world’s population and are largely due to chronic H. pylori infection. Species differences in embryonic development and architecture of the adult stomach make animal models suboptimal for studying human stomach organogenesis and pathogenesis, and there is no experimental model of normal human gastric mucosa. Here we report the de novo generation of three-dimensional human gastric tissue in vitro through the directed differentiation of human pluripotent stem cells (hPSCs). We identified that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signaling pathways and three-dimensional growth are sufficient to generate human gastric organoids (hGOs). Developing hGOs progressed through molecular and morphogenetic stages that were nearly identical to the developing antrum of the mouse stomach. Organoids formed primitive gastric gland- and pit-like domains, proliferative zones containing LGR5-expressing cells, surface and antral mucous cells, and a diversity of gastric endocrine cells. We used hGO cultures to identify novel signaling mechanisms that regulate early endoderm patterning and gastric endocrine cell differentiation upstream of the transcription factor NEUROG3. Using hGOs to model pathogenesis of human disease, we found that H. pylori infection resulted in rapid association of the virulence factor CagA with the c-Met receptor, activation of signaling and induction of epithelial proliferation. Together, these studies describe a novel and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease.
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影响因子：
29.4
作者：
Mills JC;Shivdasani RA
通讯作者：
Shivdasani RA
影响因子：
11.4
作者：
Jenny, M;Uhl, C;Gradwohl, G
通讯作者：
Gradwohl, G
影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.90.12.5791
发表时间：
1993-06-15
影响因子：
11.1
作者：
COVACCI, A;CENSINI, S;RAPPUOLI, R
通讯作者：
RAPPUOLI, R
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE