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Modelling human development and disease in pluripotent stem-cell-derived gastric organoids

机译：在多能干细胞来源的胃类器官中模拟人类发育和疾病

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摘要

Gastric diseases, including peptic ulcer disease and gastric cancer, affect 10% of the world's population and are largely due to chronic Helicobacter 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. We show that temporal manipulation of the FGF, WNT, BMP, retinoic acid and EGF signalling 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 signalling 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 signalling and induction of epithelial proliferation. Together, these studies describe a new and robust in vitro system for elucidating the mechanisms underlying human stomach development and disease.
机译：胃病，包括消化性溃疡疾病和胃癌，影响全球10％的人口，并且很大程度上是由于慢性幽门螺杆菌感染所致。成年胃的胚胎发育和结构上的物种差异使动物模型在研究人胃器官发生和发病机理方面不理想，并且没有正常人胃粘膜的实验模型。在这里，我们报告通过人类多能干细胞的定向分化在体外从头产生三维人胃组织。我们表明，FGF，WNT，BMP，视黄酸和EGF信号通路和三维增长的暂时操纵足以产生人类胃类器官（hGOs）。发育中的hGOs经历了与小鼠胃的发育窦几乎相同的分子和形态发生阶段。类器官形成原始的胃腺和凹坑样结构域，含有LGR5表达细胞，表面和胃窦黏液细胞以及多种胃内分泌细胞的增生区。我们使用hGO文化来确定新的信号传导机制，该机制调节转录因子NEUROG3上游的早期内胚层模式和胃内分泌细胞分化。使用hGOs建模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受体快速关联，激活信号并诱导上皮增殖。总之，这些研究描述了一种新的强大的体外系统，用于阐明人类胃部发育和疾病的潜在机制。

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  • 来源
    《Nature》 |2014年第7531期|400-404|共5页
  • 作者

    Kyle W. McCracken; Emily M. Cata; Calyn M. Crawford; Katie L. Sinagoga; Michael Schumacher; Briana E. Rockich; Yu-Hwai Tsai; Christopher N. Mayhew; Jason R. Spence; Yana Zavros; James M. Wells;

  • 作者单位

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA;

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA;

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA;

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA;

    Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267, USA;

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA;

    Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA;

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA;

    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA,Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA;

    Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267, USA;

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA,Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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