Publication Date:
2014-11-05
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270898/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270898/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- 5P30DK034933/DK/NIDDK NIH HHS/ -- K01 DK091415/DK/NIDDK NIH HHS/ -- K01DK091415/DK/NIDDK NIH HHS/ -- P30 DK078392/DK/NIDDK NIH HHS/ -- P30 DK0789392/DK/NIDDK NIH HHS/ -- R01 DK080823/DK/NIDDK NIH HHS/ -- R01 DK092456/DK/NIDDK NIH HHS/ -- R01 DK098350/DK/NIDDK NIH HHS/ -- R01 GM072915/GM/NIGMS NIH HHS/ -- R01DK080823/DK/NIDDK NIH HHS/ -- R01DK092456/DK/NIDDK NIH HHS/ -- T32 GM063483/GM/NIGMS NIH HHS/ -- U54 RR025216/RR/NCRR NIH HHS/ -- UL1 RR026314/RR/NCRR NIH HHS/ -- UL1 TR000077/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):400-4. doi: 10.1038/nature13863. Epub 2014 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; 1] Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA [2] Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA. ; 1] Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA [2] Division of Endocrinology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363776" target="_blank"〉PubMed〈/a〉
Keywords:
Cell Differentiation
;
Helicobacter Infections/*physiopathology
;
Helicobacter pylori
;
Humans
;
*Models, Biological
;
*Organogenesis
;
Organoids/*cytology/microbiology
;
Pluripotent Stem Cells/*cytology
;
Signal Transduction
;
Stomach/*cytology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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