CDX2-induced intestinal metaplasia in human gastric organoids derived from induced pluripotent stem cells
Takahiro Koide,
Michiyo Koyanagi-Aoi,
Keiichiro Uehara,
Yoshihiro Kakeji,
Takashi Aoi
Affiliations
Takahiro Koide
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Japan; Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan
Michiyo Koyanagi-Aoi
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe, Japan
Keiichiro Uehara
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Japan; Department of Diagnostic Pathology, Graduate School of Medicine, Kobe University, Kobe, Japan
Yoshihiro Kakeji
Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan
Takashi Aoi
Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan; Department of iPS Cell Applications, Graduate School of Medicine, Kobe University, Kobe, Japan; Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, Kobe, Japan; Corresponding author
Summary: Intestinal metaplasia is related to gastric carcinogenesis. Previous studies have suggested the important role of CDX2 in intestinal metaplasia, and several reports have shown that the overexpression of CDX2 in mouse gastric mucosa caused intestinal metaplasia. However, no study has examined the induction of intestinal metaplasia using human gastric mucosa. In the present study, to produce an intestinal metaplasia model in human gastric mucosa in vitro, we differentiated human-induced pluripotent stem cells (hiPSC) to gastric organoids, followed by the overexpression of CDX2 using a tet-on system. The overexpression of CDX2 induced, although not completely, intestinal phenotypes and the enhanced expression of many, but not all, intestinal genes and previously reported intestinal metaplasia-related genes in the gastric organoids. This model can help clarify the mechanisms underlying intestinal metaplasia and carcinogenesis in human gastric mucosa and develop therapies to restitute precursor conditions of gastric cancer to normal mucosa.
