期刊
STEM CELLS
卷 31, 期 6, 页码 1086-1096出版社
WILEY
DOI: 10.1002/stem.1344
关键词
Embryonic stem cells; Endoderm; Intestine differentiation; In vitro differentiation
资金
- Japan Society for the Promotion of Science [21390280, 21790671]
- Global COE grant (Cell Fate Regulation Research and Education Unit), the Japan Society for the Promotion of Science
- Realization of Regenerative Medicine from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Japan
- Grants-in-Aid for Scientific Research [21390280, 21790671] Funding Source: KAKEN
The studies of differentiation of mouse or human embryonic stem cells (hESCs) into specific cell types of the intestinal cells would provide insights to the understanding of intestinal development and ultimately yield cells for the use in future regenerative medicine. Here, using an in vitro differentiation procedure of pluripotent stem cells into definitive endoderm (DE), inductive signal pathways' guiding differentiation into intestinal cells was investigated. We found that activation of Wnt/beta-catenin and inhibition of Notch signaling pathways, by simultaneous application of 6-bromoindirubin-3'-oxime (BIO), a glycogen synthase kinase-3 beta inhibitor, and N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenylglycine-1,1dimethylethyl ester (DAPT), a known gamma-secretase inhibitor, efficiently induced intestinal differentiation of ESCs cultured on feeder cell. BIO and DAPT patterned the DE at graded concentrations. Upon prolonged culture on feeder cells, all four intestinal differentiated cell types, the absorptive enterocytes and three types of secretory cells (goblet cells, enteroendocrine cells, and Paneth cells), were efficiently differentiated from mouse and hESC-derived intestinal epithelium cells. Further investigation revealed that in the mouse ESCs, fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signaling act synergistically with BIO and DAPT to potentiate differentiation into the intestinal epithelium. However, in hESCs, FGF signaling inhibited, and BMP signaling did not affect differentiation into the intestinal epithelium. We concluded that Wnt and Notch signaling function to pattern the anterior-posterior axis of the DE and control intestinal differentiation.
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