Journal
DEVELOPMENT
Volume 138, Issue 5, Pages 861-871Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.055236
Keywords
Endoderm differentiation; Human embryonic stem cells; Human induced pluripotent stem cells; beta-Cell; Pancreas
Categories
Funding
- NIH/NIDDK [U01-DK072513]
- JDRF
- ASCC
- NHMRC (Australia)
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The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGF beta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25% C-peptide+cells.
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