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Stage-specific signaling through TGFβ family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells

2011; The Company of Biologists; Volume: 138; Issue: 5 Linguagem: Inglês

10.1242/dev.055236

1477-9129

M. Cristina Nostro, Farida Sarangi, Shinichiro Ogawa, Audrey Holtzinger, Barbara Corneo, Xueling Li, Suzanne J. Micallef, In‐Hyun Park, Christina Basford, Michael B. Wheeler, George Q. Daley, Andrew G. Elefanty, Edouard G. Stanley, Gordon Keller,

Genetics and Neurodevelopmental Disorders

The generation of insulin-producing β-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 TGFβ 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.