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

M. Cristiostro | Zendy; Farida Sarangi | Zendy; Shinichiro Ogawa | Zendy; Audrey Holtzinger | Zendy; Barbara Corneo | Zendy; Xueling Li | Zendy; Suzanne J. Micallef | Zendy; InHyun Park | Zendy; Christina Basford | Zendy; Michael B. Wheeler | Zendy; George Q. Daley | Zendy; Andrew G. Elefanty | Zendy; Edouard G. Stanley | Zendy; Gordon Keller | Zendy

Open Access

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

Author(s) -

M. Cristiostro,

Farida Sarangi,

Shinichiro Ogawa,

Audrey Holtzinger,

Barbara Corneo,

Xueling Li,

Suzanne J. Micallef,

InHyun Park,

Christina Basford,

Michael B. Wheeler,

George Q. Daley,

Andrew G. Elefanty,

Edouard G. Stanley,

Gordon Keller

Publication year - 2011

Publication title -

development

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 3.754

H-Index - 325

eISSN - 1477-9129

pISSN - 0950-1991

DOI - 10.1242/dev.055236

Subject(s) - biology , wnt signaling pathway , endoderm , microbiology and biotechnology , induced pluripotent stem cell , germ layer , embryonic stem cell , stem cell , nodal signaling , signal transduction , genetics , embryogenesis , embryo , gene , gastrulation

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.

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