RRC ID 4346
Author Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H.
Title Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling.
Journal Development
Abstract The canonical Wnt/beta-catenin signaling has remarkably diverse roles in embryonic development, stem cell self-renewal and cancer progression. Here, we show that stabilized expression of beta-catenin perturbed human embryonic stem (hES)-cell self-renewal, such that up to 80% of the hES cells developed into the primitive streak (PS)/mesoderm progenitors, reminiscent of early mammalian embryogenesis. The formation of the PS/mesoderm progenitors essentially depended on the cooperative action of beta-catenin together with Activin/Nodal and BMP signaling pathways. Intriguingly, blockade of BMP signaling completely abolished mesoderm generation, and induced a cell fate change towards the anterior PS progenitors. The PI3-kinase/Akt, but not MAPK, signaling pathway had a crucial role in the anterior PS specification, at least in part, by enhancing beta-catenin stability. In addition, Activin/Nodal and Wnt/beta-catenin signaling synergistically induced the generation and specification of the anterior PS/endoderm. Taken together, our findings clearly demonstrate that the orchestrated balance of Activin/Nodal and BMP signaling defines the cell fate of the nascent PS induced by canonical Wnt/beta-catenin signaling in hES cells.
Volume 135(17)
Pages 2969-79
Published 2008-9
DOI 10.1242/dev.021121
PII dev.021121
PMID 18667462
MeSH Activins / metabolism* Bone Morphogenetic Proteins / metabolism* Bone Morphogenetic Proteins / pharmacology Cell Differentiation / drug effects Cell Lineage* / drug effects Embryonic Stem Cells / cytology* Embryonic Stem Cells / drug effects Endoderm / cytology Endoderm / drug effects Endoderm / enzymology Humans MAP Kinase Signaling System / drug effects Mesoderm / cytology Mesoderm / drug effects Mesoderm / embryology Mesoderm / enzymology Nodal Protein Phosphatidylinositol 3-Kinases / antagonists & inhibitors Phosphatidylinositol 3-Kinases / metabolism Primitive Streak / cytology Primitive Streak / drug effects Protein Kinase Inhibitors / pharmacology Signal Transduction / drug effects Thermodynamics Time Factors Transforming Growth Factor beta / metabolism* Wnt Proteins / metabolism* beta Catenin / metabolism*
IF 5.763
Times Cited 165
Human embryonic stem cells KhES-1 KhES-3