Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/beta-catenin, Activin/Nodal and BMP signaling.
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.
Sumi
Tomoyuki
T
Laboratory of Embryonic Stem Cell Research, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Shogoin, Kyoto 606-8507, Japan.
Tsuneyoshi
Norihiro
N
Nakatsuji
Norio
N
Suemori
Hirofumi
H
D028341:Activins / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects; D004707:Endoderm / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D055457:Nodal Protein; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054240:Primitive Streak / Q000166:cytology / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013816:Thermodynamics; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D028341:Activins; D019485:Bone Morphogenetic Proteins; D055457:Nodal Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; C526007:NODAL protein, human