非表示:
キーワード:
Activins/metabolism
Animals
Autocrine Communication/drug effects/genetics
Benzamides/pharmacology
Bone Morphogenetic Protein 4/*pharmacology
Cell Differentiation/*drug effects/genetics
Cell Fusion
Cell Line
Chorionic Gonadotropin, beta Subunit, Human/metabolism
Dioxoles/pharmacology
Embryonic Stem Cells/*cytology/drug effects/metabolism
Endoderm/cytology/drug effects/metabolism
Female
Fibroblast Growth Factors/*antagonists & inhibitors/metabolism
Gene Expression Regulation/drug effects
Homeodomain Proteins/genetics/metabolism
Humans
Mesoderm/cytology/drug effects/metabolism
Mice
Models, Biological
Nodal Protein/antagonists & inhibitors/metabolism
Placenta/drug effects/metabolism
Pregnancy
Pyrroles/pharmacology
Signal Transduction/drug effects/genetics
Trophoblasts/*cytology/drug effects/metabolism
Wnt Proteins/metabolism
要旨:
Bone morphogenetic protein (BMP) signaling is known to support differentiation of human embryonic stem cells (hESCs) into mesoderm and extraembryonic lineages, whereas other signaling pathways can largely influence this lineage specification. Here, we set out to reinvestigate the influence of ACTIVIN/NODAL and fibroblast growth factor (FGF) pathways on the lineage choices made by hESCs during BMP4-driven differentiation. We show that BMP activation, coupled with inhibition of both ACTIVIN/NODAL and FGF signaling, induces differentiation of hESCs, specifically to betahCG hormone-secreting multinucleated syncytiotrophoblast and does not support induction of embryonic and extraembryonic lineages, extravillous trophoblast, and primitive endoderm. It has been previously reported that FGF2 can switch BMP4-induced hESC differentiation outcome to mesendoderm. Here, we show that FGF inhibition alone, or in combination with either ACTIVIN/NODAL inhibition or BMP activation, supports hESC differentiation to hCG-secreting syncytiotrophoblast. We show that the inhibition of the FGF pathway acts as a key in directing BMP4-mediated hESC differentiation to syncytiotrophoblast.
