FGF inhibition directs BMP4-mediated differentiation of human embryonic stem cells to syncytiotrophoblast.
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 βhCG 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.
Department of Vertebrate Genomics, Molecular Embryology and Aging Group, Max Planck Institute for Molecular Genetics, Berlin, Germany. sudheer@molgen.mpg.de
Smita
S
Sudheer
Raghu
R
Bhushan
Beatrix
B
Fauler
Hans
H
Lehrach
James
J
Adjaye
D028341:Activins / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002459:Cell Fusion; D002460:Cell Line; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D055457:Nodal Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D055415:Bone Morphogenetic Protein 4; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018997:Chorionic Gonadotropin, beta Subunit, Human; D004149:Dioxoles; D018398:Homeodomain Proteins; D055457:Nodal Protein; D011758:Pyrroles; C105686:SU 5402; D051153:Wnt Proteins; D028341:Activins; D005346:Fibroblast Growth Factors