BMP4 induces primitive endoderm but not trophectoderm in monkey embryonic stem cells.
Monkey embryonic stem (ES) cells share similar characteristics to human ES cells and provide a primate model of allotransplantation, which allows to validate efficacy and safety of cell transplantation therapy in regenerative medicine. Bone morphogenetic protein 4 (BMP4) is known to promote trophoblast differentiation in human ES cells in contrast to mouse ES cells where BMP4 synergistically maintains self-renewal with leukemia inhibitory factor (LIF), which represents a significant difference in signal transduction of self-renewal and differentiation between murine and human ES cells. As the similarity of the differentiation mechanism between monkey and human ES cells is of critical importance for their use as a primate model system, we investigated whether BMP4 induces trophoblast differentiation in monkey ES cells. Interestingly, BMP4 did not induce trophoblast differentiation, but instead induced primitive endoderm differentiation. Prominent downregulation of Sox2, which plays a pivotal role not only in pluripotency but also placenta development, was observed in cells treated with BMP4. In addition, upregulation of Hand1, Cdx2, and chorionic gonadotropin beta (CG-beta), which are markers of trophoblast, was not observed. In contrast, BMP4 induced significant upregulation of Gata6, Gata4, and LamininB1, suggesting differentiation into the primitive endoderm, visceral endoderm, and parietal endoderm, respectively. The threshold of BMP4 activity was estimated as about 10 ng/mL. These findings suggest that BMP4 induced differentiation into the primitive endoderm lineage but not into trophoblast in monkey ES cells.
Kobayashi
Masashi
M
Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan.
Takada
Tatsuyuki
T
Takahashi
Kentaro
K
Noda
Yoichi
Y
Torii
Ryuzo
R
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D004707:Endoderm / Q000166:cytology* / Q000502:physiology; D050991:GATA4 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D055748:SOXB1 Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
D051792:Basic Helix-Loop-Helix Proteins; D055415:Bone Morphogenetic Protein 4; D006063:Chorionic Gonadotropin; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; D018398:Homeodomain Proteins; D007797:Laminin; D055748:SOXB1 Transcription Factors; C097341:helix-loop-helix protein, eHAND