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Cell Journal، جلد ۱۶، شماره Suppl ۱، صفحات ۱۴-۱۴
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عنوان انگلیسی Is-14: The Augmented BMP Pluripotency Pathway via TGF-Β Suppression Maintains The Ground State of Embryonic Stem Cells Self-Renewal
چکیده انگلیسی مقاله Objective: Embryonic stem cells (ESCs) are pluripotent cells with capacity for differentiation into all cell types that are most frequently established from the inner cell mass (ICM) of blastocysts. However, the efficiency of ESC generation is influenced by genetic background in mice; as some strains are recalcitrance to mESC line derivation. Recently, we identified the suppression of mitogen-activated protein kinase (MAPK) kinase (also known as MEK) and transforming growth factor β (TGFβ) type I receptors by PD0325901 and SB431542, respectively-the combination named as Royan 2 inhibitors or R2i- enables the highly efficient derivation of pluripotent mouse embryonic stem cells (mESCs) from different strains. The cellular and molecular analysis indicated that R2i supports the ground state of pluripotency in a different route from wellknown 2i condition which the latter inhibits MEK and glycogen synthase kinase 3 (GSK3) by PD0325901 and CHIR99021, respectively. Materials and Methods: To investigate the molecular basis by which R2i maintains pluripotency, microarray analysis was performed in two mESC lines which were simultaneously cultivated for ten times in 2i and R2i. Our data revealed the significant elevation of BMP4-associated genes in R2i-grown cells in comparison to 2i-grown cells. For functional pathway analysis, BMP4 signaling was inhibited in R2i- and 2igrown cells by adding noggin (500 nM) or noggin (250 nM) plus dorsomorphin (5 μM), two potent BMP signaling inhibitors. Results: We observed no significant changes in the morphology of ES cells and Oct4 expression in 2igrown cells in the presence of the BMP4 signaling inhibitors, even after several passages. However, the selfrenewal capability of R2i-grown cells was strongly and adversely affected over a brief time period Conclusion: Our analysis highlighted BMP signaling as a pathway markedly induced by TGFβ inhibition in R2i-grown cells. Since several studies have indicated that BMP4 signaling through Smad1/5/8 suppresses developmental regulators such as neuroectodermal-associated genes and FGF signaling, we here demonstrated that R2i via activation of the ‘differentiation-inhibiting’ BMP4 signaling enhanced pluripotent state in mESCs even though this pathway seems to be dispensable in 2i culture condition.
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نشانی اینترنتی http://celljournal.org/journal/article/abstract/308
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