title: Inhibition of TGFβ signaling promotes ground state pluripotency.
abstract: Embryonic stem (ES) cells are considered to exist in a ground state if shielded from differentiation triggers. Here we show that FGF4 and TGFβ signaling pathway inhibitors, designated R2i, not only provide the ground state pluripotency in production and maintenance of naïve ES cells from blastocysts of different mouse strains, but also maintain ES cells with higher genomic integrity following long-term cultivation compared with the chemical inhibition of the FGF4 and GSK3 pathways, known as 2i. Global transcriptome analysis of the ES cells highlights augmented BMP4 signaling pathway. The crucial role of the BMP4 pathway in maintaining the R2i ground state pluripotency is demonstrated by BMP4 receptor suppression, resulting in differentiation and cell death. In conclusion, by inhibiting TGFβ and FGF signaling pathways, we introduce a novel defined approach to efficiently establish the ground state pluripotency.
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, PO Box 19395-4644, Tehran, Iran.
authors.forename: Seyedeh-Nafiseh
authors.initials: SN
authors.lastname: Hassani
authors.forename: Mehdi
authors.initials: M
authors.lastname: Totonchi
authors.forename: Ali
authors.initials: A
authors.lastname: Sharifi-Zarchi
authors.forename: Sepideh
authors.initials: S
authors.lastname: Mollamohammadi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Pakzad
authors.forename: Sharif
authors.initials: S
authors.lastname: Moradi
authors.forename: Azam
authors.initials: A
authors.lastname: Samadian
authors.forename: Najmehsadat
authors.initials: N
authors.lastname: Masoudi
authors.forename: Shahab
authors.initials: S
authors.lastname: Mirshahvaladi
authors.forename: Ali
authors.initials: A
authors.lastname: Farrokhi
authors.forename: Boris
authors.initials: B
authors.lastname: Greber
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.forename: Davood
authors.initials: D
authors.lastname: Sabour
authors.forename: Mehdi
authors.initials: M
authors.lastname: Sadeghi
authors.forename: Ghasem Hosseini
authors.initials: GH
authors.lastname: Salekdeh
authors.forename: Hamid
authors.initials: H
authors.lastname: Gourabi
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Hossein
authors.initials: H
authors.lastname: Baharvand
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology*; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D016212:Transforming Growth Factor beta; C506614:mirdametinib; D004159:Diphenylamine
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