title: Stat3 activation is limiting for reprogramming to ground state pluripotency.
abstract: The cytokine leukemia inhibitory factor (Lif) sustains self-renewal of mouse embryonic and induced pluripotent stem cells by activating Jak kinase and the transcription factor Stat3. Here we investigate whether Jak/Stat3 may also contribute to induction of pluripotency. EpiSCs derived from postimplantation embryos express low levels of Lif receptor and Stat3. We introduced into EpiSCs a Jak/Stat3 activating receptor (GY118F) responsive to granulocyte colony stimulating factor (Gcsf). On transfer to ground state culture, in which MAPK signaling and glycogen synthase kinase are inhibited, Gcsf induced transcriptional resetting and functional reprogramming. Activation of a tamoxifen-regulatable fusion, Stat3ER(T2), also converted EpiSCs into chimera-competent iPSCs. We exploited GY118F to increase Jak/Stat3 activity during somatic cell reprogramming. Incompletely reprogrammed cells derived from neural stem cells or fibroblasts responded to Gcsf with elevated frequencies of progression to ground state pluripotency. These findings indicate that Jak/Stat3 participate directly in molecular reprogramming and that activation of this pathway is a limiting component.
authors.affiliation: Wellcome Trust Centre for Stem Cell Research & Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Anouk L
authors.initials: AL
authors.lastname: van Oosten
authors.forename: Thorold W
authors.initials: TW
authors.lastname: Theunissen
authors.forename: Ge
authors.initials: G
authors.lastname: Guo
authors.forename: Jose C R
authors.initials: JC
authors.lastname: Silva
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D057026:Induced Pluripotent Stem Cells; D053605:Leukemia Inhibitory Factor / Q000502:physiology; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor
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