title: Local BMP-SMAD1 signaling increases LIF receptor-dependent STAT3 responsiveness and primed-to-naive mouse pluripotent stem cell conversion frequency.
abstract: Conversion of EpiSCs to naive ESCs is a rare event that is driven by the reestablishment of the naive transcription factor network. In mice, STAT3 activation is sufficient to drive conversion of EpiSCs to the naive pluripotent stem cell (PSC) state. However, the lack of responsiveness of EpiSCs to LIF presents a bottleneck in this conversion process. Here, we demonstrate that local accumulation of BMP-SMAD1 signaling, in cooperation with GP130 ligands, enhances the recovery of LIF responsiveness by directly controlling transcription of the LIF receptor (Lif-r). Addition of BMP and LIF to EpiSCs increases both LIF responsiveness and conversion frequencies to naive PSCs. Mechanistically, we show that the transcriptional cofactor P300 plays a critical role by mediating complex formation between STAT3 and SMAD1. This demonstration of how the local microenvironment or stem cell niche reactivates dormant signaling responsiveness and developmental potential may be applicable to other stem cell niche-containing systems.
authors: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors: Kento
authors: K
authors: Onishi
authors: Centre for Stem Cells and Tissue Engineering, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
authors: Peter D
authors: PD
authors: Tonge
authors: Centre for Stem Cells and Tissue Engineering, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada ; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors: Andras
authors: A
authors: Nagy
authors: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada ; Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada ; The Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada ; Heart and Stroke/Richard Lewar Centre of Excellence, 150 College Street, Toronto, ON M5S 3E2, Canada ; McEwan Centre for Regenerative Medicine, University Health Network, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Peter W
authors: PW
authors: Zandstra
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D053606:Receptors, OSM-LIF; C497399:SMAD1 protein, human; D050796:STAT3 Transcription Factor; D051898:Smad1 Protein; D000469:Alkaline Phosphatase