title: The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification.
abstract: The precise relationship of embryonic stem cells (ESCs) to cells in the mouse embryo remains controversial. We present transcriptional and functional data to identify the embryonic counterpart of ESCs. Marker profiling shows that ESCs are distinct from early inner cell mass (ICM) and closely resemble pre-implantation epiblast. A characteristic feature of mouse ESCs is propagation without ERK signalling. Single-cell culture reveals that cell-autonomous capacity to thrive when the ERK pathway is inhibited arises late during blastocyst development and is lost after implantation. The frequency of deriving clonal ESC lines suggests that all E4.5 epiblast cells can become ESCs. We further show that ICM cells from early blastocysts can progress to ERK independence if provided with a specific laminin substrate. These findings suggest that formation of the epiblast coincides with competence for ERK-independent self-renewal in vitro and consequent propagation as ESC lines.
authors.affiliation: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road Cambridge CB2 1QR, UK.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Boroviak
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK.
authors.forename: Remco
authors.initials: R
authors.lastname: Loos
authors.affiliation: 1] Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road Cambridge CB2 1QR, UK [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK [3] Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.affiliation: 1] Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road Cambridge CB2 1QR, UK [2] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
authors.affiliation: 1] Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road Cambridge CB2 1QR, UK [2] Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nichols
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D053624:Blastocyst Inner Cell Mass / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D002999:Clone Cells; D046149:Embryo Culture Techniques; D010064:Embryo Implantation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005855:Germ Layers / Q000166:cytology / Q000201:enzymology*; D005865:Gestational Age; D007797:Laminin / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D007797:Laminin; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases