title: NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency.
abstract: Mesoderm is induced at the primitive streak (PS) and patterns subsequently into mesodermal subtypes and organ precursors. It is unclear whether mesoderm induction generates a multipotent PS progenitor or several distinct ones with restricted subtype potentials. We induced mesoderm in human pluripotent stem cells with ACTIVIN and BMP or with GSK3-β inhibition. Both approaches induced BRACHYURY(+) mesoderm of distinct PS-like identities, which had differing patterning potential. ACTIVIN and BMP-induced mesoderm patterned into cardiac but not somitic subtypes. Conversely, PS precursors induced by GSK3-β inhibition did not generate lateral plate and cardiac mesoderm and favored instead somitic differentiation. The mechanism of these cell fate decisions involved mutual repression of NANOG and CDX2. Although NANOG was required for cardiac specification but blocked somitic subtypes, CDX2 was required for somitic mesoderm but blocked cardiac differentiation. In sum, rather than forming a common PS progenitor, separate induction mechanisms distinguish human mesoderm subtypes.
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK. Electronic address: sm687@cam.ac.uk.
authors.forename: Sasha
authors.initials: S
authors.lastname: Mendjan
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Mascetti
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ortmann
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Mariaestela
authors.initials: M
authors.lastname: Ortiz
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Dyah W
authors.initials: DW
authors.lastname: Karjosukarso
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ng
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moreau
authors.affiliation: The Anne McLaren Laboratory for Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0SZ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK. Electronic address: ralp2@cam.ac.uk.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Pedersen
mesh_terms: D028341:Activins / Q000378:metabolism; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D002460:Cell Line; D019070:Cell Lineage; D005326:Fetal Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D054240:Primitive Streak / Q000166:cytology; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D028341:Activins; D019485:Bone Morphogenetic Proteins; D000071616:CDX2 Transcription Factor; D005326:Fetal Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C491270:CDX2 protein, human; C486780:NANOG protein, human