title: A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization.
abstract: The earliest aspects of human embryogenesis remain mysterious. To model patterning events in the human embryo, we used colonies of human embryonic stem cells (hESCs) grown on micropatterned substrate and differentiated with BMP4. These gastruloids recapitulate the embryonic arrangement of the mammalian germ layers and provide an assay to assess the structural and signaling mechanisms patterning the human gastrula. Structurally, high-density hESCs localize their receptors to transforming growth factor β at their lateral side in the center of the colony while maintaining apical localization of receptors at the edge. This relocalization insulates cells at the center from apically applied ligands while maintaining response to basally presented ones. In addition, BMP4 directly induces the expression of its own inhibitor, NOGGIN, generating a reaction-diffusion mechanism that underlies patterning. We develop a quantitative model that integrates edge sensing and inhibitors to predict human fate positioning in gastruloids and, potentially, the human embryo.
authors.affiliation: Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA; Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Etoc
authors.affiliation: Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA; Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Ruzo
authors.affiliation: Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kirst
authors.affiliation: Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA; Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Yoney
authors.affiliation: Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA.
authors.forename: M Zeeshan
authors.initials: MZ
authors.lastname: Ozair
authors.affiliation: Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY 10065, USA. Electronic address: brvnlou@rockefeller.edu.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Brivanlou
authors.affiliation: Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: siggiae@rockefeller.edu.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Siggia
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005775:Gastrula / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D008024:Ligands; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D051898:Smad1 Protein; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein
keywords: NOGGIN; bone morphogenetic protein; embryonic patterning; gastruloid; human embryonic stem cell; human gastrulation; polarized epithelium; reaction-diffusion; self-organization