title: Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells.
abstract: Mouse embryonic stem cells (mESCs) are clonal populations derived from preimplantation mouse embryos that can be propagated in vitro and, when placed into blastocysts, contribute to all tissues of the embryo and integrate into the normal morphogenetic processes, i.e. they are pluripotent. However, although they can be steered to differentiate in vitro into all cell types of the organism, they cannot organise themselves into structures that resemble embryos. When aggregated into embryoid bodies they develop disorganised masses of different cell types with little spatial coherence. An exception to this rule is the emergence of retinas and anterior cortex-like structures under minimal culture conditions. These structures emerge from the cultures without any axial organisation. Here, we report that small aggregates of mESCs, of about 300 cells, self-organise into polarised structures that exhibit collective behaviours reminiscent of those that cells exhibit in early mouse embryos, including symmetry breaking, axial organisation, germ layer specification and cell behaviour, as well as axis elongation. The responses are signal specific and uncouple processes that in the embryo are tightly associated, such as specification of the anteroposterior axis and anterior neural development, or endoderm specification and axial elongation. We discuss the meaning and implications of these observations and the potential uses of these structures which, because of their behaviour, we suggest to call 'gastruloids'.
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Susanne C
authors.initials: SC
authors.lastname: van den Brink
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Baillie-Johnson
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Tina
authors.initials: T
authors.lastname: Balayo
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Anna-Katerina
authors.initials: AK
authors.lastname: Hadjantonakis
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Nowotschin
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Turner
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK ama11@hermes.cam.ac.uk.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martinez Arias
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002449:Cell Aggregation / Q000502:physiology; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology; D053595:Embryonic Stem Cells / Q000502:physiology*; D005434:Flow Cytometry; D005855:Germ Layers / Q000196:embryology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009420:Nervous System / Q000196:embryology*
keywords: Axial elongation; Endoderm; Gastrulation; Live cell imaging; Mesoderm; Mouse; Neural ectoderm; Pattern formation; Polarisation; Self-organisation; Symmetry breaking