Construction of a mammalian embryo model from stem cells organized by a morphogen signalling centre

Nat Commun. 2021 Jun 2;12(1):3277. doi: 10.1038/s41467-021-23653-4.

Abstract

Generating properly differentiated embryonic structures in vitro from pluripotent stem cells remains a challenge. Here we show that instruction of aggregates of mouse embryonic stem cells with an experimentally engineered morphogen signalling centre, that functions as an organizer, results in the development of embryo-like entities (embryoids). In situ hybridization, immunolabelling, cell tracking and transcriptomic analyses show that these embryoids form the three germ layers through a gastrulation process and that they exhibit a wide range of developmental structures, highly similar to neurula-stage mouse embryos. Embryoids are organized around an axial chordamesoderm, with a dorsal neural plate that displays histological properties similar to the murine embryo neuroepithelium and that folds into a neural tube patterned antero-posteriorly from the posterior midbrain to the tip of the tail. Lateral to the chordamesoderm, embryoids display somitic and intermediate mesoderm, with beating cardiac tissue anteriorly and formation of a vasculature network. Ventrally, embryoids differentiate a primitive gut tube, which is patterned both antero-posteriorly and dorso-ventrally. Altogether, embryoids provide an in vitro model of mammalian embryo that displays extensive development of germ layer derivatives and that promises to be a powerful tool for in vitro studies and disease modelling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics*
  • Ectoderm / cytology
  • Ectoderm / growth & development
  • Ectoderm / metabolism
  • Embryo, Mammalian
  • Embryoid Bodies / cytology
  • Embryoid Bodies / metabolism*
  • Embryonic Development / genetics*
  • Endoderm / cytology
  • Endoderm / growth & development
  • Endoderm / metabolism
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism
  • Gastrula / cytology
  • Gastrula / growth & development
  • Gastrula / metabolism
  • Gastrulation / genetics
  • Gene Expression Regulation, Developmental
  • HMGB Proteins / genetics
  • HMGB Proteins / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Neural Tube / cytology
  • Neural Tube / growth & development
  • Neural Tube / metabolism
  • Notochord / cytology
  • Notochord / growth & development
  • Notochord / metabolism
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism
  • Signal Transduction / genetics*

Substances

  • GATA6 Transcription Factor
  • Gata6 protein, mouse
  • HMGB Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • SOXF Transcription Factors
  • Sox17 protein, mouse