Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids

• Published in: Nature (London) Vol. 562; no. 7726; pp. 272 - 276
• Main Authors: Beccari, Leonardo, Moris, Naomi, Girgin, Mehmet, Turner, David A., Baillie-Johnson, Peter, Cossy, Anne-Catherine, Lutolf, Matthias P., Duboule, Denis, Arias, Alfonso Martinez
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2018; Nature Publishing Group
• Subjects: 13; 13/100; 14; 14/1; 14/19; 38; 38/39; 38/91; 631/136/1455; 631/532/2117; Animals; Axes (reference lines); Bioinformatics; Body Patterning - genetics; Datasets; Displays (Marketing); Elongation; Embryo; Embryo cells; Embryonic stem cells; Embryos; Gastrula - cytology; Gastrula - embryology; Gastrula - metabolism; Gastrulation; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genes; Genes, Homeobox - genetics; Genetic aspects; Genomes; Humanities and Social Sciences; Implantation; In Vitro Techniques; Kinases; Laboratory rats; Letter; Mammals; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; multidisciplinary; Organoids - cytology; Organoids - embryology; Organoids - metabolism; Principal components analysis; Science; Science (multidisciplinary); Stem cell research; Stem cell transplantation; Stem cells; Time Factors; Transcription; Transcription (Genetics); Transcription factors; Uterus; Supplementary Information File; AGGREGATION AFTER (AA); Hoxd Genes; Whole-mount In Situ Hybridization (WISH); Mouse ESC
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0578-0

The emergence of multiple axes is an essential element in the establishment of the mammalian body plan. This process takes place shortly after implantation of the embryo within the uterus and relies on the activity of gene regulatory networks that coordinate transcription in space and time. Whereas genetic approaches have revealed important aspects of these processes 1 , a mechanistic understanding is hampered by the poor experimental accessibility of early post-implantation stages. Here we show that small aggregates of mouse embryonic stem cells (ESCs), when stimulated to undergo gastrulation-like events and elongation in vitro, can organize a post-occipital pattern of neural, mesodermal and endodermal derivatives that mimic embryonic spatial and temporal gene expression. The establishment of the three major body axes in these ‘gastruloids’ 2 , 3 suggests that the mechanisms involved are interdependent. Specifically, gastruloids display the hallmarks of axial gene regulatory systems as exemplified by the implementation of collinear Hox transcriptional patterns along an extending antero-posterior axis. These results reveal an unanticipated self-organizing capacity of aggregated ESCs and suggest that gastruloids could be used as a complementary system to study early developmental events in the mammalian embryo. Cultures grown from small aggregates of mouse embryonic stem cells can be induced to organize spatial and temporal patterns of gene expression that parallel those of the early embryo, offering a potentially useful system for studying early development.