The DOI matches its Crossref record; 78 of the 78 references it cites were found in a registry or an index.
Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells
Open accessAbstract
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’.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Cerebral organoids model human brain development and microcephaly
Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., & Knoblich, J. A. (2013) · Nature · doi:10.1038/nature12517 · Cited by 5,372
Self-organizing optic-cup morphogenesis in three-dimensional culture
Eiraku, M., Takata, N., Ishibashi, H., Kawada, M., Sakakura, E., Okuda, S., Sekiguchi, K., Adachi, T., & Sasai, Y. (2011) · Nature · doi:10.1038/nature09941 · Cited by 2,001
Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture
Ying, Q.-L., Stavridis, M., Griffiths, D., Li, M., & Smith, A. (2003) · Nature Biotechnology · doi:10.1038/nbt780 · Cited by 1,504
Self-formation of optic cups and storable stratified neural retina from human ESCs
Nakano, T., Ando, S., Takata, N., Kawada, M., Muguruma, K., Sekiguchi, K., Saito, K., Yonemura, S., Eiraku, M., & Sasai, Y. (2012) · Cell stem cell · doi:10.1016/j.stem.2012.05.009 · Cited by 1,447
A method to recapitulate early embryonic spatial patterning in human embryonic stem cells
Warmflash, A., Sorre, B., Etoc, F., Siggia, E. D., & Brivanlou, A. H. (2014) · Nature Methods · doi:10.1038/nmeth.3016 · Cited by 885
Expression pattern of the mouse T gene and its role in mesoderm formation
Wilkinson, D. G., Bhatt, S., & Herrmann, B. G. (1990) · Nature · doi:10.1038/343657a0 · Cited by 855
Development of definitive endoderm from embryonic stem cells in culture
Kubo, A., Shinozaki, K., Shannon, J. M., Kouskoff, V., Kennedy, M., Woo, S., Fehling, H. J., & Keller, G. (2004) · Development · doi:10.1242/dev.01044 · Cited by 838
Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo
Arnold, S. J., & Robertson, E. J. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2618 · Cited by 816 · cited 4×
“Signalling and pattern formation during aggregate differentiation In the early postimplantation epiblast, cell fate assignments are triggered by interactions between BMP, Nodal, Wnt signalling and their antagonists, and lead to the partitioning of the embryo into anterior neuroectodermal and posterior mesendodermal po…”
InfluentialDirected differentiation of telencephalic precursors from embryonic stem cells
Watanabe, K., Kamiya, D., Nishiyama, A., Katayama, T., Nozaki, S., Kawasaki, H., Watanabe, Y., Mizuseki, K., & Sasai, Y. (2005) · Nature Neuroscience · doi:10.1038/nn1402 · Cited by 787
Direct Neural Fate Specification from Embryonic Stem Cells
Tropepe, V., Hitoshi, S., Sirard, C., Mak, T. W., Rossant, J., & van der Kooy, D. (2001) · Neuron · doi:10.1016/s0896-6273(01)00263-x · Cited by 756
Depletion of definitive gut endoderm in Sox17 -null mutant mice
Kanai-Azuma, M., Kanai, Y., Gad, J. M., Tajima, Y., Taya, C., Kurohmaru, M., Sanai, Y., Yonekawa, H., Yazaki, K., Tam, P. P. L., et al. (2002) · Development · doi:10.1242/dev.129.10.2367 · Cited by 704
Sasaki, H., & Hogan, B. L. M. (1993) · Development · doi:10.1242/dev.118.1.47 · Cited by 667
Requirement for β-Catenin in Anterior-Posterior Axis Formation in Mice
Huelsken, J., Vogel, R., Brinkmann, V., Erdmann, B., Birchmeier, C., & Birchmeier, W. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.148.3.567 · Cited by 660
Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse
Rossant, J., & Tam, P. P. L. (2009) · Development · doi:10.1242/dev.017178 · Cited by 631
Gene function in mouse embryogenesis: get set for gastrulation
Tam, P. P. L., & Loebel, D. A. F. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2084 · Cited by 602
Gadue, P., Huber, T. L., Paddison, P. J., & Keller, G. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603916103 · Cited by 560
Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells
Kalmar, T., Lim, C., Hayward, P., Muñoz-Descalzo, S., Nichols, J., Garcia-Ojalvo, J., & Martinez Arias, A. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000149 · Cited by 558
Self-citationWood, H. B., & Episkopou, V. (1999) · Mechanisms of Development · doi:10.1016/s0925-4773(99)00116-1 · Cited by 550 · cited 5×
“Acknowledgements We thank K. Niakan for the Sox17::GFP cell line, E. Davies for sharing data and J. Brickman, J. Briscoe, S. Mun ̃oz-Descalzo, J. Nichols, A. Perea-Gomez, C. Schröeter, T. Rodriguez and C. Stern for discussions and constructive criticisms.”
InfluentialWnt Signaling and the Polarity of the Primary Body Axis
Petersen, C. P., & Reddien, P. W. (2009) · Cell · doi:10.1016/j.cell.2009.11.035 · Cited by 550
Fehling, H. J., Lacaud, G., Kubo, A., Kennedy, M., Robertson, S., Keller, G., & Kouskoff, V. (2003) · Development · doi:10.1242/dev.00589 · Cited by 500
Monaghan, A. P., Kaestner, K. H., Grau, E., & Schütz, G. (1993) · Development · doi:10.1242/dev.119.3.567 · Cited by 497
How we are shaped: The biomechanics of gastrulation
Keller, R., Davidson, L. A., & Shook, D. R. (2003) · Differentiation · doi:10.1046/j.1432-0436.2003.710301.x · Cited by 494
Wnt Signaling Mediates Self-Organization and Axis Formation in Embryoid Bodies
ten Berge, D., Koole, W., Fuerer, C., Fish, M., Eroglu, E., & Nusse, R. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.09.013 · Cited by 477
Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L., & Robertson, E. J. (1998) · Cell · doi:10.1016/s0092-8674(00)81407-5 · Cited by 466
Self-Organizing Properties of Mouse Pluripotent Cells Initiate Morphogenesis upon Implantation
Bedzhov, I., & Zernicka-Goetz, M. (2014) · Cell · doi:10.1016/j.cell.2014.01.023 · Cited by 448
Neural induction: old problem, new findings, yet more questions
Stern, C. D. (2005) · Development · doi:10.1242/dev.01794 · Cited by 421 · cited 1×
“The latter requires suppression of Nodal, BMP and Wnt signalling (Andoniadou and Martinez-Barbera, 2013; Stern, 2005) and this, in terms of patterning anterior and posterior domains, can only be achieved by a localised source which, in the embryo, is provided by the AVE. Consistent with this,…”
Gastrulation: from cells to embryo
(2005) · Choice Reviews Online · doi:10.5860/choice.42-4013 · Cited by 415
Perea-Gomez, A., Vella, F. D. J., Shawlot, W., Oulad-Abdelghani, M., Chazaud, C., Meno, C., Pfister, V., Chen, L., Robertson, E., Hamada, H., et al. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00321-0 · Cited by 406
Kwon, G. S., Viotti, M., & Hadjantonakis, A.-K. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.07.017 · Cited by 402
Self-citationNext-Generation Regenerative Medicine: Organogenesis from Stem Cells in 3D Culture
Sasai, Y. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.04.009 · Cited by 401
THE MECHANICS OF SEA URCHIN DEVELOPMENT, STUDIED BY OPERATIVE METHODS
HORSTADIUS, S. (1939) · Biological Reviews · doi:10.1111/j.1469-185x.1939.tb00929.x · Cited by 394
Keller, R., & Danilchik, M. (1988) · Development · doi:10.1242/dev.103.1.193 · Cited by 368
The role and regulation of blebs in cell migration
Paluch, E. K., & Raz, E. (2013) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2013.05.005 · Cited by 365
Gastrulation: Making and Shaping Germ Layers
Solnica-Krezel, L., & Sepich, D. S. (2012) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154043 · Cited by 363
Expression pattern of the Brachyury gene in whole-mount T WIS/T WIS mutant embryos
Herrmann, B. G. (1991) · Development · doi:10.1242/dev.113.3.913 · Cited by 348
Embryoid bodies: an in vitro model of mouse embryogenesis
Desbaillets, I., Ziegler, U., Groscurth, P., & Gassmann, M. (2000) · Experimental Physiology · doi:10.1017/s0958067000021047 · Cited by 313
Niakan, K. K., Ji, H., Maehr, R., Vokes, S. A., Rodolfa, K. T., Sherwood, R. I., Yamaki, M., Dimos, J. T., Chen, A. E., Melton, D. A., et al. (2010) · Genes & Development · doi:10.1101/gad.1833510 · Cited by 308
Ferrer-Vaquer, A., Piliszek, A., Tian, G., Aho, R. J., Dufort, D., & Hadjantonakis, A.-K. (2010) · BMC Developmental Biology · doi:10.1186/1471-213x-10-121 · Cited by 299
Self-citationPrimitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3
Rivera-Pérez, J. A., & Magnuson, T. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.09.012 · Cited by 292
Stem cells, signals and vertebrate body axis extension
Wilson, V., Olivera-Martinez, I., & Storey, K. G. (2009) · Development · doi:10.1242/dev.021246 · Cited by 290
Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation
Wataya, T., Ando, S., Muguruma, K., Ikeda, H., Watanabe, K., Eiraku, M., Kawada, M., Takahashi, J., Hashimoto, N., & Sasai, Y. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803078105 · Cited by 270
Tbx6,a Mouse T-Box Gene Implicated in Paraxial Mesoderm Formation at Gastrulation
Chapman, D. L., Agulnik, I., Hancock, S., Silver, L. M., & Papaioannou, V. E. (1996) · Developmental Biology · doi:10.1006/dbio.1996.0326 · Cited by 255
Tcf3: a transcriptional regulator of axis induction in the early embryo
Merrill, B. J., Pasolli, H. A., Polak, L., Rendl, M., García-García, M. J., Anderson, K. V., & Fuchs, E. (2004) · Development · doi:10.1242/dev.00935 · Cited by 242
The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo
Norris, D. P., Brennan, J., Bikoff, E. K., & Robertson, E. J. (2002) · Development · doi:10.1242/dev.129.14.3455 · Cited by 240
Foxa2 regulates polarity and epithelialization in the endoderm germ layer of the mouse embryo
Burtscher, I., & Lickert, H. (2009) · Development · doi:10.1242/dev.028415 · Cited by 222
Stem cells, signals and vertebrate body axis extension
Wilson, V., Olivera-Martinez, I., & Storey, K. G. (2009) · Development · doi:10.1242/dev.039172 · Cited by 222
In vitro organogenesis in three dimensions: self-organising stem cells
Sasai, Y., Eiraku, M., & Suga, H. (2012) · Development · doi:10.1242/dev.079590 · Cited by 204
Holtfreter, J. (1933) · Wilhelm Roux' Archiv f�r Entwicklungsmechanik der Organismen · doi:10.1007/bf00656583 · Cited by 202
Epithelial to mesenchymal transition during gastrulation: An embryological view
Nakaya, Y., & Sheng, G. (2008) · Development, Growth & Differentiation · doi:10.1111/j.1440-169x.2008.01070.x · Cited by 188
Morkel, M., Huelsken, J., Wakamiya, M., Ding, J., van de Wetering, M., Clevers, H., Taketo, M. M., Behringer, R. R., Shen, M. M., & Birchmeier, W. (2003) · Development · doi:10.1242/dev.00859 · Cited by 185
Kouskoff, V., Lacaud, G., Schwantz, S., Fehling, H. J., & Keller, G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501672102 · Cited by 180
Gastrulation movements provide an early marker of mesoderm induction in Xenopus laevis
Symes, K., & Smith, J. C. (1987) · Development · doi:10.1242/dev.101.2.339 · Cited by 174
Wnt Signaling and the Evolution of Embryonic Posterior Development
Martin, B. L., & Kimelman, D. (2009) · Current Biology · doi:10.1016/j.cub.2009.01.052 · Cited by 172
Definitive endoderm of the mouse embryo: Formation, cell fates, and morphogenetic function
Lewis, S. L., & Tam, P. P. L. (2006) · Developmental Dynamics · doi:10.1002/dvdy.20846 · Cited by 164
Antero-posterior tissue polarity links mesoderm convergent extension to axial patterning
Ninomiya, H., Elinson, R. P., & Winklbauer, R. (2004) · Nature · doi:10.1038/nature02620 · Cited by 163
Turner, D. A., Hayward, P. C., Baillie‐Johnson, P., Rué, P., Broome, R., Faunes, F., & Arias, A. M. (2014) · Development · doi:10.1242/dev.112979 · Cited by 163
Self-citationThe Hypoblast of the Chick Embryo Positions the Primitive Streak by Antagonizing Nodal Signaling
Bertocchini, F., & Stern, C. D. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00318-0 · Cited by 158
Rhee, J. M., Pirity, M. K., Lackan, C. S., Long, J. Z., Kondoh, G., Takeda, J., & Hadjantonakis, A. (2006) · genesis · doi:10.1002/dvg.20203 · Cited by 150
Self-citationMeinhardt, H. (2012) · Interface Focus · doi:10.1098/rsfs.2011.0097 · Cited by 142
Perea-Gómez, A., Shawlot, W., Sasaki, H., Behringer, R. R., & Ang, S. (1999) · Development · doi:10.1242/dev.126.20.4499 · Cited by 138
Faunes, F., Hayward, P. C., Muñoz‐Descalzo, S., Chatterjee, S. S., Balayo, T., Trott, J., Christoforou, A., Ferrer‐Vaquer, A., Hadjantonakis, A., DasGupta, R., et al. (2013) · Development · doi:10.1242/dev.085654 · Cited by 125
Self-citationPfister, S., Steiner, K. A., & Tam, P. (2007) · Gene Expression Patterns · doi:10.1016/j.modgep.2007.01.005 · Cited by 124
Perea-Gómez, A., Camus, A., Moreau, A., Grieve, K. F., Moneron, G., Dubois, A., Cibert, C., & Collignon, J. (2004) · Current Biology · doi:10.1016/j.cub.2004.01.030 · Cited by 123
Differentiating Embryonic Stem Cells into Embryoid Bodies
Höpfl, G., Gassmann, M., & Desbaillets, I. (2004) · Humana Press eBooks · doi:10.1385/1-59259-741-6:079 · Cited by 114
Baillie‐Johnson, P., van den Brink, S., Balayo, T., Turner, D. A., & Arias, A. M. (2015) · Journal of Visualized Experiments · doi:10.3791/53252 · Cited by 104
Self-citationMarikawa, Y., Tamashiro, D. A. A., Fujita, T. C., & Alarcón, V. B. (2008) · genesis · doi:10.1002/dvg.20473 · Cited by 101
Turner, D. A., Rué, P., Mackenzie, J. P., Davies, E., & Arias, A. M. (2014) · BMC Biology · doi:10.1186/s12915-014-0063-7 · Cited by 99
Self-citationBertocchini, F., Skromne, I., Wolpert, L., & Stern, C. D. (2004) · Development · doi:10.1242/dev.01178 · Cited by 82
Cellular dynamics in the early mouse embryo: from axis formation to gastrulation
Nowotschin, S., & Hadjantonakis, A.-K. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.05.008 · Cited by 79 · cited 1×
“KEY WORDS: Mouse, Gastrulation, Self-organisation, Symmetry breaking, Polarisation, Axial elongation, Endoderm, Mesoderm, Neural ectoderm, Pattern formation, Live cell imaging”
Self-citationDevelopmental mechanisms directing early anterior forebrain specification in vertebrates
Andoniadou, C. L., & Martínez-Barberá, J. P. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1269-5 · Cited by 77
Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism
Yu, H., Takeuchi, M., LeBarron, J., Kantharia, J., London, E., Bakker, H., Haltiwanger, R. S., Li, H., & Takeuchi, H. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1927 · Cited by 74
Albazerchi, A., & Stern, C. D. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.08.057 · Cited by 62
Initiating head development in mouse embryos: integrating signalling and transcriptional activity
Arkell, R. M., & Tam, P. (2012) · Open Biology · doi:10.1098/rsob.120030 · Cited by 59
Turner, D. A., Trott, J., Hayward, P. C., Rué, P., & Arias, A. M. (2014) · Biology Open · doi:10.1242/bio.20148409 · Cited by 55
Self-citationSnapShot: Mouse Primitive Streak
Ramkumar, N., & Anderson, K. V. (2011) · Cell · doi:10.1016/j.cell.2011.07.028 · Cited by 40
Neural Induction Intermediates Exhibit Distinct Roles of Fgf Signaling
Sterneckert, J. L., Stehling, M., Bernemann, C., Araúzo-Bravo, M. J., Greber, B., Gentile, L., Ortmeier, C., Sinn, M., Wu, G., Ruau, D., et al. (2010) · Stem Cells · doi:10.1002/stem.498 · Cited by 36
Medina, A., Wendler, S., & Steinbeißer, H. (1997) · The International Journal of Developmental Biology · doi:10.1387/ijdb.9415495 · Cited by 28
Formation of the Anterior-Posterior Axis in Mammals
Perea-Gómez, A., & Meilhac, S. M. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-405945-0.00010-7 · Cited by 8
Cited by
Progress and potential in organoid research
Rossi, G., Manfrin, A., & Lutolf, M. P. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0051-9 · Cited by 1,182
Corrò, C., Novellasdemunt, L., & Li, V. S. W. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00120.2020 · Cited by 561
Programming self-organizing multicellular structures with synthetic cell-cell signaling
Toda, S., Blauch, L. R., Tang, S. K. Y., Morsut, L., & Lim, W. A. (2018) · Science · doi:10.1126/science.aat0271 · Cited by 470
Formative pluripotency: the executive phase in a developmental continuum
Smith, A. (2017) · Development · doi:10.1242/dev.142679 · Cited by 474
Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids
van den Brink, S. C., Alemany, A., van Batenburg, V., Moris, N., Blotenburg, M., Vivié, J., Baillie-Johnson, P., Nichols, J., Sonnen, K. F., Martinez Arias, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2024-3 · Cited by 404
Self-citation
Metadata
- Authors
- van den Brink, S. C., Baillie-Johnson, P., Balayo, T., Hadjantonakis, A.-K., Nowotschin, S., Turner, D. A., & Martinez Arias, A.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2014-11-15
- Volume
- 141
- Issue
- 22
- Pages
- 4231-4242
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W2166649246
- Cited by
- 478
- References
- 78
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.