Retinoic acid induces human gastruloids with posterior embryo-like structures
Gastruloids are a powerful in vitro model of early human development. However, although elongated and composed of all three germ layers, human gastruloids do not morphologically resemble post-implantation human embryos. Here we show that an early pulse of retinoic acid (RA), together with later Matrigel, robustly induces human gastruloids with posterior embryo-like morphological structures, including a neural tube flanked by segmented somites and diverse cell types, including neural crest, neural progenitors, renal progenitors and myocytes. Through in silico staging based on single-cell RNA sequencing, we find that human RA-gastruloids progress further than other human or mouse embryo models, aligning to E9.5 mouse and CS11 cynomolgus monkey embryos. We leverage chemical and genetic perturbations of RA-gastruloids to confirm that WNT and BMP signalling regulate somite formation and neural tube length in the human context, while transcription factors TBX6 and PAX3 underpin presomitic mesoderm and neural crest, respectively. Looking forward, RA-gastruloids are a robust, scalable model for decoding early human embryogenesis.
Authors
- Douglas M. Fowler (ORCID: https://orcid.org/0000-0001-7614-1713)
- Chengxiang Qiu (ORCID: https://orcid.org/0000-0002-6346-8669)
- Riddhiman K. Garge (ORCID: https://orcid.org/0000-0002-6774-0172)
- Beth Martin (ORCID: https://orcid.org/0000-0002-9661-014X)
- Wei Yang (ORCID: https://orcid.org/0000-0002-3591-2195)
- Samuel G. Regalado (ORCID: https://orcid.org/0000-0002-7793-8924)
- Riza M. Daza (ORCID: https://orcid.org/0000-0003-1635-8675)
- Nobuhiko Hamazaki (ORCID: https://orcid.org/0000-0001-9228-233X)
- Sriram Pendyala (ORCID: https://orcid.org/0000-0003-3395-3417)
- Eva K. Nichols (ORCID: https://orcid.org/0000-0002-8501-8028)
- Connor Kubo (ORCID: https://orcid.org/0000-0001-9579-2917)
- Jay Shendure (ORCID: https://orcid.org/0000-0002-1516-1865)
- Sanjay Srivatsan (ORCID: https://orcid.org/0000-0001-7282-0487)
- Choli Lee (ORCID: https://orcid.org/0000-0002-8901-1835)
- Nicholas J. Bradley (ORCID: https://orcid.org/0009-0001-2056-1679)
Institutions
- Amazon (United States) (US)
- Howard Hughes Medical Institute (US)
- California Institute for Regenerative Medicine (US)
- University of Washington (US)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Fred Hutch Cancer Center (US)
- Lineage Cell Therapeutics (United States) (US)
- Brotman Baty Institute (US)
- Seattle University (US)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1038/s41556-024-01487-8
- Citations
- 34
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 7.95
Funders
- Howard Hughes Medical Institute
- Paul G. Allen Frontiers Group
- National Human Genome Research Institute