Journal Article

Retinoic acid induces human gastruloids with posterior embryo-like structures

Bradley, Nicholas, Shendure, Jay, Nichols, Eva K., Fowler, Douglas M., Daza, Riza M., Yang, Wei, Pendyala, Sriram, Srivatsan, Sanjay, Garge, Riddhiman K., Regalado, Samuel G., Lee, Choli, Martin, Beth K., Kubo, Connor A., Hamazaki, Nobuhiko, Qiu, Chengxiang

2024

Overview

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. Hamazaki, Yang et al. report that an early pulse of retinoic acid robustly induces human gastruloids with a neural tube, segmented somites and more advanced cell types than conventional gastruloids.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/532/1360 / 631/61/2320 / Animal models / Animals / Biomedical and Life Sciences / Cancer Research / Cell Biology / Cell culture / Developmental Biology / Elongated structure / Embryo, Mammalian - drug effects / Embryo, Mammalian - metabolism / Embryogenesis / Embryonic Development - drug effects / Embryonic growth stage / Embryos / Gastrula - drug effects / Gastrula - metabolism / Gene Expression Regulation, Developmental - drug effects / Gene sequencing / Humans / Life Sciences / Macaca fascicularis - embryology / Mesoderm / Mesoderm - drug effects / Mesoderm - embryology / Mesoderm - metabolism / Mice / Morphology / Myocytes / Neural crest / Neural Crest - drug effects / Neural Crest - embryology / Neural Crest - metabolism / Neural stem cells / Neural tube / Neural Tube - drug effects / Neural Tube - embryology / Neural Tube - metabolism / Pax3 protein / PAX3 Transcription Factor - genetics / PAX3 Transcription Factor - metabolism / Progenitor cells / Retinoic acid / Signal Transduction - drug effects / Somites / Somites - drug effects / Somites - embryology / Somites - metabolism / Stem Cells / T-Box Domain Proteins - genetics / T-Box Domain Proteins - metabolism / technical-report / Transcription factors / Tretinoin - metabolism / Tretinoin - pharmacology / Wnt protein / Wnt Signaling Pathway - drug effects