Modelling late gastrulation in stem cell-derived monkey embryo models
Summary
This Nature paper describes the generation and characterisation of stem cell-derived cynomolgus monkey embryoids that model late gastrulation and early post‑implantation development (approximately D13–D25). The authors combine improved blastoid/embryoid culture methods with 3D light‑sheet imaging and large‑scale single‑cell RNA sequencing to map morphogenesis and lineage emergence (amnion, yolk sac, primitive streak, neuroectoderm, mesoderm, endoderm and primordial germ‑cell‑like cells). The embryoids recapitulate key morphological features (amnion and yolk‑sac cavities, primitive streak, neural plate and neural folding) and show transcriptional similarity to in vitro‑cultured natural monkey embryos, although some extraembryonic and later organogenic cell types are underrepresented. A genetic perturbation (TBXT knockout) demonstrates the model can be used to probe gene function during gastrulation. Extensive datasets, images and processing code are made available in public repositories.
Key Points
- Robust protocol to convert naïve monkey ESCs/iPSCs into blastoids and then embryoids that progress to late gastrulation stages (D13–D25) in vitro.
- 3D light‑sheet imaging captures formation of amnion and yolk‑sac cavities, primitive streak dynamics and neural‑folding events resembling Carnegie stages of primate embryos.
- Single‑cell RNA‑seq (≈101k cells) provides a high‑resolution cell atlas across stages, enabling integration with in vivo and in vitro monkey embryo datasets.
- Lineages identified include epiblast/ectoderm, neural plate and border, mesoderm subtypes (nascent, paraxial, lateral plate), endoderm, trophoblast subtypes and PGCLC populations.
- Comparative analysis shows good fidelity to natural monkey embryos for many embryonic tissues, but some extraembryonic/organogenic populations are reduced or missing.
- TBXT genetic perturbation impairs primitive‑streak formation and downstream development, showing the system’s utility for functional genetics.
- All raw data, imaging and processing code are deposited in public archives (GSA/GEO/BioImage Archive/GitHub), enabling reuse and reanalysis.
Content summary
The team optimised blastoid induction from 4CL naïve ESCs and extended in vitro culture conditions to generate embryoids that reliably form an embryonic disc, amnion and yolk‑sac cavities and progress through gastrulation‑like events. Morphological stages were validated by light‑sheet microscopy and immunostaining for lineage markers (OCT4, TFAP2A, SOX17, TBXT, OTX2, FOXA2, SOX2 and others).
They profiled cells by scRNA‑seq across D17–D25 embryoids and integrated these data with multiple reference datasets of natural and cultured monkey (and human) embryos. This allowed annotation of diverse cell types, pseudotime/trajectory analyses of ectoderm and mesoderm differentiation, and identification of haemato‑endothelial and gut‑like populations in the secondary yolk sac and primitive gut regions.
Functional perturbation (TBXT KO) reduced TBXT+ cells, altered developmental efficiency and impaired later embryoid morphogenesis, illustrating how genetic manipulation can reveal regulators of gastrulation in a primate context. The study supplies extensive supplementary tables, videos and source data and makes raw sequencing and imaging available in public repositories.
Context and relevance
This work advances in vitro primate embryo modelling by pushing embryoid culture into later gastrulation/early organogenesis stages and providing a deep single‑cell and 3D morphological resource. For researchers in developmental biology, stem‑cell modelling and evolutionary embryology, the paper offers a primate‑relevant platform to study lineage specification, early human‑development proxies and gene function where direct human embryo studies are limited by availability and ethics.
It also contributes to ongoing trends: increased use of embryo models to study early organogenesis, integration of multimodal imaging with single‑cell transcriptomics, and application of gene editing in a primate model system. The deposited datasets and protocols make this a practical reference for groups wanting to reproduce or extend primate embryoid studies.
Why should I read this?
Quick take: if you work on early development, stem‑cell models or want a primate system that gets beyond the very earliest stages, this paper’s a goldmine — gorgeous 3D imaging, a huge single‑cell dataset and a usable protocol. It’s basically the field’s latest playbook for modelling gastrulation in a primate setting, and the TBXT KO example shows it’s more than just pretty pictures — it’s experimentally actionable. We’ve saved you the deep dive; read the paper if you need methods, datasets or want to test gene function in a primate embryo‑like system.