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Primate gastrulation and early organogenesis at single-cell resolution

ABSTRACT: Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, non-human primates (NHPs) are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we have collected six Carnegie stage (CS) 8-CS11 cynomolgus monkey embryos and performed in-depth transcriptome analyses of 56,636 single cells. Our analyses reveal transcriptomic features of major peri-gastrulation cell types, which help shed light on morphogenetic events including primitive streak (PS) development, somitogenesis, gut tube formation, neural tube patterning, and neural crest regionalization in primates. In addition, comparative analyses with mouse embryos and human embryoids uncover conserved and divergent features of peri-gastrulation development across species, e.g. species-specific dependency on Hippo signaling during presomitic mesoderm differentiation, and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the NHP research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE193007 | GEO | 2022/10/26

REPOSITORIES: GEO

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Project description:Our ability to study early human post-implantation development remains highly limited due to the ethical and technical challenges associated with intrauterine development of the human embryo after implantation. Despite the great progress made on human blastoids or gastruloids, such elegant models do not constitute an integrated synthetic stem cell-derived embryoid models (SEMs) that includes all the key extra-embryonic tissues of the early pre-gastrulating implanted human conceptus (e.g. hypoblast, yolk-sac, trophoblasts, amnion and extraembryonic mesoderm), and thus, do not recapitulate post-implantation epiblast development within the context of these extra-embryonic compartments. Mouse naïve pluripotent stem cells (PSCs) have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation mouse SEMs, while bypassing the blastocyst-like stage, and eventually initiating organogenesis ex utero. Here, we implement critical adaptations to extend these finding in humans, using only genetically unmodified human naïve PSCs, circumventing the need for ectopic expression of lineage promoting transgenes. Such integrated human SEMs recapitulate all known compartments of early post-implantation stage human embryos, including epiblast, hypoblast, extra-embryonic mesoderm, and trophoblast surrounding the latter layers. The organized human SEMs recapitulate key hallmarks of post-implantation stage embryogenesis up to 13-14 days post-fertilization (dpf, Carnegie stage 6a), such as bilaminar disk formation, epiblast lumenogenesis, amniogenesis, anterior-posterior symmetry breaking, PGC specification, primary and secondary yolk sac formation, and extra-embryonic mesoderm expansion that defines a chorionic cavity and a connective stalk. This new platform constitutes a tractable stem cell-based model for experimentally interrogating previously inaccessible windows of human early peri- and post-implantation development.

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Primate gastrulation and early organogenesis at single-cell resolution

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