Functional interrogation of primate gastrulation and body patterning: building the embryo outside the womb (360G-Wellcome-226499_Z_22_Z)

The human body plan is specified in the gastrulating embryo shortly after implantation. In mouse, this transformation is regulated by a dynamic signalling centre, the anterior visceral endoderm (AVE). However, the function of the primate AVE in gastrulation remains elusive. Implantation and body patterning are pivotal for healthy embryo development, but in human they have been notoriously hard to study for ethical and technical reasons. My lab recently delineated primate AVE formation by spatial transcriptome profiling of gastrulating marmoset embryos in vivo. Here, we will leverage our new extraembryonic stem cell lines to model the pre-to-postimplantation transition in human and marmoset. To interrogate the crosstalk between embryonic disc and AVE, we will engineer next-generation gastruloids by ‘printing’ AVE-like cells onto micropatterns and establish stem-cell-derived blastoid postimplantation cultures. Human and marmoset embryo models will be validated by transcriptomic comparisons to the embryo and assembled with knockout AVE-like cells to elucidate AVE-function. We will test the developmental potential of marmoset blastoids by transfer into receptive marmoset hosts and conduct lineage- tracing in vivo to determine the sequence of somatic cell-fate acquisition in primate gastrulation. Collectively, this research addresses major knowledge gaps in human development and establishes a proof-of-principle for stem-cell- derived pregnancies in primates.