An advanced head-to-tail mouse embryo model with hypoxia-mediated neural patterning

The developing mammalian embryo is guided by the continuously changing signals that it receives from maternal tissues and its microenvironment. The dynamic cell-cell and cell-environment interactions that together shape the embryo largely remained unexplorable until the advance of stem cell-based embryo models. These revealed the self-organizing properties of cells in response to endogenous and exogenous cues. Among the latter, restricted oxygen (hypoxia) emerged as a critical microenvironmental regulator that influences cell type diversification in multicellular systems. Here, by combining H ypoxia and an A ntero- P osterior assembly strategy, we developed an ESC-based head-to-tail model of mouse embryogenesis called HAP-gastruloids. HAP-gastruloids contain stage-appropriate anterior brain-like tissues as well as spinal cord, somites, and gut endoderm. We show that timed hypoxia boosts anterior neural cell identities and their patterning through HIF1a and in part by modulating TGFβ superfamily activity. These results reveal a key beneficial role of hypoxia in early development and offer a unique system to investigate antero-posterior phenotypes for basic discovery and translation.