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The emergent landscape of the mouse gut endoderm at single-cell resolution

ABSTRACT: To comprehensively delineate the ontogeny of an organ system, we generated 112,217 single- cell transcriptomes representing all endoderm populations within the mouse embryo until midgestation. We employed graph-based approaches to model differentiating cells for spatio- temporal characterization of developmental trajectories. Our analysis reveals the detailed architecture of the emergence of the first (primitive or extra-embryonic) endodermal population and pluripotent epiblast. We uncover an unappreciated relationship between descendants of these lineages, before the onset of gastrulation, suggesting that mixing of extra-embryonic and embryonic endoderm cells occurs more than once during mammalian development. We map the trajectories of endoderm cells as they acquire embryonic versus extra-embryonic fates, and their spatial convergence within the gut endoderm; revealing them to be globally similar but retaining aspects of their lineage history. We observe the regionalized localization of cells along the forming gut tube, reflecting their extra-embryonic or embryonic origin, and their coordinate patterning into organ-specific territories along the anterior-posterior axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE123124 | GEO | 2019/04/10

REPOSITORIES: GEO

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Project description:An increasing number of studies suggests that embryonic development is a highly plastic process and that lineage specification can proceed via alternative routes not encompassed in canonically defined germ layers. Despite these recent revisions to fate maps, the differentiation of pluripotent stem cells (PSCs) to specific lineages tends to continue to focus on defined germ layer differentiation. Thus although recent studies suggest that the visceral organs originate from both embryonic and extra-embryonic lineages, PSC differentiation has focused on generating definitive and gut endoderm solely via an embryonic trajectory. To better resolve the lineage trajectories during development and during corresponding in vitro differentiation, we used MARS-seq to generate a single-cell RNA-seq datasets from mouse embryos expressing a Foxa2Venus reporter and in vitro embryonic stem cell (ESC) differentiation towards definitive endoderm. We coupled this data to a new simplified computational approach to compare cell types, both within our own transcriptomes and across different datasets. Based on this analysis, we captured the central intermediate in the transition between extra-embryonic and embryonic endoderm. When we assessed in vitro ESC differentiation in a number of different endoderm protocols, we found no evidence for this transient intermediate population during differentiation, only traditional embryo-like populations. We then directly tested the capacity of extra-embryonic endoderm to generate organ specific cell types, exploiting our previously defined cell culture system for naïve extra-embryonic endoderm (nEnd). We found that nEnd exhibited gene expression states that reflects early extra-embryonic identity and could be further differentiated to embryonic gut organoids. Taken together, this suggests self-renewing extra-embryonic nEnd represents a source of definitive organ cell types and suggests that in vitro differentiation should take full advantage of the recent observations about developmental plasticity.

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The emergent landscape of the mouse gut endoderm at single-cell resolution

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