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Single-cell transcriptomic comparison of the developing human fetal stomach and pluripotent stem cell-derived gastric organoids

ABSTRACT: The goal of engineering increasingly complex in vitro human organoid models is to more accurately model human organogenesis and disease. Recently, human antral gastric organoids (hAGOs) were engineered to contain splanchnic mesenchyme (SM) and enteric neural crest cells (NCCs), resulting in the formation of functional three germ layer gastric organoids. It is unclear how three-germ layer hAGOs compare with the human fetal stomach and how the added germ layers alter gastric differentiation in vitro. To determine the robustness of hAGOs and how additional germ layers impact development, we benchmarked hAGO with and without added SM and NCC to a single cell atlas of the developing human stomach. A comparison of hAGOs in vitro to fetal organs confirmed that they were gastric and most similar to 7 week stomach with the epithelium comprised primarily of gastric precursors and surface mucous cells. The SM added to hAGOs formed fetal gastrointestinal-like mesenchyme whereas the NCCs in hAGOs differentiated into neuronal precursors and glial cells similar to those found in developing endodermal organs. The addition of SM and NCCs did not drastically alter the cellular diversity of the epithelium in vitro but maintained more uncommitted precursors similar to 7 week stomach. Following transplantation and growth for 10 weeks, hAGOs with SM grew and matured into tissue more similar to the 14 week fetal stomach. Bioinformatic inference of cell-cell communication confirmed known signaling crosstalk between germ layers but also identified new signaling candidates that may regulate tissue assembly. Together, these data show that three-germ layer hAGOs faithfully modeled the multilayer complexity of the fetal stomach at a single cell transcriptomics level and provided insight into human stomach development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299243 | GEO | 2026/01/24

REPOSITORIES: GEO

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Project description:The germ layer concept has been one of the foremost organizing principles in developmental biology, classification, systematics and evolution for 150 years. Of the three germ layers, the mesoderm is found in bilaterian animals but is absent in species in the phyla Cnidaria and Ctenophora, which has been taken as evidence that the mesoderm was the final germ layer to evolve. The origin of the ectoderm and endoderm layers, however, remains unclear with models supporting the antecedence of each as well as a simultaneous origin. We hypothesized that global analysis of gene expression in each layer throughout development may resolve the early events of animal evolution. Here, we determine the temporal and spatial components of gene expression spanning embryonic development for all C. elegans genes and use it to determine the evolutionary age of the germ layers. The gene expression programs of the mesoderm is generally induced after the ectoderm and endoderm germ layers, thus making it the last germ layer to both evolve and develop. Strikingly, the C. elegans endoderm and ectoderm expression programs do not co-induce; rather the endoderm activates earlier. We also observed early expression of endoderm orthologs during the embryology of Xenopus tropicalis, Nematostella vectensis, and the sponge Amphimedon queenslandica. Querying for the phylogenetic ages of specifically expressed genes revealed that the endoderm is comprised of older genes, supporting its antecedence among the germ layers. Taken together, we propose that the endoderm program has retained the feeding functions of the last common ancestor with the choanoflagellates, thus allowing for the specialization of an ectoderm germ layer. Our work reveals that the evolutionary appearance of the germ layers continues to constrain regulatory networks in metazoans. Two temporal assays of C. elegans embryonic development, starting at the zygote: (a) Embryos collected at fixed (~10 minute) time intervals. (b) Embryo segregates, up to five lines of blastomeres, isolated in reference to mitotic events. There were 184 samples in total, representing 100 distnict data points.

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Single-cell transcriptomic comparison of the developing human fetal stomach and pluripotent stem cell-derived gastric organoids

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