Charting human development using a multi-organ atlas and organoid models
Description
Organs are composed of diverse cell types, which traverse transient states during organogenesis. To interrogate this diversity during human development, we generate a single-cell transcriptome atlas from multiple developing endodermal organs of the respiratory and gastrointestinal tract. We illuminate cell states, transcription factors, and organ-specific epithelial stem cell and mesenchyme interactions across lineages. We implement the atlas as a high-dimensional search space to benchmark pluripotent stem cell-derived human intestinal organoids (HIOs) in multiple culture conditions. We show that HIOs recapitulate reference cell states, and use HIOs to reconstruct the molecular dynamics of intestinal epithelium and mesenchyme emergence. We show that the mesenchyme-derived niche cue NRG1 enhances intestinal stem cell maturation in vitro and that the homeobox transcription factor CDX2 is required for regionalization of intestinal epithelium and mesenchyme in humans. Collectively, this work combines cell atlases and organoid technologies to understand how human organ development is orchestrated. We provide following data here: 1. Data S1 referred in the main text, which includes cellular heterogeneity of the multi-organ atlas/tHIO/developing duodenum mesenchyme/HIO mesenchyme, expression of gastrointestinal (GI) disease-associated genes in developing intestine and tHIO, intestinal stem cell and mesenchymal signaling potential over development, and transcription factors related to intestine epithelial and mesenchymal development; 2. Processed sequencing data; 3. Fetal atlas CSS model, UMAP model and other data that we used for projection of organoid data to the developing atlas; 4. Intensity and list of cell type enriched epithelium-mesenchyme interactions in each organ reported by CellPhoneDB. Related to Figure 3; 5. Regulons associated with intestinal stem cell phase 4, 5 and 6. Related to Figure 5; 6. Reference patterns for novoSpaRc. Related to ExtData-6 of Data S1; 7. TF network module associated with in vitro HIO epithelial and mesenchymal development. Related to ExtData-8A; 8. Regulons of time course in vitro HIO mesenchymal cells and epithelial cells reported by pySCENIC. Related to ExtData-8G and Figure S7A.