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Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones. We describe principles of crypt-villus axis formation; neural, vascular, mesenchymal morphogenesis, and immune population of the developing gut. We identify the differentiation hierarchies of developing fibroblast and myofibroblast subtypes and describe diverse functions for these including as vascular niche cells. We pinpoint the origins of Peyer's patches and gut-associated lymphoid tissue (GALT) and describe location-specific immune programs. We use our resource to present an unbiased analysis of morphogen gradients that direct sequential waves of cellular differentiation and define cells and locations linked to rare developmental intestinal disorders. We compile a publicly available online resource, spatio-temporal analysis resource of fetal intestinal development (STAR-FINDer), to facilitate further work.

Original publication




Journal article



Publication Date





810 - 826.e23


congenital disease, gene expression, human development, human developmental cell atlas, intestinal crypt, intestinal development, mesenchymal cells, single-cell RNA-sequencing, spatial transcriptomics, stem cells, Endothelial Cells, Enteric Nervous System, Fetus, Fibroblasts, Humans, Immunity, Intestinal Diseases, Intestinal Mucosa, Intestines, Ligands, Mesoderm, Neovascularization, Physiologic, Pericytes, Single-Cell Analysis, Stem Cells, Time Factors, Transcription Factors