Spatiotemporal analysis of human intestinal development at single-cell resolution

• Published in: Cell Vol. 184; no. 3; pp. 810 - 826.e23
• Main Authors: Fawkner-Corbett, David, Antanaviciute, Agne, Parikh, Kaushal, Jagielowicz, Marta, Gerós, Ana Sousa, Gupta, Tarun, Ashley, Neil, Khamis, Doran, Fowler, Darren, Morrissey, Edward, Cunningham, Chris, Johnson, Paul R.V., Koohy, Hashem, Simmons, Alison
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.02.2021; Cell Press
• Subjects: congenital disease; Endothelial Cells - cytology; Enteric Nervous System - cytology; Fetus - embryology; Fibroblasts - cytology; gene expression; human development; human developmental cell atlas; Humans; Immunity; intestinal crypt; intestinal development; Intestinal Diseases - congenital; Intestinal Diseases - pathology; Intestinal Mucosa - growth & development; Intestines - blood supply; Intestines - cytology; Intestines - growth & development; Ligands; mesenchymal cells; Mesoderm - cytology; Neovascularization, Physiologic; Pericytes - cytology; Resource; Single-Cell Analysis; single-cell RNA-sequencing; spatial transcriptomics; stem cells; Stem Cells - cytology; Time Factors; Transcription Factors - metabolism; single-cell RNA-sequencing; stem cells; human development; spatial transcriptomics; intestinal development; human developmental cell atlas; congenital disease; mesenchymal cells; intestinal crypt; gene expression
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.12.016

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. [Display omitted] •Multimodal atlas of human intestinal development maps 101 cell types onto tissue•Charts developmental origins of diverse cellular compartments and their progenitors•Functional diversity of fibroblasts in stem cell, vasculature, and GALT formation•Resource applied to interrogate pathology of in utero intestinal diseases Fawkner-Corbett et al. chart human intestinal morphogenesis across time, location, and cellular compartments using a combination of single-cell RNA sequencing and spatial transcriptomics. The resulting online searchable atlas describes the principles of crypt-villus axis formation as well as neural, vascular, mesenchymal morphogenesis, and immune populations of the developing gut.