Rasa Elmentaite, Natsuhiko Kumasaka, Kenny Roberts, Aaron Fleming, Emma Dann, Hamish W. King, Vitalii Kleshchevnikov, Monika Dabrowska, Sophie Pritchard, Liam Bolt, Sara F. Vieira, Lira Mamanova, Ni Huang, Francesca Perrone, Issac Goh Kai’En, Steven N. Lisgo, Matilda Katan, Steven Leonard, Thomas R. W. Oliver, C. Elizabeth Hook, Komal Nayak, Lia S. Campos, Cecilia Domínguez Conde, Emily Stephenson, Justin Engelbert, Rachel A. Botting, Krzysztof Polanski, Stijn van Dongen, Minal Patel, Michael D. Morgan, John C. Marioni, Omer Ali Bayraktar, Kerstin B. Meyer, Xiaoling He, Roger A. Barker, Holm H. Uhlig, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Menna R. Clatworthy, Muzlifah Haniffa, Kylie R. James, Sarah A. Teichmann
The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.