A Proximal-to-Distal Survey of Healthy Adult Human Small Intestine and Colon Epithelium by Single-Cell Transcriptomics

Joseph Burclaff; R Jarrett Bliton; Keith A Breau; Meryem T Ok; Ismael Gomez-Martinez; Jolene S Ranek; Aadra P Bhatt; Jeremy E Purvis; John T Woosley; Scott T Magness

doi:10.1016/j.jcmgh.2022.02.007

A Proximal-to-Distal Survey of Healthy Adult Human Small Intestine and Colon Epithelium by Single-Cell Transcriptomics

Cell Mol Gastroenterol Hepatol. 2022;13(5):1554-1589. doi: 10.1016/j.jcmgh.2022.02.007. Epub 2022 Feb 15.

Authors

Affiliations

¹ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
² Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, Chapel Hill, North Carolina.
³ Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁴ Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁵ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁶ Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁷ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁸ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill/North Carolina State University, Chapel Hill, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: magness@med.unc.edu.

Abstract

Background & aims: Single-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 human beings.

Methods: A total of 12,590 single epithelial cells from 3 independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and their capacity for response to extrinsic signals along the gut axis across different human beings.

Results: Cells were assigned to 25 epithelial lineage clusters. Multiple accepted intestinal stem cell markers do not specifically mark all human intestinal stem cells. Lysozyme expression is not unique to human Paneth cells, and Paneth cells lack expression of expected niche factors. Bestrophin 4 (BEST4)⁺ cells express Neuropeptide Y (NPY) and show maturational differences between the small intestine and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell junctions, and nutrient absorption genes show unappreciated regional expression differences across lineages. The differential expression of receptors and drug targets across lineages show biological variation and the potential for variegated responses.

Conclusions: Our study identifies novel lineage marker genes, covers regional differences, shows important differences between mouse and human gut epithelium, and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomic regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.

Keywords: BEST4; Cell Atlas; Intestinal Stem Cell; Paneth Cell; scRNAseq.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Colon
Epithelium
Humans
Intestinal Mucosa* / metabolism
Intestine, Small
Mice
Transcriptome* / genetics

Abstract

Publication types

MeSH terms

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