Mapping Development of the Human Intestinal Niche at Single-Cell Resolution

Emily M Holloway; Michael Czerwinski; Yu-Hwai Tsai; Joshua H Wu; Angeline Wu; Charlie J Childs; Katherine D Walton; Caden W Sweet; Qianhui Yu; Ian Glass; Barbara Treutlein; J Gray Camp; Jason R Spence

doi:10.1016/j.stem.2020.11.008

Mapping Development of the Human Intestinal Niche at Single-Cell Resolution

Cell Stem Cell. 2021 Mar 4;28(3):568-580.e4. doi: 10.1016/j.stem.2020.11.008. Epub 2020 Dec 4.

Authors

Affiliations

¹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
⁴ Department of Pediatrics, Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
⁵ Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland.
⁶ Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; University of Basel, Basel, Switzerland.
⁷ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA. Electronic address: [email protected].

Abstract

The human intestinal stem cell niche supports self-renewal and epithelial function, but little is known about its development. We used single-cell mRNA sequencing with in situ validation approaches to interrogate human intestinal development from 7-21 weeks post conception, assigning molecular identities and spatial locations to cells and factors that comprise the niche. Smooth muscle cells of the muscularis mucosa, in close proximity to proliferative crypts, are a source of WNT and RSPONDIN ligands, whereas EGF is expressed far from crypts in the villus epithelium. Instead, an PDGFRA^HI/F3^HI/DLL1^HI mesenchymal population lines the crypt-villus axis and is the source of the epidermal growth factor (EGF) family member NEUREGULIN1 (NRG1). In developing intestine enteroid cultures, NRG1, but not EGF, permitted increased cellular diversity via differentiation of secretory lineages. This work highlights the complexities of intestinal EGF/ERBB signaling and delineates key niche cells and signals of the developing intestine.

Keywords: NRG1; development; enteroid; human; intestine; niche; organoid; scRNA-seq; stem cell.

Publication types

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

MeSH terms

Cell Differentiation
Humans
Intestinal Mucosa
Intestines*
Stem Cell Niche*
Stem Cells

Abstract

Publication types

MeSH terms

Grants and funding