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Cell. 2018 Oct 4;175(2):372-386.e17. doi: 10.1016/j.cell.2018.08.067. Epub 2018 Sep 27.

Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.

Author information

1
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
2
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK; MRC WIMM Centre For Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
3
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford OX3 7BN, UK.
5
Novo Nordisk Research Centre Oxford, Oxford, UK.
6
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
7
OncoResponse, Inc., Seattle, WA 98104, USA.
8
Translational Development, Celgene Corporation, Cambridge, MA, USA.
9
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; MRC WIMM Centre For Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
10
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK. Electronic address: alison.simmons@imm.ox.ac.uk.

Abstract

Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts. We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.

KEYWORDS:

CyTOF; SOX6; TNFSF14; Wnts; crypt niche; inflammatory bowel disease; mesenchyme; single-cell RNA-seq; stratification; stromal cell; target discovery

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