Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease

James Kinchen,Laura Cubitt,Moustafa Attar,Kamal D Puri,David Fawkner-Corbett,Agne Antanaviciute,David Ahern,Eshita Sharma,Alison Simmons,Esther Mellado-Gomez,Hannah H Chen,Hashem Koohy,Marta Jagielowicz,Kaushal Parikh,Rory Bowden,Neil Ashley,Felix Clemens Richter ,Quin F Wills ,Jill Hénault ,François G Gervais

doi:10.1016/j.cell.2018.08.067

Abstract

SummaryIntestinal 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.

Highlights

Mesenchymal cells of the intestinal lamina propria are a heterogeneous population of non-hematopoietic, non-epithelial cell types that play instrumental roles in innate immunity, immune regulation, and epithelial barrier maintenance (Nowarski et al, 2017)
We examined expression of genes utilized for existing stromal Cre recombinase models—Myh11 targeted smooth muscle and myofibroblasts, Cspg4 (Ng2) pericytes, and Fap S3
Using published gene expression data to compare the murine colonic mesenchymal subsets we identified with murine blood or lymphatic endothelial cells, pericytes, skin and thymus fibroblasts, and fibroblastic reticular cell (FRC)

Summary

Introduction

Mesenchymal cells of the intestinal lamina propria are a heterogeneous population of non-hematopoietic, non-epithelial cell types that play instrumental roles in innate immunity, immune regulation, and epithelial barrier maintenance (Nowarski et al, 2017). Their functions are impaired in inflammatory bowel disease (IBD), where they shape the inflammatory milieu, development of bowel strictures, and inflammation-associated cancers via poorly defined pathways. Intestinal mesenchymal cells help maintain the stem cell niche by producing Wnt agonists and antagonists, bone morphogenetic proteins (BMPs), and other molecules such as Noggin, Chordin, and R-spondins Deregulated expression of these genes leads to colitis, impaired intestinal wound healing, or colon tumorigenesis (Koch, 2017). Colonic mesenchymal cells influence intestinal mucosal immune cell function during development, inflammation, and tissue repair, shifting between immunosuppressive or pro-inflammatory states to determine the function of immune cells populating connective tissue (Bernardo and Fibbe, 2013)

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