Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease

• Published in: Cell Vol. 175; no. 2; pp. 372 - 386.e17
• Main Authors: Kinchen, James, Chen, Hannah H., Parikh, Kaushal, Antanaviciute, Agne, Jagielowicz, Marta, Fawkner-Corbett, David, Ashley, Neil, Cubitt, Laura, Mellado-Gomez, Esther, Attar, Moustafa, Sharma, Eshita, Wills, Quin, Bowden, Rory, Richter, Felix C., Ahern, David, Puri, Kamal D., Henault, Jill, Gervais, Francois, Koohy, Hashem, Simmons, Alison
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.10.2018; Cell Press
• Subjects: Animals; Cell Proliferation; colitis; Colitis - genetics; Colitis - physiopathology; Colon - physiology; crypt niche; CyTOF; disease severity; epithelial cells; Epithelial Cells - metabolism; epithelium; fibroblasts; Fibroblasts - physiology; genes; Genetic Heterogeneity; Homeostasis; Humans; immunity; Inflammation; inflammatory bowel disease; Inflammatory Bowel Diseases - physiopathology; Intestinal Mucosa - immunology; Intestinal Mucosa - physiology; intestines; Intestines - immunology; Intestines - physiology; Mesenchymal Stem Cells - physiology; mesenchyme; Mesoderm - metabolism; Mesoderm - physiology; Mice; Mice, Inbred C57BL; Myofibroblasts; oxidative stress; Pericytes; protein-lysine 6-oxidase; RAW 264.7 Cells; Single-Cell Analysis - methods; single-cell RNA-seq; SOX6; SOXD Transcription Factors - physiology; stem cells; stratification; stromal cell; target discovery; Thromboplastin - physiology; TNFSF14; transcription factors; Tumor Necrosis Factor Ligand Superfamily Member 14 - genetics; tumor necrosis factors; Wnt Signaling Pathway - physiology; Wnts; stromal cell; mesenchyme; target discovery; TNFSF14; stratification; single-cell RNA-seq; SOX6; crypt niche; CyTOF; inflammatory bowel disease; Wnts
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.08.067

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. [Display omitted] •Single-cell census of the colonic mesenchyme reveals unexpected heterogeneity•Identification of the colonic crypt niche mesenchymal cell expressing SOX6 and Wnts•Definition of fundamental aspects of mesenchymal remodeling in colitis•Analysis of colitis-associated mesenchymal cells reveals pathogenicity drivers Single-cell profiling of human colonic mesenchymal cells identifies a colitis-associated population that expresses factors contributing to epithelial cell dysfunction and inflammation.