Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis

被引：845

作者：

Smillie, Christopher S. ^{[1
]}

Biton, Moshe ^{[1
,2
]}

Ordovas-Montanes, Jose ^{[1
,3
,4
,5
,6
,7
,8
]}

Sullivan, Ken M. ^{[9
,10
]}

Burgin, Grace ^{[1
]}

Graham, Daniel B. ^{[2
,9
,10
,11
,12
,13
]}

Herbst, Rebecca H. ^{[1
,14
]}

Rogel, Noga ^{[1
]}

Slyper, Michel ^{[1
]}

Waldman, Julia ^{[1
]}

Sud, Malika ^{[1
]}

Andrews, Elizabeth ^{[9
,10
]}

Velonias, Gabriella ^{[9
,10
]}

Haber, Adam L. ^{[1
]}

Jagadeesh, Karthik ^{[1
]}

Vickovic, Sanja ^{[1
]}

Yao, Junmei ^{[16
]}

Stevens, Christine ^{[11
]}

Dionne, Danielle ^{[1
]}

Nguyen, Lan T. ^{[1
]}

Villani, Alexandra-Chloe ^{[1
,15
]}

Hofree, Matan ^{[1
]}

Creasey, Elizabeth A. ^{[16
]}

Huang, Hailiang ^{[17
,18
]}

Rozenblatt-Rosen, Orit ^{[1
]}

Garber, John J. ^{[9
,10
]}

Khalili, Hamed ^{[9
,10
]}

Desch, A. Nicole ^{[11
,16
]}

Daly, Mark J. ^{[17
,18
,19
]}

Ananthakrishnan, Ashwin N. ^{[9
,10
]}

Shalek, Alex K. ^{[1
,3
,4
,5
,6
]}

Xavier, Ramnik J. ^{[2
,9
,10
,11
,12
,13
,16
]}

Regev, Aviv ^{[1
,20
,21
]}

机构：

[1] Broad Inst, Klarman Cell Observ, Cambridge, MA 02142 USA

[2] MGH, Dept Mol Biol, Boston, MA 02114 USA

[3] MIT, IMES, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] MIT, Dept Chem, Cambridge, MA 02139 USA

[5] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] MIT & Harvard, Ragon Inst MGH, Cambridge, MA 02139 USA

[7] Boston Childrens Hosp, Div Infect Dis, Boston, MA USA

[8] Boston Childrens Hosp, Div Gastroenterol, Boston, MA USA

[9] MGH, Gastrointestinal Unit, Boston, MA 02114 USA

[10] MGH, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA

[11] Broad Inst, Cambridge, MA 02142 USA

[12] Harvard Med Sch, Boston, MA 02115 USA

[13] MIT, Ctr Microbiome Informat & Therapeut, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[14] Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA

[15] MGH, Dept Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA

[16] MGH, Ctr Computat & Integrat Biol, Boston, MA 02114 USA

[17] Broad Inst, Med & Populat Genet, Cambridge, MA USA

[18] MGH, Analyt & Translat Genet Unit, Boston, MA USA

[19] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[20] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[21] MIT, Dept Biol, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

来源：

CELL | 2019年 / 178卷 / 03期

关键词：

INFLAMMATORY-BOWEL-DISEASE; GENE-EXPRESSION; RNA-SEQ; DENDRITIC CELLS; T-CELLS; DATABASE; LOCI; DIFFERENTIATION; ASSOCIATION; ANTIBODIES;

D O I：

10.1016/j.cell.2019.06.029

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4(+) enterocytes, microfold-like cells, and IL13RA2(+)IL11(+) inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and coregulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

引用

页码：714 / +

页数：39

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