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

Smillie, Christopher; Biton, Moshe; Ordovás-Montañés, José; Sullivan, Keri M.; Burgin, Grace; Graham, Daniel B.; Herbst, Rebecca H.; Rogel, Noga; Slyper, Michal; Waldman, Julia; Sud, Malika; Andrews, Elizabeth; Velonias, Gabriella; Haber, Adam L.; Jagadeesh, Karthik A.; Vicković, Sanja; Yao, Junmei; Stevens, Christine; Dionne, Danielle; Nguyễn, Lan; Villani, Alexandra‐Chloé; Hofree, Matan; Creasey, Elizabeth A.; Huang, Hailiang; Rozenblatt-Rosen, Orit; Garber, John J.; Khalili, Hamed; Desch, A. Nicole; Daly, Mark J.; Ananthakrishnan, Ashwin N.; Shalek, Alex K.; Xavier, Ramnik J.; Regev, Aviv

doi:10.1016/j.cell.2019.06.029

Cited by 1,004 publications

(1,469 citation statements)

References 77 publications

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“…Of interest, LEFTY1 is a developmental gene, the role of which in adult tissue remains to be investigated. Recently, LEFTY1 has been identified as a marker of colonic stem cells both in fetal and adult large intestine . This is consistent with the LEFTY1 staining we observed in the normal colon.…”

Section: Discussionsupporting

confidence: 91%

Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas

Sohier

Sanson

Audebourg

et al. 2019

The Journal of Pathology

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Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label‐free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin‐fixed paraffin‐embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well‐individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFβ pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 91%

Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas

Sohier

Sanson

Audebourg

et al. 2019

The Journal of Pathology

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“…The effect of IL11 on the vasculature will be discussed elsewhere. Considered together with patient studies that show IL11 to be highly upregulated in the colonic mucosa of patients with ulcerative colitis or Crohn's disease [24][25][26], our results highlight IL11 as a promising therapeutic target for IBD, particularly in the context of anti-TNF therapy resistance.…”

Section: Discussionmentioning

confidence: 54%

“…In humans, IL11 is highly upregulated in the colonic mucosa of patients with either ulcerative colitis or Crohn's disease who do not respond to anti-TNF therapy, with recent single cell RNA-seq studies localizing IL11 to inflammatory mucosal stromal cells [24][25][26]. To better understand the effect of IL11 in the colon, recombinant human IL11 has been used in rodent models of IBD [27][28][29][30] and it was suggested that IL11 may have a protective role in the bowel.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 11 expression causes murine inflammatory bowel disease

Lim

Widjaja

et al. 2019

Preprint

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Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11 SMC ). Within days of transgene activation, Il11 SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11 SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11 Fib mouse. This additional model largely phenocopied the Il11 SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn's disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease. Main textNon-striated smooth muscle cells (SMCs) line the walls of hollow organs and the vasculature. In adults, SMCs are not terminally differentiated and their cellular phenotype remains plastic. A variety of extracellular cues such as humoral factors, mechanical or oxidative stress and cell-cell interactions can induce a spectrum of cellular states ranging from contractile SMCs to highly synthetic and proliferative SMCs [1]. Synthetic SMCs are associated with a wide variety of vascular pathologies such as atherosclerosis or hypertension [1] and other disorders such as asthma [2] and inflammatory bowel disease (IBD) [3]. Many fibro-inflammatory diseases have a component, or are defined by, SMCdysfunction. This is exemplified by systemic sclerosis, which presents with global organ fibrosis and specific vascular abnormalities [4] and is characterized by elevated transforming growth factor beta (TGFB) 2 and interleukin 11 (IL11) expression in dermal stromal cells [5,6]. This co-occurrence of fibrosis and SMC dysfunction may in part be explained by molecular similarities of the fibrogenic fibroblast-to-myofibroblast conversion and the SMC contractile-to-synthetic phenotype switch. Both these cellular transitions are characterized by extracellular matrix (ECM) production, cell proliferation, invasion and migration. They can also be triggered by the same extracellular cues including TGFB family members [1,7].We recently identified IL11 as a critical driver of fibroblast activation in the cardiovascular system, liver and lung downstream of a variety of pro-fibrotic factors including TGFB1 [8][9][10].In a study from 1999, IL11 was also found to be secreted by ...

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“…While fibroblasts have been implicated in inflammation-associated pathology of rheumatoid arthritis, colitis and IPF (7,(15)(16)(17)(18), it has not been shown conclusively whether the stroma is a modifier or primary driver of the inflammatory response. In the BLM model of lung fibrosis, we found that the deletion of IL11 signaling in fibroblasts alone is sufficient to protect mice from inflammation in the lung.…”

Section: Combined Results and Discussionmentioning

confidence: 99%

“…Further studies are required to delineate whether distinct subpopulations of IL11-responsive fibroblasts drive lung fibrosis and inflammation. It will also be important to examine whether IL11-dependent, fibroblast-mediated inflammation occurs in other lung diseases, such as asthma (26,27) or additional conditions such as rheumatoid arthritis or colitis (15)(16)(17)(18). Preliminary functional studies suggest this may be the case, at least for colitis (10), which is characterized by IL11expressing inflammatory fibroblasts that predict disease severity in patients (17).…”

Section: Combined Results and Discussionmentioning

confidence: 99%

Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation

Dong

Sivakumar

et al. 2019

Preprint

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Tissue injury leads to activation of resident stromal, parenchymal and immune cells to initiate reparative processes that, if unresolved, can lead to fibrosis and organ damage. The directionality of effect between fibrosis and inflammation in the lung has been a point of debate for many years. Here, we tested the hypothesis that Interleukin 11 (IL11) signaling in fibroblasts is of primary importance for pulmonary fibrosis and that this event is upstream of lung inflammation. We generated mice with loxP-flanked Il11ra1 alleles and crossed them to a Col1a2-CreERT strain to enable Il11ra1 deletion in adult fibroblasts (Il11ra1-CKO mice). Lung fibroblasts from Il11ra1-CKO mice were selectively deleted for Il11ra1 and refractory to TGFβ1 stimulation. In the mouse model of bleomycin-induced lung fibrosis, Il11ra1-CKO mice had markedly reduced pulmonary fibrosis and lesser lung damage, which was accompanied by diminished ERK activation in the stromal compartment. Bleomycin lung injury in Il11ra1-CKO mice was also associated with diminished STAT3 activation in inflammatory cells, fewer pulmonary immune cell infiltrates and almost complete inhibition of NF-kB activation. These data reveal an essential role for IL11 signaling in fibroblasts for lung fibrosis and show that inflammation in the lung can be secondary to stromal activation.

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

Cited by 1,004 publications

References 77 publications

Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas

Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas

Interleukin 11 expression causes murine inflammatory bowel disease

Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation

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