Arachidonic Acid Promotes Intestinal Regeneration by Activating WNT Signaling

Wang, Qingyu; Lin, Yingying; Sheng, Xiaole; Xu, Jiuzhi; Hou, Xuening; Li, Yuan; Zhang, Hao; Guo, Huiyuan; Yu, Zhengquan; Ren, Fazheng

doi:10.1016/j.stemcr.2020.06.009

Cited by 33 publications

(28 citation statements)

References 38 publications

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“…A recent study showed that arachidonic acid negatively regulated intestinal epithelial cell differentiation and induced mouse enteroids to develop into cystic structures. 26 Although enteroids are Wnt-dependent and spheroids can grow in the RSPO1-depleted medium, these spheroids retained the potential to form buds in the presence of RSPO1. 7 We also found that STp suppressed the Wnt/β-catenin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Heat-stable enterotoxin inhibits intestinal stem cell expansion to disrupt the intestinal integrity by downregulating the Wnt/β-catenin pathway

et al. 2021

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Enterotoxigenic Escherichia coli causes severe infectious diarrhea with high morbidity and mortality in newborn and weanling pigs mainly through the production of heatstable enterotoxins (STs). However, the precise regulatory mechanisms involved in STinduced intestinal epithelium injury remain unclear. Consequently, we conducted the experiments in vivo (mice), ex vivo (mouse and porcine enteroids), and in vitro (MODE-K and IPEC-J2 cells) to explore the effect of STp (one type of STa) on the integrity of the intestinal epithelium. The results showed that acute STp exposure led to small intestinal edema, disrupted intestinal integrity, induced crypt cell expansion into spheroids, and downregulated Wnt/β-catenin activity in the mice. Following a similar trend, the enteroid-budding efficiency and the expression of Active β-catenin, β-catenin, Lgr5, PCNA, and KRT20 were significantly decreased after STp treatment, as determined ex vivo. In addition, STp inhibited cell proliferation, induced cell apoptosis, destroyed cell barriers, and reduced Wnt/β-catenin activity by downregulating its membrane receptor Frizzled7 (FZD7). In contrast, Wnt/β-catenin reactivation protected the IPEC-J2 cells from STp-induced injury. Taking these findings together, we conclude that STp inhibits intestinal stem cell expansion to disrupt the integrity of the intestinal mucosa through the downregulation of the Wnt/β-catenin signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Heat-stable enterotoxin inhibits intestinal stem cell expansion to disrupt the intestinal integrity by downregulating the Wnt/β-catenin pathway

et al. 2021

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“…They discovered that AA promotes the proliferation of SI epithelial cells post irradiation in an Ascl2I and WNT signaling manner. Most notably, AA’s regenerative effect was mediated via the regulation of Msi1+ radiation resistant cells, not Lgr5 + cells, but the exact mechanism is not known ( Wang et al, 2020 ).…”

Section: The Role Of +4 Position Cells and Secretory Precursors In Rementioning

confidence: 99%

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Rees

Tandun

Yau

et al. 2020

Front. Cell Dev. Biol.

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The intestinal epithelium is replenished every 3–4 days through an orderly process that maintains important secretory and absorptive functions while preserving a continuous mucosal barrier. Intestinal epithelial cells (IECs) derive from a stable population of intestinal stem cells (ISCs) that reside in the basal crypts. When intestinal injury reaches the crypts and damages IECs, a mechanism to replace them is needed. Recent research has highlighted the existence of distinct populations of acute and chronic damage-associated ISCs and their roles in maintaining homeostasis in several intestinal perturbation models. What remains unknown is how the damage-associated regenerative ISC population functions in the setting of chronic inflammation, as opposed to acute injury. What long-term consequences result from persistent inflammation and other cellular insults to the ISC niche? What particular “regenerative” cell types provide the most efficacious restorative properties? Which differentiated IECs maintain the ability to de-differentiate and restore the ISC niche? This review will cover the latest research on damage-associated regenerative ISCs and epigenetic factors that determine ISC fate, as well as provide opinions on future studies that need to be undertaken to understand the repercussions of the emergence of these cells, their contribution to relapses in inflammatory bowel disease, and their potential use in therapeutics for chronic intestinal diseases.

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“…Although not a microbiota-derived metabolite per se, arachidonic acid deserves mention as an essential dietary fatty acid with broad anti-microbial properties that may influence both the microbiota landscape [ 213 ] and ISC function [ 214 ]. As such, arachidonic acid is thought to selectively favour the growth of commensal bacteria but suppress the proliferation of pathogenic microbiota [ 213 ], in addition to enhancing the proliferative and regenerative response of the small-intestinal epithelium to irradiation [ 214 ]. Mechanistically, arachidonic acid elevates the expression of Ascl2 , the master regulator of Wnt signalling [ 73 , 214 ].…”

Section: Microbiota-derived Metabolites and Isc Functionmentioning

confidence: 99%

“…As such, arachidonic acid is thought to selectively favour the growth of commensal bacteria but suppress the proliferation of pathogenic microbiota [ 213 ], in addition to enhancing the proliferative and regenerative response of the small-intestinal epithelium to irradiation [ 214 ]. Mechanistically, arachidonic acid elevates the expression of Ascl2 , the master regulator of Wnt signalling [ 73 , 214 ]. Yet, interestingly, arachidonic acid exerts its pro-regenerative effects on the recently described Msi1 + radioresistant ISC pool [ 45 , 214 ], rather than Lgr5 + ISCs, which are in fact depleted by arachidonic acid treatment [ 214 ].…”

Section: Microbiota-derived Metabolites and Isc Functionmentioning

confidence: 99%

“…Mechanistically, arachidonic acid elevates the expression of Ascl2 , the master regulator of Wnt signalling [ 73 , 214 ]. Yet, interestingly, arachidonic acid exerts its pro-regenerative effects on the recently described Msi1 + radioresistant ISC pool [ 45 , 214 ], rather than Lgr5 + ISCs, which are in fact depleted by arachidonic acid treatment [ 214 ].…”

Section: Microbiota-derived Metabolites and Isc Functionmentioning

confidence: 99%

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Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

Sphyris

Hodder

Sansom

2021

Cancers

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The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints (“ISC emancipation”) and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.

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Arachidonic Acid Promotes Intestinal Regeneration by Activating WNT Signaling

Cited by 33 publications

References 38 publications

Heat-stable enterotoxin inhibits intestinal stem cell expansion to disrupt the intestinal integrity by downregulating the Wnt/β-catenin pathway

Heat-stable enterotoxin inhibits intestinal stem cell expansion to disrupt the intestinal integrity by downregulating the Wnt/β-catenin pathway

Regenerative Intestinal Stem Cells Induced by Acute and Chronic Injury: The Saving Grace of the Epithelium?

Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

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