L-glutamate requires β-catenin signalling through Frizzled7 to stimulate porcine intestinal stem cell expansion

Qin, Ying-Chao; Zhou, Jiayi; Zhu, Min; Zan, Geng-xiu; Gao, Chun‐qi; Yan, Huichao; Li, Xiangguang; Wang, Xiu-Qi

doi:10.1007/s00018-022-04545-2

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…Gastrointestinal health issues and related problems are major economic costs in the pig production industry. Our previous studies confirm several signals, including excitatory amino acid transporter 3, the mTOR/S6K1 pathway, the IR/IRS/PI3K/Akt pathway, and the Frizzled7/β-catenin pathway, are involved in the glutamate-induced proliferation of porcine intestinal epithelial cells and the expansion of intestinal stem cells [11][12][13][14]. In most cells, glutamine is rapidly metabolized into glutamate by the enzyme glutaminase.…”

Section: Introductionsupporting

confidence: 78%

Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells

Zhu,

Lai,

Yao

et al. 2023

Animals

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The intestinal epithelium is known for its rapid self-renewal, and glutamine is crucial in providing carbon and nitrogen for biosynthesis. However, understanding how glutamine affects gene expression in the intestinal epithelium is limited, and identifying the essential genes and signals involved in regulating intestinal epithelial cell growth is particularly challenging. In this study, glutamine supplementation exhibited a robust acceleration of intestinal epithelial cell proliferation and stem cell expansion. RNA sequencing indicated diverse transcriptome changes between the control and glutamine supplementation groups, identifying 925 up-regulated and 1152 down-regulated genes. The up-regulated DEGs were enriched in the KEGG pathway of cell cycle and GO terms of DNA replication initiation, regulation of phosphatidylinositol 3-kinase activity, DNA replication, minichromosome maintenance protein (MCM) complex, and ATP binding, whereas the down-regulated DEGs were enriched in the KEGG pathway of p53 signaling pathway, TNF signaling pathway, and JAK-STAT signaling pathway and GO terms of inflammatory response and intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress. Furthermore, GSEA analysis revealed a significant up-regulation of the cell cycle, DNA replication initiation, ATP-dependent RNA helicase activity, and down-regulation of the TNF signaling pathway. The protein–protein association network of the intersecting genes highlighted the significance of DNA replication licensing factors (MCM3, MCM6, and MCM10) in promoting intestinal epithelial growth in response to glutamine. Based on these findings, we propose that glutamine may upregulate DNA replication licensing factors, leading to increased PI3K/Akt signaling and the suppression of TNF, JAK-STAT, and p53 pathways. Consequently, this mechanism results in the proliferation of porcine intestinal epithelial cells and the expansion of intestinal stem cells.

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Section: Introductionsupporting

confidence: 78%

Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells

Zhu,

Lai,

Yao

et al. 2023

Animals

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“…28,29 Importantly, FZD7 receives a wide range of beneficial or harmful signals. 13,30 Besides Wnt ligands, FZD7 can also bind with non-Wnt ligands, such as Clostridium difficile toxin B (TcdB) and glutamate, to regulate ISC expansion. 31,32 In our study, morin might have interacted with FZD7, which reactivates β-catenin to initiate the βcatenin axis in the ISCs.…”

Section: Discussionmentioning

confidence: 99%

“…Canonical Wnt/β-catenin signaling is mediated by the membrane receptor subtype FZD1/2/7 . The FZD7, but not FZD1 or FZD2, is frequently upregulated and required for robust Wnt-dependent processes during regeneration in mammalian ISCs. , Importantly, FZD7 receives a wide range of beneficial or harmful signals. , Besides Wnt ligands, FZD7 can also bind with non-Wnt ligands, such as Clostridium difficile toxin B (TcdB) and glutamate, to regulate ISC expansion. , In our study, morin might have interacted with FZD7, which reactivates β-catenin to initiate the β-catenin axis in the ISCs. However, how STb interacts with FZD7/β-catenin is not clear.…”

Section: Discussionmentioning

confidence: 99%

Mulberry Leaf-Derived Morin Activates β-Catenin by Binding to Frizzled7 to Promote Intestinal Stem Cell Expansion upon Heat-Stable Enterotoxin b Injury

Zhou,

Xie,

et al. 2024

J. Agric. Food Chem.

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Intestinal stem cells (ISCs) sustain epithelial renewal by dynamically altering behaviors of proliferation and differentiation in response to various nutrition and stress inputs. However, how ISCs integrate bioactive substance morin cues to protect against heat-stable enterotoxin b (STb) produced by Escherichia coli remains an uncertain question with implications for treating bacterial diarrhea. Our recent work showed that oral mulberry leaf-derived morin improved the growth performance in STbchallenged mice. Furthermore, morin supplementation reinstated the impaired small-intestinal epithelial structure and barrier function by stimulating ISC proliferation and differentiation as well as supporting intestinal organoid expansion ex vivo. Importantly, the Wnt/β-catenin pathway, an ISC fate commitment signal, was reactivated by morin to restore the jejunal crypt-villus architecture in response to STb stimulation. Mechanically, the extracellular morin-initiated β-catenin axis is dependent or partially dependent on the Wnt membrane receptor Frizzled7 (FZD7). Our data reveal an unexpected role of leaf-derived morin, which represents molecular signaling targeting the FZD7 platform instrumental for controlling ISC regeneration upon STb injury.

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“… 138 L-glutamate has been found to regulate ISC fate through complex mechanisms, involving the EGFR-ERK-mTORC1 pathway 139 and the amplification of β-catenin through the switching of the membrane receptor Frizzled7. 140 In Drosophila , L-glutamate stimulates ISC fate through regulating calcineurin and CREB-regulated transcriptional co-activator via Ca 2+ signaling. 141 Glutamine, another crucial amino acid, serves as the preferred energy substrate for intestinal epithelial cells, promoting ISC activity to accelerate intestinal epithelial regeneration through enhanced Wnt signaling.…”

Section: Interplay Between Host and Microbiota In Isc Homeostasismentioning

confidence: 99%

Host-microbiota interaction in intestinal stem cell homeostasis

Wu,

Mu,

et al. 2024

Gut Microbes

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Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host–microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.

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L-glutamate requires β-catenin signalling through Frizzled7 to stimulate porcine intestinal stem cell expansion

Cited by 7 publications

References 31 publications

Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells

Glutamine Regulates Gene Expression Profiles to Increase the Proliferation of Porcine Intestinal Epithelial Cells and the Expansion of Intestinal Stem Cells

Mulberry Leaf-Derived Morin Activates β-Catenin by Binding to Frizzled7 to Promote Intestinal Stem Cell Expansion upon Heat-Stable Enterotoxin b Injury

Host-microbiota interaction in intestinal stem cell homeostasis

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