Acute exposure to deoxynivalenol inhibits porcine enteroid activity via suppression of the Wnt/β-catenin pathway

Li, Xiangguang; Zhu, Min; Chen, Mingxia; Fan, Hongyuan; Fu, Hou-Long; Zhou, Jiayi; Zhai, Zhe; Gao, Chun‐qi; Yan, Huichao; Wang, Xiu-Qi

doi:10.1016/j.toxlet.2019.01.008

Cited by 65 publications

(55 citation statements)

References 39 publications

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“…Furthermore, considering the high similarity between pig and human physiological conditions, the ISC model of porcine may provide a feasible approach for predicting and treating some intestinal diseases. Thus, we established a three‐dimensional culture system of the porcine enteroid and used the model to simulate the effects of heat exposure on the intestine structure and function (X. G. Li et al, 2019; Zhou, Huang, et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Wnt/β‐catenin‐mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress

Zhou

Huang

Zhu

et al. 2020

Journal Cellular Physiology

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Heat stress induced by continuous high ambient temperatures or strenuous exercise in humans and animals leads to intestinal epithelial damage through the induction of intracellular stress response. However, the precise mechanisms involved in the regulation of intestinal epithelial cell injury, especially intestinal stem cells (ISCs), remain unclear. Thereby, in vitro a confluent monolayer of IPEC‐J2 cells was exposed to the high temperatures (39, 40, and 41°C), the IPEC‐J2 cell proliferation, apoptosis, differentiation, and barrier were determined, as well as the expression of GRP78, which is a marker protein of endoplasmic reticulum stress (ERS). The Wnt/β‐catenin pathway‐mediated regenerative response was validated using R‐spondin 1 (Rspo1). And ex‐vivo, three‐dimensional cultured enteroids were developed from piglet jejunal crypt and employed to assess the ISC activity under heat exposure. The results showed that exposure to 41°C for 72 hr, rather than 39°C and 40°C, decreased IPEC‐J2 cell viability, inhibited cell proliferation and differentiation, induced ERS and cell apoptosis, damaged barrier function and restricted the Wnt/β‐catenin pathway. Nevertheless, Wnt/β‐catenin reactivation via Rspo1 protects the intestinal epithelium from heat exposure‐induced injury. Furthermore, exposure to 41°C for 24 hr reduced ISC activity, stimulated crypt‐cell apoptosis, upregulated the expression of GRP78 and caspase‐3, and downregulated the expression of β‐catenin, Lgr5, Bmi1, Ki67, KRT20, ZO‐1, occludin, and claudin‐1. Taken together, we conclude that heat exposure induces ERS and downregulates the Wnt/β‐catenin signaling pathway to disrupt epithelial integrity by inhibiting the intestinal epithelial cell proliferation and stem cell expansion.

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Section: Introductionmentioning

confidence: 99%

Wnt/β‐catenin‐mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress

Zhou

Huang

Zhu

et al. 2020

Journal Cellular Physiology

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“…The enteroids prepared from the crypts were cultured for four days before evaluation ( Figure 5 A). Enteroid-forming efficiency, broadly used to assess stem cell function [ 18 , 19 , 22 , 23 ], was significantly decreased in enteroids from mice orally administrated with DON ( Figure 5 B,C). Furthermore, intestinal cell proliferation was significantly suppressed in enteroids from the mice after oral DON administration ( Figure 5 D,E).…”

Section: Resultsmentioning

confidence: 99%

“…Subsequently, establishing a protocol to generate enteroids was the breakthrough in studying intestinal stem cells in vitro [ 17 ]. Using this model, Li et al [ 22 ] demonstrated that basolateral DON exposure (adding DON to a porcine enteroid culture medium) inhibited intestinal stem cell activity through the Wnt/β-catenin pathway. Thus, we further explored the effects of luminal or basolateral DON exposure on intestinal stem cells.…”

Section: Discussionmentioning

confidence: 99%

Mycotoxin Deoxynivalenol Has Different Impacts on Intestinal Barrier and Stem Cells by Its Route of Exposure

Hanyu

Yokoi

Nakamura

et al. 2020

Toxins

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The different effects of deoxynivalenol (DON) on intestinal barrier and stem cells by its route of exposure remain less known. We explored the toxic effects of DON on intestinal barrier functions and stem cells after DON microinjection (luminal exposure) or addition to a culture medium (basolateral exposure) using three-dimensional mouse intestinal organoids (enteroids). The influx test using fluorescein-labeled dextran showed that basolateral DON exposure (1 micromolar (µM) disrupted intestinal barrier functions in enteroids compared with luminal DON exposure at the same concentration. Moreover, an immunofluorescence experiment of intestinal epithelial proteins, such as E-cadherin, claudin, zonula occludens-1 (ZO-1), and occludin, exhibited that only basolateral DON exposure broke down intestinal epithelial integrity. A time-lapse analysis using enteroids from leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)-enhanced green fluorescence protein (EGFP) transgenic mice and 5-ethynyl-2-deoxyuridine (EdU) assay indicated that only the basolateral DON exposure, but not luminal DON exposure, suppressed Lgr5+ stem cell count and proliferative cell ratio, respectively. These results revealed that basolateral DON exposure has larger impacts on intestinal barrier function and stem cells than luminal DON exposure. This is the first report that DON had different impacts on intestinal stem cells depending on the administration route. In addition, RNA sequencing analysis showed different expression of genes among enteroids after basolateral and luminal DON exposure.

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“…Species-specific organoids, as recently demonstrated (Li et al, 2019), can be predictive models for adverse effects, suggesting further applications for an innovative approach in toxicology.…”

Section: Future Perspective Of Species-specific Models In Toxicologymentioning

confidence: 85%

“…Porcine enteroids were recently used as an in vitro predictive tool in toxicology to study the effects of the mycotoxin deoxynivalenol, through the evaluation of specific endpoints (Li et al, 2019).…”

Section: Swine Intestinal Organoidsmentioning

confidence: 99%

Organoids are promising tools for species‐specific in vitro toxicological studies

Augustyniak

Bertero

Coccini³

et al. 2019

J of Applied Toxicology

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Organoids are three‐dimensional self‐aggregating structures generated from stem cells (SCs) or progenitor cells in a process that recapitulates molecular and cellular stages of early organ development. The differentiation process leads to the appearance of specialized mature cells and is connected with changes in the organoid internal structure rearrangement and self‐organization. The formation of organ‐specific structures in vitro with highly ordered architecture is also strongly influenced by the extracellular matrix. These features make organoids as a powerful model for in vitro toxicology. Nowadays this technology is developing very quickly. In this review we present, from a toxicological and species‐specific point of view, the state of the art of organoid generation from adult SCs and pluripotent SCs: embryonic SCs or induced pluripotent SCs. The current culture organoid techniques are discussed for their main advantages, disadvantages and limitations. In the second part of the review, we concentrated on the characterization of species‐specific organoids generated from tissue‐specific SCs of different sources: mammary (bovine), epidermis (canine), intestinal (porcine, bovine, canine, chicken) and liver (feline, canine).

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Acute exposure to deoxynivalenol inhibits porcine enteroid activity via suppression of the Wnt/β-catenin pathway

Cited by 65 publications

References 39 publications

Wnt/β‐catenin‐mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress

Wnt/β‐catenin‐mediated heat exposure inhibits intestinal epithelial cell proliferation and stem cell expansion through endoplasmic reticulum stress

Mycotoxin Deoxynivalenol Has Different Impacts on Intestinal Barrier and Stem Cells by Its Route of Exposure

Organoids are promising tools for species‐specific in vitro toxicological studies

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