Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting Enteropathy

Das, Balaram; Okamoto, Kevin; Rabalais, John; Young, Jocelyn; Barrett, Kim E.; Sivagnanam, Mamata

doi:10.1016/j.jcmgh.2021.06.015

Cited by 6 publications

(7 citation statements)

References 47 publications

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“…Increased cleavage and the resulting loss of EpCAM function were proposed as the mechanism leading to intestinal insufficiency in CTE individuals carrying SPINT2 mutations ( Wu et al, 2017 ; Das et al, 2021 ). Indeed, intestinal defects in two recently developed Spint2 -deficient mouse models of CTE are associated with a substantial decrease in detectable EpCAM protein and a loss of its membrane localization ( Szabo and Bugge, 2018 ; Kawaguchi et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM

et al. 2023

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Congenital tufting enteropathy (CTE) is a life-threatening intestinal disorder resulting from loss-of-function mutations in EPCAM and SPINT2. Mice deficient in Spint2, encoding protease inhibitor HAI-2, develop CTE-like intestinal failure associated with a progressive loss of EpCAM protein that is caused by unchecked activity of the serine protease, matriptase. Here, we show that loss of HAI-2 leads to an increased proteolytic processing of EpCAM. Elimination of the reported matriptase cleavage site strongly suppressed proteolytic processing of EpCAM in vitro and in vivo. Unexpectedly, expression of cleavage-resistant EpCAM failed to prevent intestinal failure and postnatal lethality in Spint2-deficient mice. In addition, genetic inactivation of intestinal matriptase counteracted the effect of Spint2 deficiency in mice expressing cleavage-resistant EpCAM, indicating that matriptase does not drive intestinal dysfunction by excessive proteolysis of EpCAM. Interestingly, mice expressing cleavage-resistant EpCAM developed late-onset intestinal defects and exhibited a shortened life span even in the presence of HAI-2, suggesting that EpCAM cleavage is indispensable for EpCAM function. Our findings provide new insights into the role of EpCAM and the etiology of the enteropathies driven by the Spint2 deficiency.

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Section: Resultsmentioning

confidence: 99%

Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM

et al. 2023

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“…Notch signaling plays a vital role in regulating cell fate determination in differentiation as well as maintaining intestinal homeostasis and regeneration 12,44 . − 46 Downregulation of the Notch signaling pathway has been demonstrated to cause disruption of the intestinal epithelial differentiation pattern 47 . Hippo signaling is critical in maintaining IESC survival and growth in colon colonoid culture and has been involved in the regulation of intestinal tissue homeostasis 10,27 .…”

Section: Discussionmentioning

confidence: 99%

Colonic crypt stem cell functions are controlled by tight junction protein claudin‐7 through Notch/Hippo signaling

Naser,

Xing,

Tatum

et al. 2024

Annals of the New York Academy of Sciences

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The tight junction protein claudin‐7 is essential for tight junction function and intestinal homeostasis. Cldn7 deletion in mice leads to an inflammatory bowel disease‐like phenotype exhibiting severe intestinal epithelial damage, weight loss, inflammation, mucosal ulcerations, and epithelial hyperplasia. Claudin‐7 has also been shown to be involved in cancer metastasis and invasion. Here, we test our hypothesis that claudin‐7 plays an important role in regulating colonic intestinal stem cell function. Conditional knockout of Cldn7 in the colon led to impaired epithelial cell differentiation, hyperproliferative epithelium, a decrease in active stem cells, and dramatically altered gene expression profiles. In 3D colonoid culture, claudin‐7–deficient crypts were unable to survive and form spheroids, emphasizing the importance of claudin‐7 in stem cell survival. Inhibition of the Hippo pathway or activation of Notch signaling partially rescued the defective stem cell behavior. Concurrent Notch activation and Hippo inhibition resulted in restored colonoid survival, growth, and differentiation to the level comparable to those of wild‐type derived crypts. In this study, we highlight the essential role of claudin‐7 in regulating Notch and Hippo signaling–dependent colonic stem cell functions, including survival, self‐renewal, and differentiation. These new findings may shed light on potential avenues to explore for drug development in colorectal cancer.

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“…In our samples there was a great deal of variability in epithelial height, which often showed marked irregularity resembling tufting enteropathy. Tufting enteropathy is a severe congenital childhood enteropathy which has now been reproduced in vitro in an EpCAM mutation model ( 44 ). It would be of interest to determine if disturbances of EpCAM expression play a role in environmental enteropathy.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Abnormalities in the Small Intestine of Zambian Children With Stunting

et al. 2022

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BackgroundEnvironmental enteropathy (EE) contributes to impaired linear growth (stunting), in millions of children worldwide. We have previously reported that confocal laser endomicroscopy (CLE) shows fluorescein leaking from blood to gut lumen in vivo in adults and children with EE. We set out to identify epithelial lesions which might explain this phenomenon in Zambian children with stunting non-responsive to nutritional support.MethodsWe performed confocal laser endomicroscopy (CLE) in 75 children and collected intestinal biopsies for histology in 91 children. CLE videos were evaluated, employing the Watson score to determine severity of leakiness. Morphometry was carried out on well-orientated mucosa and 3 biopsies were examined by electron microscopy.ResultsConfocal laser endomicroscopy demonstrated substantial leakage from circulation to gut lumen in 73 (97%) children. Histology consistently showed characteristic changes of EE: villus blunting, lamina propria and epithelial inflammation, and depletion of secretory cells (Paneth cells and goblet cells). Epithelial abnormalities included marked variability in epithelial height, disorganised and shortened microvilli, dilated intercellular spaces, pseudostratification, formation of synechiae between epithelium on adjacent villi, crypt destruction, and abundant destructive lesions which may correspond to the microerosions identified on CLE.ConclusionEpithelial abnormalities were almost universal in Zambian children with non-responsive stunting, including epithelial microerosions, cell-cell adhesion anomalies, and defects in secretory cells which may all contribute to impairment of mucosal barrier function and microbial translocation.

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Aberrant Epithelial Differentiation Contributes to Pathogenesis in a Murine Model of Congenital Tufting Enteropathy

Cited by 6 publications

References 47 publications

Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM

Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM

Colonic crypt stem cell functions are controlled by tight junction protein claudin‐7 through Notch/Hippo signaling

Epithelial Abnormalities in the Small Intestine of Zambian Children With Stunting

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