Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis

Li, Bo; Lee, Carol; Cadete, Marissa; Zhu, Haitao; Koike, Yuhki; Hock, Alison; Wu, Richard; Botts, Steven R.; Minich, Adam; Alganabi, Mashriq; Chi, Lijun; Zani‐Ruttenstock, Elke; Miyake, Hideaki; Chen, Yong; Mutanen, Annika; Ngan, Bo; Johnson‐Henry, Kathene C.; Coppi, Paolo De; Eaton, Simon; Määttänen, Pekka; Delgado-Olguı́n, Paul; Sherman, Philip M.; Zani, Augusto; Pierro, Agostino

doi:10.1038/s41419-019-1987-1

Cited by 75 publications

(62 citation statements)

References 48 publications

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“…Experimental pups undergoing NEC induction (number for each study reported below) were separated from their mothers, while controls remained with mothers to breastfeed ( n = 10). NEC was induced in neonatal C57BL/6 mixed sex mice from postnatal day 5–9 by gavage feeding of hyperosmolar formula, exposure to hypoxia and oral LPS injection (day 6 and 7, 4 mg/kg) for 4 days 7 . At postnatal day 9, pups were sacrificed, and the ileum was harvested for further studies.…”

Section: Methodsmentioning

confidence: 99%

“…Murine small intestine-derived organoids were cultured according to a previous publication 7 . Briefly, small intestine was harvested from neonatal C57BL/6 mice and cut into small segments.…”

Section: Methodsmentioning

confidence: 99%

“…ISC depletion correlates with severe gut damage during NEC development 6 , and dietary agents that promote ISC expansion ameliorate NEC 5 . We recently demonstrated that ISC impairment in NEC is caused by defective Wnt signaling 7 , a pathway that plays a central role in the regulation of stem cells and tissue homeostasis 8 , 9 , including gastrointestinal epithelium 10 . To avoid the broader effects of Wnt activation that can lead to potential undesirable consequences including tumorigenesis, controlled Wnt activation is highly desirable to provide a treatment strategy for NEC.…”

Section: Introductionmentioning

confidence: 99%

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Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis

Lee

O'Connell

et al. 2020

Cell Death Dis

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Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm neonates and causing high morbidity, high mortality, and huge costs for the family and society. The treatment and the outcome of the disease have not changed in recent decades. Emerging evidence has shown that stimulating the Wnt/β-catenin pathway and enhancing intestinal regeneration are beneficial in experimental NEC, and that they could potentially be used as a novel treatment. Amniotic fluid stem cells (AFSC) and AFSC-derived extracellular vesicles (EV) can be used to improve intestinal injury in experimental NEC. However, the mechanisms by which they affect the Wnt/β-catenin pathway and intestinal regeneration are unknown. In our current study, we demonstrated that AFSC and EV attenuate NEC intestinal injury by activating the Wnt signaling pathway. AFSC and EV stimulate intestinal recovery from NEC by increasing cellular proliferation, reducing inflammation and ultimately regenerating a normal intestinal epithelium. EV administration has a rescuing effect on intestinal injury when given during NEC induction; however, it failed to prevent injury when given prior to NEC induction. AFSC-derived EV administration is thus a potential emergent novel treatment strategy for NEC.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis

Lee

O'Connell

et al. 2020

Cell Death Dis

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“…Lastly, it is important to remember that Paneth cell loss may also impact the stem cell niche. A healthy stem cell cohort is critical to induce epithelial restitution following injury as Paneth cells support the stem cell niche through the production of EGF, Notch, and Wnt (27,88,104,138).…”

Section: Paneth Cells and Necrotizing Enterocolitis (Nec)mentioning

confidence: 99%

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

2020

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Paneth cells were first described in the late 19th century by Gustav Schwalbe and Josef Paneth as columnar epithelial cells possessing prominent eosinophilic granules in their cytoplasm. Decades later there is continued interest in Paneth cells as they play an integral role in maintaining intestinal homeostasis and modulating the physiology of the small intestine and its associated microbial flora. Paneth cells are highly specialized secretory epithelial cells located in the small intestinal crypts of Lieberkühn. The dense granules produced by Paneth cells contain an abundance of antimicrobial peptides and immunomodulating proteins that function to regulate the composition of the intestinal flora. This in turn plays a significant role in secondary regulation of the host microvasculature, the normal injury and repair mechanisms of the intestinal epithelial layer, and the levels of intestinal inflammation. These critical functions may have even more importance in the immature intestine of premature infants. While Paneth cells begin to develop in the middle of human gestation, they do not become immune competent or reach their adult density until closer to term gestation. This leaves preterm infants deficient in normal Paneth cell biology during the greatest window of susceptibility to develop intestinal pathology such as necrotizing enterocolitis (NEC). As 10% of infants worldwide are currently born prematurely, there is a significant population of infants contending with an inadequate cohort of Paneth cells. Infants who have developed NEC have decreased Paneth cell numbers compared to age-matched controls, and ablation of murine Paneth cells results in a NEC-like phenotype suggesting again that Paneth cell function is critical to homeostasis to the immature intestine. This review will provide an up to date and comprehensive look at Paneth cell ontogeny, the impact Paneth cells have on the host-microbial axis in the immature intestine, and the repercussions of Paneth cell dysfunction or loss on injury and repair mechanisms in the immature gut.

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“…It is now well established that intestinal crypt cells respond to damage induced by high-dose irradiation or chemicals by activation of reserve stem cells 5,[25][26][27] . Here, we reveal intestinal crypt cells exhibit a novel response to a diarrheal virus (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transmissible gastroenteritis virus targets Paneth cells to inhibit the self-renewal and differentiation of Lgr5 intestinal stem cells via Notch signaling

Zhang

et al. 2020

Cell Death Dis

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Infection with transmissible gastroenteritis virus (TGEV) has been associated with villous atrophy within 48 h, which seriously disrupts intestinal homeostasis. However, the underlying mechanisms remain elusive. In this study, we found that TGEV infection severely disrupted intestinal homeostasis via inhibition of self-renewal and differentiation in Lgr5 intestinal stem cells (ISCs). Profoundly, TGEV-encoded NSP10/NSP16 protein complex-mediated the inactivation of Notch signaling provided a mechanistic explanation for this phenomenon. Initial invasions by TGEV-targeted Paneth cells through aminopeptidase N (APN) receptor, then inducing mitochondrial damage and ROS generation in them, ultimately causing Paneth cell decrease and loss of Notch factors (DII4 and Hes5), which are essential for Lgr5 ISCs selfrenewal and differentiation. Interestingly, loss of Notch signaling induced goblet cells differentiation at the cost of absorptive enterocytes and promoted mucins secretion, which accelerated TGEV replication. Therefore, the more differentiation of goblet cells, the greater TGEV infection in jejunum. These results provide a detailed mechanistic pathway by which villous atrophy sharply occurs in TGEV-infected jejunum within 48 h. Thus, the pathogenesis of TGEV can be described as a "bottom up scenario", which is contrary to the traditional "top down" hypothesis. Together, our findings provide a potential link between diarrheal virus infection and crypt cells response that regulates Paneth cells function and Lgr5 ISCs fate and could be exploited for therapeutic application.

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Impaired Wnt/β-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis

Cited by 75 publications

References 48 publications

Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis

Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis

The Paneth Cell: The Curator and Defender of the Immature Small Intestine

Transmissible gastroenteritis virus targets Paneth cells to inhibit the self-renewal and differentiation of Lgr5 intestinal stem cells via Notch signaling

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