AQP5 enriches for stem cells and cancer origins in the distal stomach

Tan, Si Hui; Yada, Swathi; Tan, Shawna; Goh, Jonathan; Seishima, Ryo; Murakami, Kazuhiro; Oshima, Masanobu; Tsuji, Toshikatsu; Phuah, Phyllis; Tan, Liang Juin; Wong, Esther; Fatehullah, Aliya; Tong, S. Y.; Ho, Shamaine Wei Ting; Grabsch, Heike; Srivastava, Supriya; Teh, Ming; Denil, Simon; Mustafah, Seri; Tan, Patrick; Shabbir, Asim; So, Jimmy Bok Yan; Yeoh, Khay Guan; Barker, Nick

doi:10.1038/s41586-020-1973-x

Cited by 98 publications

(105 citation statements)

References 45 publications

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“…Consistent with this, Reg KO mice shows significantly decelerated growth and migration of intestinal epithelial cells towards the villus tip (29). Indeed, several Reg family genes are expressed in the endogenous gastric stem cell compartment (Supplementary Figure 8a, b) (4,30). Whilst administration of REGs cannot fully compensate for Wnt withdrawal, Reg genes clearly supported organoid growth.…”

Section: Discussionsupporting

confidence: 64%

Genome-Scale CRISPR Screening reveals novel factors regulating Wnt-dependent regeneration of mouse gastric organoids

Murakami

Terakado

Saito

et al. 2020

Preprint

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An ability to safely harness the powerful regenerative potential of adult stem cells for clinical applications is critically dependent on a comprehensive understanding of the underlying mechanisms regulating their activity. Epithelial organoid cultures accurately recapitulate many features of in vivo stem cell-driven epithelial regeneration, providing an excellent ex vivo platform for interrogation of key regulatory mechanisms. Here, we employed a Genome-Scale CRISPR Knock-Out (GeCKO) screening assay using mouse gastric epithelial organoids to identify novel modulators of Wnt-driven stem cell-dependent epithelial regeneration in the gastric mucosa. In addition to known Wnt pathway regulators such as Apc, we found that knock-out (KO) of Alk, Bclaf3 or Prkra supports the Wnt independent self-renewal of gastric epithelial cells ex vivo. In adult mice, expression of these factors is predominantly restricted to non Lgr5-expressing stem cell zones above the gland base, implicating a critical role for these factors in suppressing Wnt-dependent self-renewal of gastric epithelia. Furthermore, using comprehensive RNA-sequencing analysis, we found that these factors influence epithelial regeneration by regulating Wnt signalling, apoptosis and expression of Reg family genes which could contribute to the epithelial regeneration through JAK/STAT3 pathway.

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Section: Discussionsupporting

confidence: 64%

Genome-Scale CRISPR Screening reveals novel factors regulating Wnt-dependent regeneration of mouse gastric organoids

Murakami

Terakado

Saito

et al. 2020

Preprint

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“…It has been shown that for many gene set analysis methods, whether competitive or self-contained, the results of the analysis are not reproducible for small sample sizes (Maleki et al, 2019a ). However, regardless of this issue, studies with small sample sizes ( n < 5 per group) continue to be analyzed using these methods (Dumesic et al, 2019 ; Weinberg et al, 2019 ; Tan et al, 2020 ). Therefore, it should be stressed that the size of a dataset is an important consideration when deciding on an appropriate gene set analysis method or whether it is appropriate to use gene set analysis at all.…”

Section: Challengesmentioning

confidence: 99%

Gene Set Analysis: Challenges, Opportunities, and Future Research

et al. 2020

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Gene set analysis methods are widely used to provide insight into high-throughput gene expression data. There are many gene set analysis methods available. These methods rely on various assumptions and have different requirements, strengths and weaknesses. In this paper, we classify gene set analysis methods based on their components, describe the underlying requirements and assumptions for each class, and provide directions for future research in developing and evaluating gene set analysis methods.

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“…Cholecystokinin type-B receptor (CCK2R)-positive cells are another set of stem cells which does not overlap with Lgr5 + cell population at the antral gastric units, and treatment with progastrin interconverts CCKR2 + Lgr5 neg or low antral stem cells into typical antral Lgr5 high cells that expand the active stem cells in the antrum (Hayakawa et al, 2015b). More recently, AQP5 expressing populations are identified to overlap with Lgr5 + stem cells at the base of pyloric gland, where this population of stems cells comprises the pyloric lineages expressing Muc5AC, gastric intrinsic factor, gastrin and chromogranin A (Tan et al, 2020).…”

Section: Gastric Stem Cell Marker Candidatesmentioning

confidence: 99%

“…Besides Lgr5 + cells, Klf-4 (Kruppel-like factor 4) disruption or PPARD (peroxisome proliferator-activated receptor delta) overexpression in Villin promoter-expressing stem cells spontaneously result in gastric carcinogenesis (Li et al, 2012;Zuo et al, 2019), CCK2R + cells potentially explains the gastrin-mediated effects on gastric cancer progression (Hayakawa et al, 2015b). More recently, AQP5 + stem cells are identified as a source of Wnt-driven gastric cancer, and AQP5 + tumor cells could reproducibly generate organoids in the absence of exogenous growth factors, indicating the stem potential of this cell populations (Tan et al, 2020). For gastric cancer occurred in the corpus, Mist1 + isthmus stem cells can serve as an origin.…”

Section: Gastric Carcinogenesismentioning

confidence: 99%

Gastric Stem Cells: Physiological and Pathological Perspectives

Xiao

Zhou

2020

Front. Cell Dev. Biol.

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Gastric epithelium operates in a hazardous environment that curtails the lifespan of the constituent cells, imposing a requirement for continuous epithelial renewal. Stem cells that reside in the stomach are thus essential for regulating physiological tissue renewal and injury repair because of their self-renewal, high proliferation capacity and multiple differentiation potentials. Recent investigations using lineage tracing models have identified diverse populations of gastric stem cells and even fully differentiated cells that can regain stem cell capacity, so enriching our understanding on the identity and plasticity of gastric stem cells. These cell populations include the Villin promotor, Lgr5 + , CCKR2 + , Axin2 + and AQP5 + stem cells in the antrum, TFF2 mRNA, Mist1 + cells and Troy + mature chief cells in the corpus, as well as Sox2, eR1, Lrig1, Bmi1-marked cell in both the antrum and the corpus. Establishment of gastric organoids derived from primary gastric tissues and pluripotent stem cells or embryonic stem cells characterizes niche factors required by the gastric stem cell populations, and further provides new insights into stomach development, host-Helicobacter pylori interactions and malignant transformation. Furthermore, focus on the gastric stem cells and their niches uncovers the initiation of stomach precancerous lesions and origin of gastric cancer, providing options for cancer prevention and intervention. In summary, with the development of stem cell research, gastric stem cells give us more opportunities to prevent and treat stomach diseases.

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AQP5 enriches for stem cells and cancer origins in the distal stomach

Abstract: This is a repository copy of AQP5 enriches for stem cells and cancer origins in the distal stomach.

Cited by 98 publications

References 45 publications

Genome-Scale CRISPR Screening reveals novel factors regulating Wnt-dependent regeneration of mouse gastric organoids

Genome-Scale CRISPR Screening reveals novel factors regulating Wnt-dependent regeneration of mouse gastric organoids

Gene Set Analysis: Challenges, Opportunities, and Future Research

Gastric Stem Cells: Physiological and Pathological Perspectives

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