Regulation of Gastric Metaplasia, Dysplasia, and Neoplasia by Bone Morphogenetic Protein Signaling

Todisco, Andrea

doi:10.1016/j.jcmgh.2017.01.014

Cited by 27 publications

(28 citation statements)

References 79 publications

(111 reference statements)

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“…The actions of these proteins can be blocked by secreted inhibitory molecules, such as noggin, gremlin, and chordin, which are expressed in vivo to modulate the actions of the BMPs. 24 , 25 It has been shown that loss of BMP signaling in the stomach leads to perturbations of the normal homeostatic mechanisms of the gastric mucosa, leading to the development of metaplasia, dysplasia, and neoplasia. 25 , 26 , 27 In support of these observations studies have shown that BMP receptors such as BMPR1A and the BMP signal transducing proteins Smad1, 5, and 8 are widely expressed in the glandular stomach.…”

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confidence: 99%

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Takabayashi

Yang

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsGastric Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) cells exert important functions during injury and homeostasis. Bone morphogenetic protein (BMP) signaling regulates gastric inflammation and epithelial homeostasis. We investigated if BMP signaling controls the fate of Lgr5+ve cells during inflammation.MethodsThe H+/K+-adenosine triphosphatase β-subunit promoter was used to express the BMP inhibitor noggin (Nog) in the stomach (H+/K+-Nog mice). Inhibition of BMP signaling in Lgr5 cells was achieved by crossing Lgr5-EGFP-ires-CreERT2 (Lgr5-Cre) mice to mice with floxed alleles of BMP receptor 1A (Lgr5-Cre;Bmpr1aflox/flox mice). Lgr5/GFP+ve cells were isolated using flow cytometry. Lineage tracing studies were conducted by crossing Lgr5-Cre mice to mice that express Nog and tdTomato (Lgr5-Cre;H+/K+-Nog;Rosa26-tdTom). Infection with Helicobacter felis was used to induce inflammation. Morphology of the mucosa was analyzed by H&E staining. Distribution of H+/K+-adenosine triphosphatase-, IF-, Ki67-, CD44-, CD44v9-, and bromodeoxyuridine-positive cells was analyzed by immunostaining. Expression of neck and pit cell mucins was determined by staining with the lectins Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, respectively. Id1, Bmpr1a, Lgr5, c-Myc, and Cd44 messenger RNAs were measured by quantitative reverse-transcription polymerase chain reaction.ResultsLgr5-Cre;Bmpr1aflox/flox mice showed diminished expression of Bmpr1a in Lgr5/GFP+ve cells. Infection of Lgr5-Cre;Bmpr1aflox/flox mice with H felis led to enhanced inflammation, increased cell proliferation, parietal cell loss, and to the development of metaplasia and dysplasia. Infected Lgr5-Cre;H+/K+-Nog;Rosa26-tdTom mice, but not control mice, showed the presence of tomato+ve glands lining the lesser curvature that stained positively with Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, and with anti-IF, -CD44, -CD44v9, and -bromodeoxyuridine antibodies.ConclusionsInflammation and inhibition of BMP signaling activate Lgr5+ve cells, which give rise to metaplastic, dysplastic, proliferating lineages that express markers of mucus neck and zymogenic cell differentiation.

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confidence: 99%

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Takabayashi

Yang

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

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“…Some of the major regulators of gastric stem cell proliferation and differentiation include sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs) signaling pathways. These have been found to exert important effects on gastrointestinal development and differentiation (Lees et al, 2005;Todisco, 2017). In the human stomach, Shh expression is restricted to the parietal cells and the glandular portion (van den Brink et al, 2001), where it controls epithelial cell proliferation and serves as a polarizing signal for fundic gland differentiation Lgr5 leucine-rich repeat-containing G-protein coupled receptor 5, TFF2 trefoil factor 2, Sox2 sex-determining region Y box protein 2, CCK2R cholecystokinin type-B receptor, Lrig1 leucine-rich repeats and immunoglobulin-like domains 1, AQP5 aquaporin 5, Ach acetylcholine, EGF epidermal growth factor, FGF10 fibroblast growth factor 10, BMPs bone morphogenetic proteins, Shh sonic hedgehog.…”

Section: Gastric Stem Cells and Their Nichementioning

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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“…Mechanistically, HH produced by epithelial cells induces the expression of COUP-TFII in mesenchymal cells to block the excessive expansion of circular smooth muscle cells and enteric neurons. At the same time COUP-TFII indirectly inhibits the epithelium proliferation; the mediator of this negative feedback loop is probably the secreted factor BMP-4, as demonstrated by the fact that the reduction of BMP signaling increases epithelial proliferation [154,155].…”

Section: Infertility and Alterations Of Mesenchymal Commitmentmentioning

confidence: 99%

COUP-TFII in Health and Disease

Polvani

Pepe

Milani

et al. 2019

Cells

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The nuclear receptors (NRs) belong to a vast family of evolutionary conserved proteins acting as ligand-activated transcription factors. Functionally, NRs are essential in embryogenesis and organogenesis and in adulthood they are involved in almost every physiological and pathological process. Our knowledge of NRs action has greatly improved in recent years, demonstrating that both their expression and activity are tightly regulated by a network of signaling pathways, miRNA and reciprocal interactions. The Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII, NR2F2) is a NR classified as an orphan due to the lack of a known natural ligand. Although its expression peaks during development, and then decreases considerably, in adult tissues, COUP-TFII is an important regulator of differentiation and it is variably implicated in tissues homeostasis. As such, alterations of its expression or its transcriptional activity have been studied and linked to a spectrum of diseases in organs and tissues of different origins. Indeed, an altered COUP-TFII expression and activity may cause infertility, abnormality in the vascular system and metabolic diseases like diabetes. Moreover, COUP-TFII is actively investigated in cancer research but its role in tumor progression is yet to be fully understood. In this review, we summarize the current understanding of COUP-TFII in healthy and pathological conditions, proposing an updated and critical view of the many functions of this NR.

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Regulation of Gastric Metaplasia, Dysplasia, and Neoplasia by Bone Morphogenetic Protein Signaling

Cited by 27 publications

References 79 publications

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Gastric Stem Cells: Physiological and Pathological Perspectives

COUP-TFII in Health and Disease

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