EGF and BMPs Govern Differentiation and Patterning in Human Gastric Glands

Wölffling, Sarah; Daddi, Alice Anna; Imai-Matsushima, Aki; Fritsche, Kristin; Goosmann, Christian; Traulsen, Jan; Lisle, Richard J.; Schmid, Monika S.; Reines-Benassar, Maria del Mar; Pfannkuch, Lennart; Brinkmann, Volker; Bornschein, Jan; Malfertheiner, Peter; Ordemann, J.; Link, Alexander; Meyer, Thomas F.; Boccellato, Francesco

doi:10.1053/j.gastro.2021.04.062

Cited by 32 publications

(28 citation statements)

References 61 publications

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“…It has also provided cell lines that can be cultured long-term. It is of note that organoid cultures established from different regions of the stomach (corpus or antrum) retained gene expression patterns typical of the source; this further supports the idea that the stem cells in each region are different [ 32 ], or perhaps that the assemblage of stem cells expressing different markers (Mist1, Lrig1, Lgr5, Sox, for example) are characteristic of the region.…”

Section: Discussionmentioning

confidence: 60%

“…Similarly, the inclusion of myofibroblasts in more complex models will permit detailed analyses of their response to inflammatory stimuli. Recent studies have underlined the importance of growth factor gradients for gastric homeostasis [ 32 ], and we predict that cytokine gradients will also be key to understanding the effects of cytokines on gastric stem cells. To this end, controlled-release delivery using nanoparticles or other engineered systems to generate gradients in vitro will be advantageous (see for example [ 99 ]).…”

Section: Discussionmentioning

confidence: 99%

“…The cell fate decisions for differentiation or proliferation for Lgr5 + stem cells have been shown to be regulated by Notch protein signalling [ 29 , 30 , 31 ]. More recently, Wölffling et al used human adult organoids to perform a detailed analysis of the growth factors required to differentiate different cell types in the gastric gland [ 32 ]. Bone marrow morphogenic protein (BMP) is known to suppress Wnt/β-catenin signalling [ 33 ], and BMP4 was shown to be expressed in the isthmus region in the human gastric corpus.…”

Section: Gastric Homeostasis: the Key Role Of Adult Stem Cells In The...mentioning

confidence: 99%

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Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer

Idowu

Bertrand

Walduck

2022

IJMS

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Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Gastric Homeostasis: the Key Role Of Adult Stem Cells In The...mentioning

confidence: 99%

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Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer

Idowu

Bertrand

Walduck

2022

IJMS

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“…Samples of undifferentiated antrum and corpus have also been used for gene expression analysis by Wölffling et al . (Wölffling et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

“…Single color Agilent SurePrint G3 Custom Gene Expression Microarray 8 x 60K (Agilent, Agilent-048908; GEO Platform GPL21272) was used for gene expression analysis according to the manufacturer’s protocol. Note: a part of the gene expression results obtained with the samples of +W/R antrum and +/W/R corpus has already been published (Wölffling et al, 2021). Here, we used these samples combined with the respective -W/R samples and extended the data set to +W/R and -W/R fundus.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation in human gastric epithelial cells allows cell type-related plasticity and defines regional identity

Fritsche

Boccellato

Schlaermann

et al. 2022

Preprint

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Background: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. Results: Here, we describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach (i.e., antrum, corpus, fundus) together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1, and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. Conclusions: By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation already characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics as a starting point for further studies.

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A Natural Peptide from A Traditional Chinese Medicine Has the Potential to Treat Chronic Atrophic Gastritis by Activating Gastric Stem Cells

Li,

Ma,

et al. 2024

Advanced Science

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Chronic atrophic gastritis (AG) is initiated mainly by Helicobacter pylori infection, which may progress to stomach cancer following the Correa's cascade. The current treatment regimen is H. pylori eradication, yet evidence is lacking that this treatment is effective on later stages of AG especially gastric gland atrophy. Here, using AG mouse model, patient samples, gastric organoids, and lineage tracing, this study unraveled gastric stem cell (GSC) defect as a crucial pathogenic factor in AG in mouse and human. Moreover, a natural peptide is isolated from a traditional Chinese medicine that activated GSCs to regenerate gastric epithelia in experimental AG models and revitalized the atrophic gastric organoids derived from patients. It is further shown that the peptide exerts its functions by stabilizing the EGF‐EGFR complex and specifically activating the downstream ERK and Stat1 signaling. Overall, these findings advance the understanding of AG pathogenesis and open a new avenue for AG treatment.

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EGF and BMPs Govern Differentiation and Patterning in Human Gastric Glands

Cited by 32 publications

References 61 publications

Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer

Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer

DNA methylation in human gastric epithelial cells allows cell type-related plasticity and defines regional identity

A Natural Peptide from A Traditional Chinese Medicine Has the Potential to Treat Chronic Atrophic Gastritis by Activating Gastric Stem Cells

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