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Signaling basis of gastric epithelial cell differentiation revealed by human and mouse organoids [scRNA-Seq]

ABSTRACT: The directed differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis. Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation, the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood. In this study, by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways, we achieved efficient differentiation of various gastric epithelial cell types in mouse and human gastric organoids. These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues. Specifically, we showed that BMP4 signaling stimulates parietal cell differentiation, EGF and BMP4 signaling work together to enhance pit cell differentiation, while TGF-β inhibition facilitates chief cell differentiation. In addition, the small molecule Isoxazole 9, which has been shown to stimulate differentiation of neuronal cells, pancreatic β-cells, and intestinal enteroendocrine cells, promotes parietal and endocrine cell differentiation in gastric organoids. Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human. Together, our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human.

ORGANISM(S): Mus musculus

PROVIDER: GSE269974 | GEO | 2025/05/29

REPOSITORIES: GEO

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Signaling basis of gastric epithelial cell differentiation revealed by human and mouse organoids [ChIP-Seq]

Project description:The directed differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis. Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation, the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood. In this study, by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways, we achieved efficient differentiation of various gastric epithelial cell types in mouse and human gastric organoids. These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues. Specifically, we showed that BMP4 signaling stimulates parietal cell differentiation, EGF and BMP4 signaling work together to enhance pit cell differentiation, while TGF-β inhibition facilitates chief cell differentiation. In addition, the small molecule Isoxazole 9, which has been shown to stimulate differentiation of neuronal cells, pancreatic β-cells, and intestinal enteroendocrine cells, promotes parietal and endocrine cell differentiation in gastric organoids. Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human. Together, our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human.

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Signaling basis of gastric epithelial cell differentiation revealed by human and mouse organoids [RNA-Seq]

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Expression profiling of Troy positive gastric cells

Project description:Proliferation of the self-renewing epithelium of the gastric corpus occurs almost exclusively in the isthmus of the glands, from where cells migrate bi-directionally towards pit and base. The isthmus is therefore generally viewed as the stem cell zone. We find that the stem cell marker Troy is expressed at the gland base by a small subpopulation of chief cells. By lineage tracing using a Troy-eGFP-ires-CreERT2 allele, single marked cells are shown to generate entirely labeled gastric units over periods of months. This phenomenon accelerates upon tissue damage. Troy+ chief cells can be cultured to generate long-lived gastric organoids. Troy marks a specific, 'plastic' subset of differentiated chief cells capable of replenishing entire gastric units, essentially serving as a quiescent ‘reserve’ stem cell. An EGFP-ires-CreERT2 cassette was introduced into the transcriptional start side of Tnfrsf19 (Troy), resulting in the expression of EGFP and CreERT2 under the control of endogenous Troy-regulatory sequences. Troy is expressed in basally located chief and parietal cells. Using FACS, Troy positive chief and parietal cells can be isolated separately. Expression profiling was performed on these two cell types: three arrays of sorted chief cells, two arrays of sorted parietal cells. As a reference, two arrays of separately isolated whole gastric corpus glands were added. In addition, single sorted Troy positive chief cells can be placed in culture, forming 3D cultures called organoids. Three arrays were generated from different organoid cultures, one time in normal medium containing the factors EGF, Gastrin, FGF10, Noggin, Wnt3a and Rspondin (EGFNWR medium) and one time in medium containing only EGF and Rspondin (ER medium).

2013-10-23 | E-GEOD-44060 | biostudies-arrayexpress

Signaling basis of gastric epithelial cell differentiation revealed by human and mouse organoids [RNA-Seq]

Project description:Purpose:One goal of this bulk RNA-seq is to compare genome-wide transcriptome profiles in gastric organoids cultured in CM and differentiation media including Nog WD, BMP4, EB, Isx-9, BI, NRC and NRCA in mouse and EB, NRCSI and BIMDP in human. The other aim is to identify the differential biological process underpinning gastric epithelial cell differentiation and the conservative or divergent process between human and mouse. Methods: For human and mouse gastric organids, we isolated and digested with Tryple and then extracted total RNA. Bulk RNA-seq was performed using the Illumina Hiseq X. Sequence reads that passed quality filters were analysed at the transcript isoform level using two methods: Burrows-Wheeler Aligner (BWA) followed by ANOVA and TopHat followed by Cufflinks. Results: By comparing RNA-seq data, we identified the signature genes involved in gastric epithelial cell lineage and enrichment of biological processes during differentiation. Conclusion: EB is optimal medium for pit cell differentiation in both human and mouse, BI and BIMDP media are optimal media for parietal cell differentiation in human and mouse respectively, NRCS and NRCSI media are optimal media for chief cell differentiation in human and mouse respectively.

2025-05-29 | GSE226195 | GEO

Gene expression in gastric Mist1+ cells.

Project description:Mist1+ cells and parietal cells in mouse stomach were separatedly sorted, and RNAs were isolated. Mist1 (also known as Bhlha15) is expressed in gastric chief cells and gastric stem cells in mice. However, more specific genes for each population needs to be identified to better understand the precise biology in these cell populations. In order to address cell specific gene signature, we separately sorted Mist1+ gastric chief cells and Mist1+ gastric stem cells by FACS, and performed microarray analysis. Mist1+ gastric chief cells were sorted by using Mist1-CreERT; R26-TdTomato mouse stomach, immediately after tamoxifen administration. Mist1+ gastric stem cells were sorted by chief cell-ablated Mist1-CreERT; R26-TdTomato mouse stomach, combining with Lgr5-DTR mice. Lgr5-expressing chief cells were ablated by giving DT into these mice. As a control, acid-secreting gastric parietal cell samples were used. Mice were treated with or without Lgr5-DT ablation before sorting.

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Project description:Gastric ulcer, which affect many of patients and is deeply related with gastric cancer, is caused by chronic gastric acid stimulation. Stomach fundus, the main body of stomach, is a major source of gastric acid and peptidase for food digestion. Recapturing the main body of stomach requires mainly 3 functionally differentiated cells; parietal (oxyntic) cells, chief (zymogenic) cells, and surface mucous foveolar (pit) cells. We have previously shown the induction of stomach tissue with functional secreting activities by directed differentiation of mouse embryonic stem cells (ES cells) to stomach primordium with both gut epithelium and splanchnic mesoderm. However, generating human stomach with fundus and such functions has been elucidated and a long-desired goal. Here, we describe the method for establishing human embryonic stem cell-derived stomach organoids with fundus gland structure. Along with mouse stomach development and de novo stomach generation from mouse ES cells in vitro, we observed gut-like structure formation from human embryonic stem cells by induction of both endoderm and mesoderm. These human embryonic gut could differentiate into stomach primordium by growth factor stimulation as well as stomach development, and form stomach tissue in three-dimensional organoid culture. Furthermore, these stomach organoids contain fundus-like gland with parietal cells and chief cells, some of secreting activities, and is transcriptionally close to human stomach. Human functional stomach derived from embryonic stem cells represent powerful tools for analying human stomach development, and gastric ulcer related disease including gastric tumorgenesis.

2017-08-31 | GSE79673 | GEO

A profile of murine gastric epithelial cells: Parietal, Zymogenic, Pit

2006-10-20 | GSE5018 | GEO

Signaling basis of gastric epithelial cell differentiation revealed by human and mouse organoids [scRNA-Seq]

Project description:Purpose:One goal of this single RNA-seq is to compare scRNA profiles in gastric organoids cultured in CM and differentiation media including EB, BI and NRCA in mouse and EB, NRCSI and BIMDP in human. The other aim is to identify the differential biological process underpinning gastric epithelial cell differentiation and the conservative or divergent process between human and mouse. Methods: For human and mouse gastric organids, we isolated and digested with Tryple and then were sorted by flow cytometry.ScRNA-seq libraries were generated using the Chromium Single Cell 3’ Reagent Ki V3 (10X Genomics). The libraries were sequenced as paired-end with Illumina Novaseq 6000.The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. Results: By comparing scRNA-seq data, we identified the signature genes involved in gastric epithelial cell lineage and enrichment of biological processes during differentiation. Conclusion: EB is optimal medium for pit cell differentiation in both human and mouse, BI and BIMDP media are optimal media for parietal cell differentiation in human and mouse respectively, NRCS and NRCSI media are optimal media for chief cell differentiation in human and mouse respectively.

2025-05-29 | GSE226196 | GEO

Transcription profiling of mouse gastric epithelial cell types: parietal, zymogenic, and pit

Project description:Continuous regeneration of digestive enzyme (zymogen) secreting chief cells is a normal aspect of stomach function that is disrupted in pre-cancerous lesions. Regulation of zymogenic cell (ZC) differentiation is poorly understood. Here we profile Parietal, Pit, and Zymogenic cells for comparison and study. Experiment Overall Design: Samples were obtained through Laser-capture microdisection of gastric epithelium. The three samples come from enrichments for Zymogenic Cells (ZC), Parietal Cells (PC), and Mucus Pit Cells (Pit). Experiment Overall Design: Individual parietal cells (visualized by DBA-positivity and autofluorescence) from well-oriented gastric units were dissected (PixCell II LCM apparatus, 7.5-Âµm spot diameter; CapSure HS LCM caps, Arcturus, Mountain View, CA) one-at-a-time from the pit zone and collected for GeneChips. Pit cells (E-cadherin-positive, DBA-negative) were then collected from the same gastric units. Only the pit cells in a 2-3-cell-thick region at the apex of the gastric unit â?? but not yet upon the gastric surface â?? were taken. ZCs (E-cadherin-positive, GSII/DBA-negative cells in the base zones) were collected from different slides in corpus gastric units after potentially contaminating basal parietal cells had first been dissected and discarded. 3000-5000 individual cells from each cell lineage were isolated from 4-5 individual mice, and RNA was purified by PicoPure kit (Arcturus). RNA integrity was verified, and RNAs for each lineage were pooled from multiple mice and multiple dissections to make 20 ng total RNA, which was then amplified, labeled, and fragmented (by the Arcturus RiboAmp HS kit followed by the RNA Amplification and Labeling Kit from Enzo Life Sciences). The resulting biotinylated cRNA probes were hybridized to Affymetrix (Santa Clara, CA) GeneChipÂ® Mouse Genome 430 2.0 microarrays.

2008-06-13 | E-GEOD-5018 | biostudies-arrayexpress

Transplantation of gastric organoid-derived spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) cell lineage promotes ulcer repair in the aged stomach

Project description:Background & Aims: Spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) is known to emerge following parietal cell loss and during Helicobacter pylori infection, however its role in gastric ulcer repair is unknown. Therefore, we sought to investigate if SPEM plays a role in epithelial regeneration. Methods: Acetic acid ulcers were induced in young (2-3 months) C57BL/6 mice to determine the quality of ulcer repair. Gastric tissue was collected and analyzed to determine the expression of SPEM within the regenerating epithelium. As a comparison to native tissue the expression of SPEM was also identified within cultured gastric mouse-derived organoids. Results: Wound healing in the mice coincided with the emergence of SPEM expressing CD44v within the ulcerated region. The emergence of SPEM was also observed in cultured gastric organoids. Conclusions: These data demonstrate the SPEM may play a role in epithelial regeneration. Conclusions: These data demonstrate the SPEM may play a role in epithelial regeneration. 4 samples were used for ulcerated and uninjured tissue. 1 sample was used for intact tissue and organoid-derived RNA. The 'Ulcerated' samples represent C57BL/6 mice with ulcers and the 'Uninjured' samples represent the healthy controls (for "ulcerated" samples). The "Intact stomach tissue" and "Gastric organoids" samples are other types of samples that compared separately. "Gastric organoids" in this comparison are derived from "Intact stomach tissue".

2015-09-23 | E-GEOD-73336 | biostudies-arrayexpress

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