The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids
Abstract The efficient 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 underlyin...
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| Format: | Article |
| Language: | English |
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SpringerOpen
2025-05-01
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| Series: | Cell Regeneration |
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| Online Access: | https://doi.org/10.1186/s13619-025-00237-x |
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| author | Fan Hong Xiaodan Wang Nanshan Zhong Ze Zhang Shibo Lin Mengxian Zhang Haonan Li Yuan Liu Yalong Wang Lianzheng Zhao Xiao Yang Hongwen Zhou Hui Liang Ye-Guang Chen |
| author_facet | Fan Hong Xiaodan Wang Nanshan Zhong Ze Zhang Shibo Lin Mengxian Zhang Haonan Li Yuan Liu Yalong Wang Lianzheng Zhao Xiao Yang Hongwen Zhou Hui Liang Ye-Guang Chen |
| author_sort | Fan Hong |
| collection | DOAJ |
| description | Abstract The efficient 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 effective 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, BMP4 signaling stimulates pit cell and parietal cell differentiation. Furthermore, BMP4 and EGF signaling cooperate to enhance pit cell differentiation, whereas inhibition of TGF-β and BMP4 signaling promotes chief cell differentiation. We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation. In addition, BMP4, together with the small molecule Isoxazole 9, promotes parietal and enteroendocrine cell differentiation. 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, laying a foundation for future investigation and potential clinical use of gastric organoids. |
| format | Article |
| id | doaj-art-aff0bcce6efe46909e9e759f1cbd7389 |
| institution | OA Journals |
| issn | 2045-9769 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Cell Regeneration |
| spelling | doaj-art-aff0bcce6efe46909e9e759f1cbd73892025-08-20T02:32:04ZengSpringerOpenCell Regeneration2045-97692025-05-0114112010.1186/s13619-025-00237-xThe critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoidsFan Hong0Xiaodan Wang1Nanshan Zhong2Ze Zhang3Shibo Lin4Mengxian Zhang5Haonan Li6Yuan Liu7Yalong Wang8Lianzheng Zhao9Xiao Yang10Hongwen Zhou11Hui Liang12Ye-Guang Chen13Guangzhou National LaboratoryThe State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua UniversityThe MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversityGuangzhou National LaboratoryDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityThe State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua UniversityThe State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua UniversityThe State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua UniversityGuangzhou National LaboratoryThe State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua UniversityState Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of LifeomicsDepartment of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of General Surgery, The First Affiliated Hospital of Nanjing Medical UniversityGuangzhou National LaboratoryAbstract The efficient 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 effective 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, BMP4 signaling stimulates pit cell and parietal cell differentiation. Furthermore, BMP4 and EGF signaling cooperate to enhance pit cell differentiation, whereas inhibition of TGF-β and BMP4 signaling promotes chief cell differentiation. We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation. In addition, BMP4, together with the small molecule Isoxazole 9, promotes parietal and enteroendocrine cell differentiation. 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, laying a foundation for future investigation and potential clinical use of gastric organoids.https://doi.org/10.1186/s13619-025-00237-xNiche factorsGastric epitheliumCell differentiationOrganoidsSingle cell RNA-seq |
| spellingShingle | Fan Hong Xiaodan Wang Nanshan Zhong Ze Zhang Shibo Lin Mengxian Zhang Haonan Li Yuan Liu Yalong Wang Lianzheng Zhao Xiao Yang Hongwen Zhou Hui Liang Ye-Guang Chen The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids Cell Regeneration Niche factors Gastric epithelium Cell differentiation Organoids Single cell RNA-seq |
| title | The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids |
| title_full | The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids |
| title_fullStr | The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids |
| title_full_unstemmed | The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids |
| title_short | The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids |
| title_sort | critical role of bmp signaling in gastric epithelial cell differentiation revealed by organoids |
| topic | Niche factors Gastric epithelium Cell differentiation Organoids Single cell RNA-seq |
| url | https://doi.org/10.1186/s13619-025-00237-x |
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