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  3. The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids

The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids

  • Cell Regen. 2025 May 16;14(1):18. doi: 10.1186/s13619-025-00237-x.
Fan Hong # 1,  Xiaodan Wang # 2 3,  Nanshan Zhong 4,  Ze Zhang 1,  Shibo Lin 5,  Mengxian Zhang 2,  Haonan Li 2,  Yuan Liu 2,  Yalong Wang 1,  Lianzheng Zhao 2,  Xiao Yang 6,  Hongwen Zhou 7,  Hui Liang 5,  Ye-Guang Chen 8 9 10
Affiliations

Affiliations

  • 1 Guangzhou National Laboratory, Guangzhou, 510005, China.
  • 2 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 3 State Key Laboratory of Trauma, Burns and Combined Injury, Department of Shock and Transfusion, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China.
  • 4 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
  • 5 Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 6 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China.
  • 7 Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 8 Guangzhou National Laboratory, Guangzhou, 510005, China. ygchen@tsinghua.edu.cn.
  • 9 The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China. ygchen@tsinghua.edu.cn.
  • 10 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China. ygchen@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 40377813 DOI: 10.1186/s13619-025-00237-x
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.

Keywords

Cell differentiation; Gastric epithelium; Niche factors; Organoids; Single cell RNA-seq.

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