Directed differentiation of pancreatic δ cells from human pluripotent stem cells

  • Nat Commun. 2024 Jul 27;15(1):6344. doi: 10.1038/s41467-024-50611-7.
Lihua Chen  #  1  2 ,  Nannan Wang  #  2  3 ,  Tongran Zhang  #  2  4 ,  Feng Zhang  2 ,  Wei Zhang  2 ,  Hao Meng  1  2 ,  Jingyi Chen  2  5 ,  Zhiying Liao  1  2 ,  Xiaopeng Xu  2 ,  Zhuo Ma  6 ,  Tao Xu  7  8 ,  Huisheng Liu  9  10  11  12
Affiliations
  • 1. School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 2. Guangzhou National Laboratory, Guangzhou, Guangdong, China.
  • 3. College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 4. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 5. School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China.
  • 6. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 7. School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
  • 8. Guangzhou National Laboratory, Guangzhou, Guangdong, China. [email protected].
  • 9. School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, China. [email protected].
  • 10. Guangzhou National Laboratory, Guangzhou, Guangdong, China. [email protected].
  • 11. College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 12. School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 39068220 DOI: 10.1038/s41467-024-50611-7
Abstract

Dysfunction of pancreatic δ cells contributes to the etiology of diabetes. Despite their important role, human δ cells are scarce, limiting physiological studies and drug discovery targeting δ cells. To date, no directed δ-cell differentiation method has been established. Here, we demonstrate that Fibroblast Growth Factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic δ-cell lineage via FGF receptor 1. We develop a differentiation method to generate δ cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These δ cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress Insulin secretion from in vitro co-cultured β cells and mouse β cells upon transplantation. The generation of human pancreatic δ cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes.

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