Directed differentiation of pancreatic δ cells from human pluripotent stem cells

Lihua Chen, Nannan Wang, Tongran Zhang, Feng Zhang, Wei Zhang, Hao Meng, Jingyi Chen, Zhiying Liao, Xiaopeng Xu, Zhuo Ma, Tao Xu () and Huisheng Liu ()
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Lihua Chen: Guangzhou Medical University
Nannan Wang: Guangzhou National Laboratory
Tongran Zhang: Guangzhou National Laboratory
Feng Zhang: Guangzhou National Laboratory
Wei Zhang: Guangzhou National Laboratory
Hao Meng: Guangzhou Medical University
Jingyi Chen: Guangzhou National Laboratory
Zhiying Liao: Guangzhou Medical University
Xiaopeng Xu: Guangzhou National Laboratory
Zhuo Ma: Institute of Biophysics, Chinese Academy of Sciences
Tao Xu: Guangzhou Medical University
Huisheng Liu: Guangzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50611-7

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