Directed differentiation of pancreatic δ cells from human pluripotent stem cells

• Published in: Nature communications 2024-07, Vol.15 (1), p.6344-22, Article 6344
• Main Authors: Chen, Lihua, Wang, Nannan, Zhang, Tongran, Zhang, Feng, Zhang, Wei, Meng, Hao, Chen, Jingyi, Liao, Zhiying, Xu, Xiaopeng, Ma, Zhuo, Xu, Tao, Liu, Huisheng
• Format: Article
• Language: English
• Subjects: 13/100; 13/89; 14/19; 14/28; 38/91; 631/532/2064/2158; 631/532/2435; 631/61/2320; Animals; Beta cells; Cell Differentiation; Cell Lineage; Diabetes; Diabetes mellitus; Differentiation (biology); Drug discovery; Endoderm; Endoderm - cytology; Endoderm - metabolism; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Fibroblast growth factor receptor 7; Fibroblast growth factors; Gene expression; Granule cells; Growth factors; Hormones; Humanities and Social Sciences; Humans; In vitro methods and tests; In vivo methods and tests; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Mice; multidisciplinary; Pancreas - cytology; Pancreas - metabolism; Pancreas transplantation; Physiological effects; Pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Progenitor cells; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Science; Science (multidisciplinary); Secretory vesicles; Somatostatin; Somatostatin - metabolism; Somatostatin-Secreting Cells - cytology; Somatostatin-Secreting Cells - metabolism; Stem cell transplantation; Stem cells; Transcription factors; Transplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50611-7

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. Human pancreatic δ cells play important roles in the balance of pancreatic hormones. Here, the authors develop a directed differentiation method to generate in vitro and in vivo functional δ cells from human stem cells by combining FGF2 with FGF7.