Abstract
In vitro differentiation of human induced pluripotent stem cells (iPSCs) into functional islets holds immense potential to create an unlimited source of islets for diabetes research and treatment. A continuous challenge in this field is to generate glucose-responsive mature islets. We herein report a previously undiscovered angiopoietin signal for in vitro islet development. We revealed, for the first time, that angiopoietins, including angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) permit the generation of islets from iPSCs with elevated glucose responsiveness, a hallmark of mature islets. Angiopoietin-stimulated islets exhibited glucose synchronized calcium ion influx in repetitive glucose challenges. Moreover, Ang2 augmented the expression of all islet hormones, including insulin, glucagon, somatostatin, and pancreatic polypeptide; and β cell transcription factors, including NKX6.1, MAFA, UCN3, and PDX1. Furthermore, we showed that the Ang2 stimulated islets were able to regulate insulin exocytosis through actin-filament polymerization and depolymerization upon glucose challenge, presumably through the CDC42-RAC1-gelsolin mediated insulin secretion signaling pathway. We also discovered the formation of endothelium within the islets under Ang2 stimulation. These results strongly suggest that angiopoietin acts as a signaling molecule to endorse in vitro islet development from iPSCs.
Highlights
In vitro differentiation of human induced pluripotent stem cells into functional islets holds immense potential to create an unlimited source of islets for diabetes research and treatment
We report, for the first time, an inductive effect of angiopoietins on induced pluripotent stem cells (iPSCs) islet development and maturation
Mechanistic study revealed active F-actin remodeling aided by activated cell division control protein 42 (CDC42)-related C3 botulinum toxin substrate 1 (RAC1)-gelsolin pathway in addition to glucose level synchronous C a2+ influx dynamics in Ang[2] stimulated islets
Summary
In vitro differentiation of human induced pluripotent stem cells (iPSCs) into functional islets holds immense potential to create an unlimited source of islets for diabetes research and treatment. We discovered the formation of endothelium within the islets under Ang[2] stimulation These results strongly suggest that angiopoietin acts as a signaling molecule to endorse in vitro islet development from iPSCs. Diabetes is a global epidemic posing significant challenges for human health and wellbeing. While PP cells are one of the most poorly understood cell types in islets, pancreatic polypeptide (PPY) secreted from PP cells is found to be correlated to somatostatin levels in response to eating and fasting[23,24] These evidences strongly suggest the necessity of generating whole islets that encompass β, and α, δ, and PP cells. It has been reported that Ang[2] contributes to Scientific Reports | (2021) 11:13558
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