Recent progress in pancreatic islet cell therapy

Abstract

Human pluripotent stem cells (PSCs), including human embryonic stem cells and induced pluripotent stem cells, are promising cell sources in regenerating pancreatic islets through in vitro directed differentiation. Recent progress in this research field has made it possible to generate glucose-responsive pancreatic islet cells from PSCs. Single-cell RNA sequencing techniques have been applied to analyze PSC-derived endocrine beta-cells, which are then compared with human islets. This has led to the identification of novel signaling pathways and molecules involved in lineage commitment during pancreatic differentiation and maturation processes. Single-cell transcriptomics are also used to construct a detailed map of in vivo endocrine differentiation of developing mouse embryos to study pancreatic islet development. Mimicking those occurring in vivo, it was reported that differentiating PSCs can generate similar islet cell structures, while metabolomics analysis highlighted key components involved in PSC-derived pancreatic islet cell function, providing information for the improvement of in vitro pancreatic maturation procedures. In addition, cell transplantation into diabetic animal models, together with the cell delivery system, is studied to ensure the therapeutic potentials of PSC-derived pancreatic islet cells. Combined with gene-editing technology, the engineered mutation-corrected PSC lines originated from diabetes patients could be differentiated into functional pancreatic islet cells, suggesting possible autologous cell therapy in the future. These PSC-derived pancreatic islet cells are a potential tool for studies of disease modeling and drug testing. Herein, we outlined the directed differentiation procedures of PSC-derived pancreatic islet cells, novel findings through transcriptome and metabolome studies, and recent progress in disease modeling.

Keywords: Directed differentiation; Disease modeling; Pancreatic islets; Pluripotent stem cells; Transplantation.

Fig. 1

Directed differentiation of PSCs into pancreatic beta cells. a The schematic diagram of directed differentiation into pancreatic beta cells using PSCs. PSCs are directed through 5 stages; each stage utilizes the inhibition (↓) or activation (↑) of various signaling pathways. Genes specifically expressed at each stage are shown. b Genes expressed in various cell groups revealed from scRNA-seq analysis. PSCs pluripotent stem cells, DE definitive endoderm, PG primitive gut tube, PP pancreatic progenitor, EP endocrine progenitor, EC endocrine cell, SHH sonic hedgehog, FGFs fibroblast growth factors, BMP bone morphogenic protein, RA retinoic acid, PKC protein kinase C, NA Nicotinamide, NAC N-acetyl-cysteine, Alk5i transforming growth factor-beta receptor inhibitor, T3 thyroid hormone

Fig. 2

Macro- and micro-encapsulation devices for the delivery of PSC-derived islet cells. The delivery system of PSC-derived islet cells focusing on macro- and micro-encapsulation devices. Both devices can be loaded with PSC-derived endocrine cell clusters, protect the cells from immune cells, and allow penetration of oxygen, nutrients, and hormone flow

Fig. 3

Combining gene-editing and directed differentiation for the development of novel therapeutics. Patient-derived endocrine cells can be applied in disease modeling and drug testing, while corrected PSC-derived endocrine cells can be a promising source for autologous cell therapy