iPSC technology-based regenerative therapy for diabetes

Abstract

The directed differentiation of human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), into pancreatic endocrine lineages has been vigorously examined by reproducing the in vivo developmental processes of the pancreas. Recent advances in this research field have enabled the generation from hESCs/iPSCs of functionally mature β-like cells in vitro that show glucose-responsive insulin secretion ability. The therapeutic potentials of hESC/iPSC-derived pancreatic cells have been evaluated using diabetic animal models, and transplantation methods including immunoprotective devices that prevent immune responses from hosts to the implanted pancreatic cells have been investigated towards the development of regenerative therapies against diabetes. These efforts led to the start of a clinical trial that involves the implantation of hESC-derived pancreatic progenitors into type 1 diabetes patients. In addition, patient-derived iPSCs have been generated from diabetes-related disorders towards the creation of novel in vitro disease models and drug discovery, although few reports so far have analyzed the disease mechanisms. Considering recent advances in differentiation methods that generate pancreatic endocrine lineages, we will see the development of novel cell therapies and therapeutic drugs against diabetes based on iPSC technology-based research in the next decade.

Keywords: Cell therapy; Disease model; Induced pluripotent stem cells.

Figure 1

Schematic diagram of the differentiation strategy to produce pancreatic endocrine lineages from such as human embryonic stem cells and induced pluripotent stem cells (hESCs/iPSCs) by mimicking in vivo development. The developmental stages and their corresponding marker genes are shown.

Figure 2

Pancreatic endoderm cells differentiated from human embryonic stem cells (hESCs) mature into β‐cells in vivo. (a) Section immunostaining images of hESC‐derived pancreatic endoderm cells for PDX1 (green) and NKX6.1 (red), (b) human pancreatic tissues generated 30 days after implantation of hESC‐derived pancreatic endoderm into immunodeficient mice for PDX1 (green), INSULIN (red) and GLUCAGON (blue), and (c) human islet‐like structures generated 210 days after implantation. (d) Plasma human C‐peptide levels in host immunodeficient mice. Scale bars, 100 μm. Adapted from Toyoda et al.22 with permission (licensed under Creative Commons Attribution).

Figure 3

Device‐based methods for implanting human embryonic stem cells and induced pluripotent stem cells (hESCs/iPSCs)‐derived pancreatic cells. hESC/iPSC‐derived pancreatic cells encapsulated with immunoprotective devices are implanted into the bodies of diabetes animal models or diabetes patients. Oxygen, nutrients, insulin and glucose can pass through the porous membrane of the device to promote the survival, differentiation, maturation and glucose‐responsive insulin secretion of encapsulated pancreatic cells. In contrast, immune cells or molecules, such as antibodies and complements, cannot pass, which prevents immune rejection or autoimmune responses against the cells.

Figure 4

Disease modeling using patient‐derived induced pluripotent stem cells (iPSCs). (a) In vitro type 1 diabetes disease models using the differentiation of patient‐derived iPSCs into pancreatic β‐ and immune cells. (b) iPSCs derived from a type 1 diabetes patient and (c) insulin‐secreting cells differentiated from the iPSCs. Scale bars, 300 μm in (b) and 100 μm in (c). Figures (b) and (c) were provided by Drs Yoshiya Hosokawa, Akihisa Imagawa and Iichiro Shimomura, Department of Metabolic Medicine, Osaka University Graduate School of Medicine.