Beta-cell replacement strategies for diabetes

Abstract

Diabetes is characterized by elevated levels of blood glucose as a result of insufficient production of insulin from loss or dysfunction of pancreatic islet β-cells. Here, we review several approaches to replacing β-cells that were recently discussed at a symposium held in Kyoto, Japan. Transplant of donor human islets can effectively treat diabetes and eliminate the need for insulin injections, supporting research aimed at identifying abundant supplies of cells. Studies showing the feasibility of producing mouse islets in rats support the concept of generating pigs with human pancreas that can serve as donors of human islets, although scientific and ethical challenges remain. Alternatively, in vitro differentiation of both human embryonic stem cells and induced pluripotent stem cells is being actively pursued as an islet cell source, and embryonic stem cell-derived pancreatic progenitor cells are now in clinical trials in North America in patients with diabetes. Macro-encapsulation devices are being used to contain and protect the cells from immune attack, and alternate strategies of immune-isolation are being pursued, such as islets contained within long microfibers. Recent advancements in genetic engineering tools offer exciting opportunities to broaden therapeutic strategies and to probe the genetic involvement in β-cell failure that contributes to diabetes. Personalized medicine might eventually become a possibility with genetically edited patient-induced pluripotent stem cells, and the development of simplified robust differentiation protocols that ideally become standardized and automated. Additional efforts to develop a safe and effective β-cell replacement strategy to treat diabetes are warranted.

Keywords: Genetic engineering; Islet transplantation; Stem cell.

Figure 1

Strategies being explored for the development of novel therapies for diabetes. Embryonic stem (ES) and induced pluripotent stem (iPS) cells combined with genome editing technologies are valuable tools to probe disease mechanisms, engineer in desired attributes such as safety switches and upon differentiation to use as potential replacement cell sources. Other potential cell sources are pigs, possibly with human pancreas. Such ‘humanized’ animals might also prove valuable for disease modeling, as will other genetically modified species. To accompany cell sources some form of immunoprotection will be required, such as retrievable planar, bead or fiber encapsulation devices.