Stem Cell-Based Approaches for the Treatment of Diabetes

SAGE-Hindawi Access to Research Stem Cells International Volume 2011, Article ID 424986, 8 pages doi:10.4061/2011/424986 Review Article Stem Cell-Based Approaches for the Treatment of Diabetes Catriona Kelly,1, 2 Cara C. S. Flatt,1 and Neville H. McClenaghan1 1 SAAD Centre for Pharmacy & Diabetes, Biomedical Sciences Research Institute, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK 2 Institute for Science & Technology in Medicine, Keele University, Keele ST5 5BG, UK Correspondence should be addressed to Catriona Kelly, Received 15 December 2010; Accepted 18 March 2011 Academic Editor: Claudio Napoli Copyright © 2011 Catriona Kelly et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The incidence of diabetes and the associated debilitating complications are increasing at an alarming rate worldwide. Current therapies for type 1 diabetes focus primarily on administration of exogenous insulin to help restore glucose homeostasis. However, such treatment rarely prevents the long-term complications of this serious metabolic disorder, including neuropathy, nephropathy, retinopathy, and cardiovascular disease. Whole pancreas or islet transplantations have enjoyed limited success in some individuals, but these approaches are hampered by the shortage of suitable donors and the burden of lifelong immunosuppression. Here, we review current approaches to differentiate nonislet cell types towards an islet-cell phenotype which may be used for larger-scale cell replacement strategies. In particular, the differentiation protocols used to direct embryonic stem cells, progenitor cells of both endocrine and nonendocrine origin, and induced pluripotent stem cells towards an islet-cell phenotype are discussed. 1. The Need for Islet Cell Replacement Strategies The World Health Organisation (WHO) estimates that 220 million people suffer from diabetes worldwide, while approximately 3.4 million individuals died as a result of hyperglycaemic complications in 2004. Administration of exogenous insulin is the fundamental means of treating hyperglycaemia in type 1 diabetes, but it does not restore the physiological regulation of blood glucose. Additionally, patients with poorly controlled type 2 diabetes are increasingly being prescribed insulin therapy, with studies suggesting that intensive insulin therapy even in newly diagnosed type 2 diabetes can improve beta-cell survival and function compared with oral hypoglycaemic agents [1]. However, tight glycaemic control, with its inherent risk of hypoglycaemia, is required to prevent many of the long-term complications of diabetes including cardiovascular disorders, nephropathies, and diabetic retinopathy. WHO figures show that 50% of people with diabetes die of cardiovascular disease, while kidney failure accounts for 10–20% of deaths. Given these shortcomings, recent research has been directed towards establishing cellular-based therapies that avoid the need for exogenous insulin delivery by conventional injection or more modern pump technology (see the study by Cohen and Shaw [2]). Arguably one of the most attractive of these strategies involves replacement of insulin-producing islet-cells by transplantation therapy [3, 4]. The first successful transplantation of isolated pancreatic islets was conducted in rodents by Ballinger and Lacy in 1972 [5]. Although this study offered hope that a cure for diabetes was possible, four decades later, islet transplantation in humans is not commonplace. The lack of fresh viable donor material coupled with problems of immunocompatability and life-long immunosuppression to prevent graft rejection has made the widespread application of both techniques almost impossible [3, 4, 6]. Stem cells are found in multicellular organisms and have the potential to differentiate into a variety of different cell types. Stem cells are largely divided according to their potency or ability to differentiate. Totipotent stem cells may generate any somatic or germline cell, while pluripotent stem cells may give rise to cells originating from any of the three germ layers: endoderm, mesoderm, or ectoderm. The current paper examines advances in the field of stem cell therapy for the treatment of diabetes and outlines the varied approaches that have been used to create insulin-producing cells. In 2 Stem Cells International Pax4 Endocrine cell Pdx1 Ngn3 MafA Nkx 2.2 Nkx 6.1 Pdx1 Beta-cell Brn4 MafB Pax6 Alpha-cell Pdx1 Delta-cell Pax6 Acinar Endodermal cell Exocrine cell Brn4 Pdx1 MafB (a) Glucagon Day of embryonic development Glucagon/ insulin E9.5 Insulin E14 Somatostatin PP E18 (b) Figure 1: Regulation of pancreatic development. (a) Pancreatic cells (both endocrine and exocrine) originate from the same Pdx-1 expressing endodermal cells. The transcription factor Ngn3 is required for differentiation into an endocrine phenotype. Further development into insulin-, glucagon-, or somatostatin-secreting cells is tightly regulated by a range of transcription factors as indicated in the figure. Pax, NKX, Pdx-1, and Brn4 are homeodomain proteins which are generally involved in morphogenesis, while MafA and MafB are members of the large Maf protein family which regulates pancreatic development. (b) Timescale showing emergence of islet hormone-producing cells in the rodent embryo. particular, the exploitation of developmental biology pathways, which are briefly outlined in the following, to direct embryonic stem cells (ESCs) towards an insulin-producing phenotype is examined. Alternative approaches including the use of pancreatic adult stem cells, islet progenitor cells of both endocrine and nonendocrine origin, and induced pluripotent stem cells are also considered. 2. Development of the Endocrine Pancreas The pancreas is formed during embryogenesis from fusion of the dorsal and ventral primordia and has both exocrine and endocrine functions [7]. The transcriptional regulation of pancreas differentiation is shown in Figure 1. The adult human pancreas is comprised of approximately 1 million islets of Langerhans that form the endocrine portion of the gland, constituting 2-3% of the total pancreatic mass [8]. Acinar and ductal tissues largely comprise the exocrine pancreas. Islets are anatomically complex microorgans comprised of heterogenous cell types that secrete insulin from the beta-cell, glucagon from the alpha-cell, somatostatin from the delta-cell, and pancreatic polypeptide (PP) from PP cells [8]. During differentiation of the endocrine tissue, progenitor cells coexpress various endocrine hormones prior to final maturation into cells expressing a single hormone [7]. In rodent models, the first endocrine cells detected are glucagon-secreting cells which are evident from approximately embryonic day 9.5 [9, 10]. This (...truncated)