Generation of Transplantable Beta Cells for Patient-Specific Cell Therapy

Hindawi Publishing Corporation International Journal of Endocrinology Volume 2012, Article ID 414812, 7 pages doi:10.1155/2012/414812 Review Article Generation of Transplantable Beta Cells for Patient-Specific Cell Therapy Xiaojie Wang,1 Daniel L. Metzger,2 Mark Meloche,1 Jianqiang Hao,1 Ziliang Ao,1 and Garth L. Warnock1 1 Department of Surgery, University of British Columbia, 3100, 910 West 10th Avenue, Vancouver, BC, Canada V5Z 4E3 2 Department of Pediatrics, University of British Columbia, 3100, 910 West 10th Avenue, Vancouver, BC, Canada V5Z 4E3 Correspondence should be addressed to Garth L. Warnock, Received 2 November 2011; Accepted 24 February 2012 Academic Editor: Bashoo Naziruddin Copyright © 2012 Xiaojie Wang 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. Islet cell transplantation offers a potential cure for type 1 diabetes, but it is challenged by insufficient donor tissue and side effects of current immunosuppressive drugs. Therefore, alternative sources of insulin-producing cells and isletfriendly immunosuppression are required to increase the efficiency and safety of this procedure. Beta cells can be transdifferentiated from precursors or another heterologous (non-beta-cell) source. Recent advances in beta cell regeneration from somatic cells such as fibroblasts could circumvent the usage of immunosuppressive drugs. Therefore, generation of patient-specific beta cells provides the potential of an evolutionary treatment for patients with diabetes. 1. Introduction Type 1 diabetes is one of the most common chronic diseases in children and adolescents caused by autoimmune destruction of insulin-producing beta cells of islets of Langerhans. Thus patients depend on insulin injection all their life. The majority of young patients depend on life-long treatment with insulin injections to control hyperglycemia. However, an exogenous supply of insulin often leads to severe hypoglycemia-related complications. Hence, insulin therapy saves life but is not a cure. On the other hand, beta-cell replacement therapy by transplantation may offer a cure because transplantation of functional beta cells can reestablish glucose-responsive insulin secretion and provide optimal control to prevent hypoglycemia when insulin is secreted [1–9]. Whole-pancreas transplantation can restore endogenous insulin production, but it has rarely been carried out in children with diabetes due to the risk of perioperative morbidity related to the damage by digestive enzymes from the exocrine pancreas during the surgical procedure. In contrast, islet-cell transplantation provides insulin-producing beta cells in a relatively noninvasive manner. It becomes a more feasible option for young recipients. In fact, much progress has been made in islet-cell transplantation following the success of the Edmonton protocol that emphasizes both a sufficient amount of donor islets and steroid-free immunosuppressive regimens [3, 4, 8, 9]. However, the requirement of 2 to 4 donors to reverse diabetes results in a considerable lack of transplantable islets. The destruction of transplanted islets by the cytotoxicity of immunosuppressive drugs further worsens this shortage [7]. In this regard, use of an alternative source of beta cells is a key to bridge the gap between cell supply and demand. Therefore, a major goal of diabetes therapy is to promote the formation of new beta cells. In consideration of elimination of immunosuppressants, autologous cells may offer a safer alternative. Ideally, a patientspecific approach can enhance the success and safety of islet transplantation. The pancreas is fundamental to the regulation of nutritional homeostasis. The pancreas is composed of exocrine and endocrine compartments. The former consists of acinar and ductal cells that produce and transport digestive enzymes into the duodenum, and the latter of the islets of Langerhans that make hormones for adaptive glucose metabolism. Each islet can secret five hormones (glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide), 2 International Journal of Endocrinology Exocrine Other endocrine cell Nonpancreatic cell Induced pluripotent stem cell Pancreatic beta cell Embryonic stem cell Somatic cell Figure 1: Generation of pancreatic beta cells. New beta cells can be generated by manipulation of different cell sources, such as from other endocrine, exocrine, and nonpancreatic cells, induced pluripotent stem cells, embryonic stem cells, and somatic cells. which are produced by alpha, beta, delta, epsilon, and PP cells, respectively [10]. There is a great interest in developing novel sources of transplantable beta cells for replacement therapy. Adult beta cells possess a limited capacity to replicate under normal physiologic conditions. However, beta-cell mass expands during times of metabolic changes such as during pregnancy and obesity [11, 12]. Beta cells can also be regenerated after the destruction of existing beta cells, such as by chemical treatment with streptozotocin or the partial removal of pancreas by a surgical procedure [13, 14]. In theory, new beta cells could arise through differentiation of progenitors or other nonbeta cells (Figure 1). Embryonic stem cells have the ability to differentiate into any cell type. For this reason, they are considered as an ideal starting material [15– 18]. Some nonpancreatic cells, including hepatic cells, can also differentiate into insulin-positive cells [19, 20]. Nonendocrine pancreatic cells, such as ductal and acinar cells, may retain a degree of plasticity to differentiate into other cell types, including beta cells [21–24]. Beta cells can also be transdifferentiated from other endocrine cells, such as alpha cells [25–27]. Recent advances in stem cell biology have established the feasibility of converting one cell type into another [28– 31]. This breakthrough directs autologous cell therapy that drives the transdifferentiation of readily available cells, such as fibroblasts, into therapeutically desirable cells, such as blood, neuron, cardiomyocyte, and islet-like cells. Significant applications of such patient-specific therapy include the engineering of new beta cells from patients’ own cells, and the elimination of the life-long usage of immunosuppressants, bioincompatibility, and disease transmission coupled with donor cells. Transcription factors for pancreatic stem cell development and the differentiation of beta cell play a critical role in this process. 2. Transcription Factors Determine the Development of Beta Cells Transcription factors have been recognized as the key mediators of cellular identity. Cell-specific gene expression is controlled at the transcriptional level and in large part by the interface among multiple transcription factors interacting with the promoter and/or enhancer regi (...truncated)