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The Potential for Stem Cell Therapy in Diabetes

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The Potential for Stem Cell Therapy in Diabetes 0031-3998/06/5904-0065R PEDIATRIC RESEARCH Vol. 59, No. 4, Pt 2, 2006 Copyright © 2006 International Pediatric Research Foundation, Inc. Printed in U.S.A. The Potential for Stem Cell Therapy in Diabetes JURIS J. MEIER, ANIL BHUSHAN, AND PETER C. BUTLER Larry Hillblom Islet Research Center, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095 ABSTRACT: Both type 1 and type 2 diabetes are characterized by studies reporting scattered beta-cells and occasional islets with a marked deficit in beta-cell mass causing insufficient insulin secre- beta-cells present in patients with long standing type 1 diabe- tion. Beta-cell replacement strategies may eventually provide a cure tes (12–14,25). Indirect evidence suggests that these beta-cells for diabetes. Current therapeutic approaches include pancreas and may be present because of ongoing beta-cell formation, al- islet transplantation, but the chronic shortage of donor organs re- though the source of these cells remains unknown (25). stricts this treatment option to a small proportion of affected patients. Type 2 diabetes is also characterized by an ϳ65% decrease Moreover, recent evidence shows a progressive decline in beta-cell ϳ function after islet transplantation so that most patients have to revert in beta-cell mass (9,26), associated with a 10-fold increase to insulin treatment within a few years. In this article recent progress in beta-cell apoptosis (9,27). In contrast to type 1 diabetes this in the generation, culture and targeted differentiation of human increased apoptosis is not thought to be due to autoimmune embryonic stem (ES) cells is reviewed, and some of the issues disease. Toxic oligomers of human islet amyloid polypeptide surrounding their use as a source of beta-cells are discussed. (Pediatr (hIAPP) (9,28,29), glucose and FFA-induced toxicity have all Res 59: 65R–73R, 2006) been implicated (30–34). A comparable reduction in beta-cell mass in pigs, dogs and non-human primates also leads to hyperglycemia (35–39). Taken together, these data highlight A SOURCE OF BETA-CELLS, THE NEED the importance of beta-cell mass for the maintenance of normoglycemia. Therefore, beta-cell replacement is a poten- lucose homeostasis requires finely regulated insulin se- tial therapy that might reverse rather than simply palliate both G cretion by pancreatic beta-cells present in islets of type 1 and type 2 diabetes. Pancreas transplantation is effec- Langerhans (1). In health, under fasting basal conditions tive, improving quality if not duration of life in people with insulin is secreted at a rate of ϳ2 pmol/kg/min (2,3) and after ϳ type-1 diabetes (40–42). However, limited organ availability meal ingestion this rate increases by as much as 5–10-fold and the risks associated with relatively major surgery and (4). To accomplish this requires not only normally functioning life-long immunosuppression limit the use of this option beta-cells, but also a sufficient number of beta-cells, collec- (41,42). Islet transplantation overcomes the need for major tively often referred to as beta-cell mass. In health, the human surgery but is far from being a risk-free procedure; it does not pancreas contains approximately one million islets, each con- overcome the limitation of organ availability and is much less taining approximately two thousand beta-cells (5–8). Thus, ϳ successful than pancreas transplantation at accomplishing sus- the beta-cells constitute 1.5% of the total pancreatic mass tained insulin independence (43–46). The continued need for (1–2 g in total) (8). While in humans, an up to 40% loss of an alternative means of replacing beta-cells in people with beta-cells can be tolerated without a significant deterioration diabetes has fostered scientific and public interest in the of glucose tolerance (9), a further reduction in beta-cell mass potential of embryonic stem (ES) cells as a potential therapy. leads to hyperglycemia. Type 1 diabetes is caused by autoimmune-mediated de- WHY EMBRYONIC STEM CELLS? struction of beta-cells (10–16). Longitudinal studies of insulin secretion in humans at risk for type 1 diabetes show declining Human ES cells are derived from the inner cell layer of the first phase insulin secretion years before the onset of hyper- blastocyst (Fig. 1) (47,48). These cells subsequently give rise glycemia which has been interpreted as being due to declining to all differentiated cells in the adult through a series of cell beta-cell mass (17,18). Once hyperglycemia develops as much fate choices that involve self-renewal and differentiation (47– as 90% of beta-cells have been lost (12–14,19,20). Some 51). Therefore they can theoretically be differentiated into any residual insulin secretion may persist in people with long- definitive cell type, including pancreatic beta-cells, when ex- standing type 1 diabetes (21–24), consistent with autopsy posed to the appropriate signals in the correct sequence and Received November 18, 2005; accepted December 6, 2005. Abbreviations: ES cells, embryonic stem cells; FACS, fluorescence-acti- Correspondence: Peter C. Butler, Larry Hillblom Islet Research Center, UCLA David vated cell sorting; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like Geffen School of Medicine, 24-130 Warren Hall, 900 Veteran Avenue, Los Angeles, CA 90095-7073; e-mail: [email protected] peptide 1; hIAPP, human islet amyloid polypeptide; NGN3, neurogenin3; Supported by grants from the US Public Health Service NIH DK 59579 and 61539 XIAP, X-linked inhibitor of apoptosis protein [P.C.B.] and DK68763 [A.B.], the Larry L. Hillblom Foundation, the Juvenile Diabetes Research Foundation (7-2005-1152 [P.C.B.], 1-2005-1174 [A.B.] and 5-2006-330 [A.B.]) and the Deutsche Forschungsgemeinschaft (Me 2096/2-1). DOI: 10.1203/01.pdr.0000206857.38581.49 65R 66R MEIER ET AL Figure 2. The role of islet transcription factors in endocrine differentiation in the developing pancreas. Figure adapted from Wilson et al., Mech Dev 120:65-80, Copyright © 2003 by Elsevier Science Ireland Ltd., with permis- sion. President George W. Bush saying that, “There is no such thing Figure 1. Generation of human embryonic stem cells. A few-celled embryo as a spare embryo” (New York Times, May 26, 2005). A gives rise to the blastocyst, a structure comprised of an outer cell layer, the central question relating to this discussion is, when an embryo trophoectoderm, and the inner cell mass. The inner cell mass is harvested and is to be considered dead. Thus, Landry and Zucker recently plated on feeder cells to yield a population of embryonic stem cells. (Figure pointed out that depending on the definition of death before adapted from Landry et al., J Clin Invest 114:1184–1186, copyright © 2004 the onset of neural development, a significant fraction of these by the American Society for Clinical Investigation, with permission.) human embryos will be found to be “organismically” dead (56). Based on this standpoint, using such embryos to generate over the appropriate time periods (pluripotency) (48). More- human stem cell lines would not contradict the ethics of the over, if the source of such cells was truly unlimited, it would Catholic Church and other religious authorities. Just recently, be possible to provide new treatments from time to time as two papers have been published describing novel techniques required if the cells were not self renewing once terminally to derive mouse stem cells without affecting the subsequent differentiated. To obtain an unlimited supply of human ES development of the embryo (57,58). If similar techniques can cells it is necessary to establish human ES cells lines that be applied to human embryos, this may resolve some of the behave like primary ES cells. ethical concerns regarding the generation of ES cell line. Establish and expand cell lines. The first step before ES OBSTACLES ASSOCIATED WITH THE USE OF cells can be used as therapy is to obtain ES cell lines from EMBRYONIC STEM CELLS human embryos and to expand these without loss of their pluripotential properties, or being contaminated in ways that Despite the obvious appeal of ES cell-based beta-cell re- would preclude use as a therapy. ES cell lines have been placement therapy for diabetes, there are several major obsta- established from rodents, rabbits, pigs, primates and humans cles that must be overcome to before this approach can be (48,50,51,59–62). Human ES cells have typically been ex- realistically considered as a therapeutic option. panded as undifferentiated colonies on feeding layers of Ethical and religious sensitivities. There are ethical and mouse embryonic fibroblasts. ES cells differentiate into ecto- religious sensitivities concerning use of human embryos that dermal, mesodermal and endodermal structures after removal still hamper the broader use of ES cells for research purposes, from this layer (50). The use of mouse fibroblasts as feeding and many governments ban or at least highly restrict this kind layers has contaminated some of the limited supply of human of research (52,53). The Roman Catholic Church has repeat- ES cells available with mouse genes, precluding their thera- edly demanded an international ban of human ES cell re- peutic potential (50,51,63,64). However, it is possible to search, since this requires the destruction of human embryos, expand human ES cells without mouse feeder layer cells so and in their view, the human embryo has all the moral rights that in future human ES cells can be expanded without this and protection as any other human being (54,55). Owing to problem (65), although obtaining new ES cell lines is limited these moral concerns, the United States Congress has enacted by the unresolved religious and ethical concerns raised earlier.
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