Stem cell therapy for diabetes (original) (raw)
Related papers
Stem cells to replace or regenerate the diabetic pancreas: Huge potential existing hurdles
Indian Journal of Medical Research
Various stem cell sources are being explored to treat diabetes since the proof-of-concept for cell therapy was laid down by transplanting cadaveric islets as a part of Edmonton protocol in 2000. Human embryonic stem (hES) cells derived pancreatic progenitors have got US-FDA approval to be used in clinical trials to treat type 1 diabetes mellitus (T1DM). However, these progenitors more closely resemble their foetal counterparts and thus whether they will provide long-term regeneration of adult human pancreas remains to be demonstrated. In addition to lifestyle changes and administration of insulin sensitizers, regeneration of islets from endogenous pancreatic stem cells may benefit T2DM patients. The true identity of pancreatic stem cells, whether these exist or not, whether regeneration involves reduplication of existing islets or ductal epithelial cells transdifferentiate, remains a highly controversial area. We have recently demonstrated that a novel population of very small embryonic-like stem cells (VSELs) is involved during regeneration of adult mouse pancreas after partial-pancreatectomy. VSELs (pluripotent stem cells in adult organs) should be appreciated as an alternative for regenerative medicine as these are autologous (thus immune rejection issues do not exist) with no associated risk of teratoma formation. T2DM is a result of VSELs dysfunction with age and uncontrolled proliferation of VSELs possibly results in pancreatic cancer. Extensive brainstorming and financial support are required to exploit the potential of endogenous VSELs to regenerate the pancreas in a patient with diabetes.
Stem Cell Therapy for Islet Regeneration
Stem Cells in Clinic and Research, 2011
Diabetes mellitus is an endocrine disorder characterised by inadequate production or use of insulin, resulting in abnormally high blood glucose levels. High blood glucose leads to the formation of reactive advanced glycation end-products (Feldman et al., 1997), which are responsible for complications such as blindness, kidney failure, cardiovascular disease, stroke, neuropathy and vascular dysfunction. Diabetes mellitus is classified as either type 1 or type 2. Type 1 diabetes mellitus (insulin-dependent diabetes mellitus) results from the autoimmune destruction of the pancreatic beta cells, whereas type 2 diabetes mellitus (noninsulin-dependent diabetes mellitus) results from insulin resistance and impaired glucose tolerance. Approximately 7.8% (23.6 million people) of the US population has been diagnosed with diabetes mellitus, and another 57 million people are likely to develop diabetes mellitus in the coming years (American Diabetes Association, 2007). The number of people with diabetes mellitus is set to continue to rapidly increase between now and 2030, especially in developing countries. Over the last decade, a new form of treatment called islet transplantation therapy was thought to provide good patient outcomes; however, few islets are available for transplantation. Typically, the pooled islets isolated from two pancreases are enough to treat a single patient. Since the enormous potential of stem cells was discovered, it was hoped that they would provide the most effective treatment for diabetes mellitus. Over the past two decades, hundreds of studies have looked at the potential of stem cell therapy for treating diabetes mellitus. Successful stem cell therapy would eliminate the cause of the disease and lead to stable, long-term results; hence, the term "pancreatic regeneration" was coined. The hypothesis was that stem cells could regenerate the damaged pancreas. After careful consideration of the aetiology of diabetes mellitus, scientists have put forward two general treatment strategies: stem cell therapy to treat the autoimmune aspect of the disease, and stem cell therapy to treat the degenerative aspect of the disease. In this review, we focus on stem cell-based therapies aimed at islet regeneration through stem cell or insulinproducing cell (IPC) transplantation. We will also discuss the latest strategies for treating both type 1 and type 2 diabetes mellitus using stem cell therapy, along with the (initially promising) results. www.intechopen.com Stem Cells in Clinic and Research 552 2. Islet regeneration by cell replacement 2.1 Stem cell sources Many different types of stem cells have been used in the research, testing and treatment of diabetes mellitus, including stem cells that can be used to regenerate pancreatic islets, e.g. embryonic stem cells, adult stem cells and infant stem cells (umbilical cord stem cells isolated from umbilical cord blood). 2.1.1 Embryonic stem cells Human embryonic stem cells (ESCs) were first isolated at the University of Wisconsin-Madison in 1998 by James Thomson (Thomson et al., 1998). These cells were established as immortal pluripotent cell lines that are still in existence today. The ESCs were derived from blastocysts donated by couples undergoing treatment for infertility using methodology developed 17 years earlier to obtain mouse ESCs. Briefly, the trophectoderm is first removed from the blastocyst by immunosurgery and the inner cell mass is plated onto a feeder layer of mouse embryonic fibroblasts (Trounson et al., 2001; 2002). However, cells can also be derived from early human embryos at the morula stage (Strelchenko et al. 2004) after the removal of the zona pellucida using an acidified solution, or by enzymatic digestion by pronase (Verlinsky et al., 2005). Nowadays, ESCs can be isolated from many different sources (Fig. 1). ESCs are pluripotent, which means that they can differentiate into any of the functional cells derived from the three germ layers, including beta cells or insulin-producing cells (IPCs). The differentiation of ESCs into IPCs is prerequisite for their use as a diabetes mellitus treatment, and may occur either in vivo (after transplantation) or in vitro (before transplantation). In vivo differentiation is based on micro environmental conditions at the graft site, whereas in vitro differentiation requires various external factors that induce the phenotypic changes required to produce IPCs. This means that diabetes mellitus can be treated either by direct transplantation of ESCs, or by indirect transplantation of IPCs that have been differentiated from ESCs. However, Naujok et al. (2009) showed that ESCs could modify gene expression and exhibit a phenotype similar to that of islet cells when transplanted into the pancreas only if they are first differentiated in vitro, and that in vitro differentiation is a prerequisite for successful in vivo differentiation (Naujok et al., 2009). Moreover, using ESCs for pancreatic regeneration carries with it the risk of tumour formation after transplantation. Therefore, the in vitro differentiation of ESCs into IPCs is necessary before they can be used to treat diabetes mellitus. Studies looking at the in vitro differentiation of ESCs into IPCs were first performed in 2001 using mouse cells (Lumelsky et al., 2001). However, the results could not be repeated in subsequent studies (Rajagopal et al., 2003; Hansson et al., 2004; Sipione et al., 2004). Researchers then developed a strategy for selecting ESCs expressing genes related to pancreatic cells (e.g. nestin), and successfully generated IPCs from these ESCs (Soria et al., 2000; Leon-Quinto et al., 2004). Other workers succeeded in creating IPCs from ESCs using gene transfer (Blyszczuk et al., 2003; Schroeder et al., 2006), or phosphoinositol-3 kinase inhibitors (Hori et al., 2002). The differentiation of ESCs into IPCs usually involves differentiation into embryoid bodies. This relatively long process comprises two phases: the embryoid body stage (4-5 days) and the differentiation stage (30-40 days). In 2005, Shi et al. decreased the time taken for this differentiation process to 15 days (Shi et al., 2005).
Stem-cell therapy for diabetes mellitus
The Lancet, 2004
Embryonic stem cells (ESC) can be differentiated into insulin-producing cells by manipulating culture conditions. In-vitro differentiation of mouse ESC can generate embryoid bodies, which, after selection for nestinexpressing ESC, were stimulated to differentiate towards a -cell-like phenotype. 1 The addition of phosphoinositide kinase inhibitors promoted differentiation of larger numbers of ESC towards functional  cells. 2 Variations in ESC-culture conditions generate cells with properties of  cells. [3][4][5] With manipulation of culture conditions and use of pax4 or pdx-1, transcription factors associated with -cell lineage 6,7 yield promising results. Some doubt has been cast on whether ESC differentiation protocols truly yield cells that produce insulin, or cells that merely absorb insulin from the medium. 8 These differentiated cells must actively synthesise and secrete insulin rather than insulin being detected. Functioning molecular components of regulated secretion of insulin and insulin-containing vesicles are additional features that indicate a -cell phenotype. Transplantation of ESCderived insulin-producing cells reverses diabetes in rodents, 2,6 indicating that these cells do synthesise and release insulin. The early and uncontrolled introduction of transcription factors into ESC during in-vitro differentiation might not yield the desired results. 5 Regulated expression of introduced transcription factors that can be turned on during in-vitro differentiation of ESC might be more successful. 7 ESC, genetically selected for insulin expression and injected into diabetic rats, improve glucose control. 10 Human ESC produce insulin under different culture conditions. 11,12 Techniques that do not require murine feeder cells have been developed, allowing for singlespecies propagation of ESC and avoiding possible zoonotic infection of cells intended for clinical use. 13 Problems in control of differentiation and teratoma formation from ESC-derived insulin-producing cells remain to be overcome. 14 Existing ESC lines are not assumed to be identical or ideal for generating islets or  cells. Hence additional ESC lines continue to be generated. 15 Ethical concerns about the use of ESC need to be addressed and resolved in the face of this powerful technology.
Biomedicine & Pharmacotherapy, 2001
Diabetes mellitus is a metabolic disorder affecting 2-5% of the population. Transplantation of isolated islets of Langerhans from donor pancreata could be a cure for diabetes; however, such an approach is limited by the scarcity of the transplantation material and the long-term side effects of immunosuppressive therapy. These problems may be overcome by using a renewable source of cells, such as islet cells derived from stem cells. Stem cells are defined as clonogenic cells capable of both self-renewal and multilineage differentiation. This mean that these cells can be expanded in vivo or in vitro and differentiated to produce the desired cell type. There exist several sources of stem cells that have been demonstrated to give rise to pluripotent cell lines: 1) embryonic stem cells; 2) embryonic germ cells; 3) embryonic carcinoma cells; and 4) adult stem cells. By using in vitro differentiation and selection protocols, embryonic stem cells can be guided into specific cell lineages and selected by applying genetic selection when a marker gene is expressed. Recently, differentiation and cell selection protocols have been used to generate embryonic stem cell-derived insulin-secreting cells that normalise blood glucose when transplanted into diabetic animals. Some recent reports suggest that functional plasticity of adult stem cells may be greater than expected. The use of adult stem cells will circumvent the ethical dilemma surrounding embryonic stem cells and will allow autotransplantation. These investigations have increased the expectations that cell therapy could be one of the solutions to diabetes. © 2001 Éditions scientifiques et médicales Elsevier SAS diabetes / stem cells / transplantation Diabetes mellitus is a heterogeneous metabolic disorder affecting 2-5% of the adult population in developed countries. Worldwide prevalence figures give an estimate of 130 million people in 2000 and 300 million in 2025. Diabetes mellitus can be classified broadly into two groups: the insulin-dependent type (IDDM or type 1), in which the treatment mainly relies on the self-injection of insulin several times daily, and the non-insulin-dependent type (NIDDM or type 2). Despite the distinct etiology et pathophysi-ology both types may result in late complications (nephropathy, retinopathy, neuropathy, etc.). The Diabetes Control and Complications Trial [36] has shown that tight control of blood glucose can delay and diminish the progression of long-term complications; however, intensive insulin therapy (5-6 injections daily) and almost permanent blood glucose control requires highly motivated patients and does not liberate them from insulin therapy. Transplantation of insulin-producing cells isolated from donor pancreata could be a cure for type 1 and some cases of type 2 diabetes. In recent years, islet transplantation failed to materialize the hope for long-term
Cytotherapy, 2010
Background aims. Stem cells (SC) in different locations have individual characteristics. Important questions to be answered include how these specialties are generated, what the mechanism underlying their generation is, and what their biologic and clinical merits are. A basic approach to answering these questions is to make comparisons between the differences and similarities among the various SC types. They may focus on aspects of biologic marker discovery, capacity of proliferation and differentiation, along with other characteristics. The aim of this study was to characterize in detail the SC isolated from pancreatic islet (PI) and compare their properties with bone marrow (BM)-derived mesenchymal stromal cells (MSC) of the rat. Methods. Immunophenotypic characteristics, proliferation capacities, telomerase activities, pluripotent-related gene expressions, ultrastructure and the potential for multilineage differentiation of PI SC and BM MSC were studied. Results. We found that PI SC expressed markers of embryonic SC (Oct-4, Sox-2 and Rex-1) and had a high proliferation capacity, proven also by high telomerase activities. Surprisingly, markers belonging to differentiated cells were expressed by these cells in a constitutive manner. PI SC ultrastructure showed more developed and metabolically active cells.
PANCREATIC ORGANOGENESIS -A NEW APPROACH BY STEM CELL THERAPY
International Research Journal of Modernization in Engineering Technology and Science, 2020
The pancreas is produced using two specific segments: the exocrine pancreas, a store of stomach related proteins, and the endocrine islets, the wellspring of the fundamental metabolic hormone insulin. Human islets have restricted regenerative capacity; the misfortune of islet β-cells in ailments, such as type 1 diabetes, requires helpful mediation. The main procedure for the rebuilding of β-cell mass is through the age and transplantation of new β-cells obtained from human pluripotent immature microorganisms. Different methodologies incorporate animating endogenous β-cell expansion, reconstructing non-β-cells to β-like cells, and gathering islets from hereditarily built creatures. Together these methodologies structure a rich pipeline of restorative improvement for pancreatic recovery.
Adult Pancreas Generates Multipotent Stem Cells and Pancreatic and Nonpancreatic Progeny
STEM CELLS, 2004
Insulin injections alleviate hyperglycemia in most patients with diabetes. However, they do not provide dynamic control of glucose homeostasis. Consequently, patients with longterm diabetes commonly develop life-threatening complications such as cardiovascular and kidney disease, neuropathy, and blindness. It has recently been shown that sustained independence from insulin injections can be achieved by transplantation of pancreatic islets into patients with diabetes [1]. Unfortunately, practical application of this clinical protocol is severely hampered by the shortage of islets available for transplantation. If functional β-cells and islets could be generated ex vivo, present severe islet shortage could be overcome. Another possible approach for restoration of islet cell mass is enhancement of endogenous regenerative capacity of endocrine pancreas. Recent results in rodents and humans suggest that pancreas has an extensive capacity to regenerate after injury [2-4]. In fact, it has been hypothesized that diabetes might result from β-cell destruction overpowering βcell regeneration and that even a long time after the onset of
Gastrointestinal Stem Cells I. Pancreatic stem cells
AJP: Gastrointestinal and Liver Physiology, 2005
The transplantation of islets isolated from donor pancreas has renewed the interest in cell therapy for the treatment of diabetes. In addition, the capacity that stem cells have to differentiate into a wide variety of cell types makes their use ideal to generate β-cells for transplantation therapies. Several studies have reported the generation of insulin-secreting cells from embryonic and adult stem cells that normalized blood glucose values when transplanted into diabetic animal models. Finally, although much work remains to be done, there is sufficient evidence to warrant continued efforts on stem cell research to cure diabetes.