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The recent successful application of hematopoietic stem cell transplantation (HSCT) to the treatment of severe or refractory rheumatic autoimmune diseases has led to speculation of whether stem cell transplantation might benefit patients with endocrine autoimmune diseases. Autoimmune type 1 diabetes mellitus is a prime candidate for hematopoietic stem cell therapies because of both the severity of the disease and associated long-term complications of chronic hyperglycemia. HSCT in patients with recent-onset type 1 diabetes may prevent further autoimmune-mediated destruction of islet β cells and thus decrease acute and chronic risks of hyperglycemia. In patients with type 1 diabetes, however, pancreas or islet transplant is necessary to restore endogenous insulin production, and current protocols require the use of chronic immunosuppressive therapies to control autoimmunity and prevent allograft rejection. HSCT may overcome limitations associated with pancreas and islet transplant by inducing immunologic tolerance to islet β cells. Nevertheless, autologous HSCT is associated with autoimmune disease relapse, and correction of genetic susceptibility to the development of type 1 diabetes would require allogeneic HSCT with human leukocyte antigen (HLA)-DQ or DR (HLA class II) mismatched donors, which leads to a high risk of acute graft versus host disease. In this chapter, we examine both the potential therapeutic benefits and risks of HSCT for treatment of autoimmune type 1 diabetes mellitus as a model for HSCT in the treatment of endocrine autoimmune diseases. [ABSTRACT FROM AUTHOR]

Stem cell-based therapy holds great promise for the treatment of human diseases attributable to the loss or dysfunction of a single cell type. However, before stem cells can be used clinically, their safety and efficacy must be clearly established. This is particularly important for endocrine applications in which hormone replacement treatments are available. Indeed, new stem cell-based treatments must meet or exceed the gold standard already established for safety and efficacy (1). Traditional hormone replacement therapies are, however, frequently inadequate, either overtreating or undertreating the respective disorder. Stem cell therapies could offer the significant advantage of linking hormone release to physiologic stimuli resulting in improved hormonal control. This potential must be established and the risks assessed through rigorous preclinical testing before stem cell-based therapies are applied to humans. [ABSTRACT FROM AUTHOR]

Spermatogenesis is a biological process that results in the conversion of the relatively undifferentiated germ cell into the highly differentiated spermatozoan. In man, the process initiates at puberty and may be continuous for the adult life of the individual. The cells that replenish the differentiating cells are the spermatogenic stem cells. These male germ line stem cells can both self-renew and provide daughter cells that can differentiate into the terminal cell types (1-4). [ABSTRACT FROM AUTHOR]

Bone homeostasis is a dynamic process consisting of mutually dependent interactions between cells, substrates, and molecular signals that are, in turn, influenced by hormones, mitogens and differentiation factors. In general, when this environment is perturbed as a consequence of disease, including osteoporosis or injury, cell and molecular signals initiate a cascade of genetically programmed repair processes. Depending on the molecular signals and responding cells, the response to injury typically promotes regeneration to a form and function virtually indistinguishable from the preinjured state. However, if the injury becomes too extensive (i.e., becomes of a critical size), these regenerative processes are insufficient for meaningful repair. In these cases, a variety of therapeutic interventions including autografting, grafting from banked bone, or grafts of supplemental bone graft substitute materials are used. For numerous reasons, each of these therapies is associated with an unacceptably high failure rate (1). [ABSTRACT FROM AUTHOR]

Type 1 and type 2 diabetes, though different diseases, both involve inadequate cell mass of insulin-producing β cells, the most abundant cell type of pancreatic islets of Langerhans. Insulin injections alleviate hyperglycemia in the majority of diabetic patients. However, insulin therapy cannot provide the finely tuned control of glucose homeostasis afforded by native pancreatic islets. As a result, diabetic patients commonly develop multiple life-threatening complications, such as cardiovascular and kidney disease, neuropathy, and blindness. Recent successes in pancreatic islet transplantation (1) fueled new hope that this procedure could significantly improve the quality of life for diabetic patients. Unfortunately, because the islets needed for transplantation are obtained from cadaveric donors only, few patients can receive this therapy. The shortage of islets could potentially be overcome by deriving them from alternative sources such as embryonic stem (ES) cells. This chapter will provide a review of the recent progress in generating islet-like hormone-producing cell clusters from ES cells. [ABSTRACT FROM AUTHOR]

Liver repopulation with transplanted cells should be of significant interest for multiple genetic and acquired disorders. The regenerative potential of liver cells offers many opportunities for genetic manipulations and cell transplantation research. The general consideration is that use of mature hepatocytes or stem/progenitor cells for this purpose will provide effective ways to ameliorate specific diseases. Recent progress in various aspects of liver-directed cell therapy has been highly promising. For instance, it has become clear that transplanted cells can engraft efficiently and proliferate under suitable conditions to repopulate significant portions of the liver. Moreover, specific disorders can be corrected by hepatocyte transplantation. Also, genetic manipulation of cells before transplantation offers further opportunities for treating diseases. However, a variety of relevant issues still need to be resolved, including the types of cells that will be most efficacious for clinical applications, effective ways to cryopreserve cells for use at short notice, and abrogation of allograft rejection by nontoxic means. Contemplating liver-directed cell therapy for major endocrine disorders such as type 1 diabetes mellitus requires identification of suitable cells that could be modified to induce regulated hormone or enzyme expression. Recent studies suggest that stem/progenitor cell populations isolated from the fetal human liver will be effective for this purpose. Of course, advances in stem cell biology raise hopes for generating alternative sources of cells in view of the limited supply of adult human organs, which should further facilitate applications of liver cell therapy. [ABSTRACT FROM AUTHOR]

Loss of endocrine gland function from a variety of causes (e.g., autoimmune destruction, infection, injury) is commonly encountered in clinical endocrinology. Although hormone replacement is generally adequate to replace the basic function of the gland and maintain viability, it typically cannot reproduce the intricate regulation of hormone secretion. Thus, despite the availability of hormone replacement, those who require it are often at risk for the development of long-term problems (e.g., microvascular complications or severe hypoglycemia in diabetes, complications of long-term overreplacement of hydrocortisone or inadequate hydrocortisone replacement during times of stress). Thus cell replacement therapy capable of restoring endocrine function similar to that of the native gland would represent a major therapeutic advance. To that end, the differentiation of stem cells to generate new endocrine cells offers great potential. [ABSTRACT FROM AUTHOR]

The search for new sources of β cells is driven by the shortage of islets of Langerhans suitable for replacement therapy for type I diabetes. Recent advances in stem cell research, described in other sections of this book, have led to promising sources of insulin-producing cells (1-5). In addition, significant progress in the elucidation of the molecular program that guides the differentiation of islet cells during development (6-22) will certainly provide tools to expand the population of embryonic β-precursor cells and promote their differentiation into mature, insulin-producing cells. The adult pancreas is another potential source of β-precursor cells. The existence of islet progenitor cells in mature pancreas can be inferred from the fact that new islets are normally formed during postnatal life (23,24) and that a dramatic increase in islet number occurs in response to various stimuli (25-27). The presence of "endocrine stem/progenitor cells" could not only provide a source of cells suitable for transplantation, but also could replenish the β-cell population that has been depleted by injury or disease. [ABSTRACT FROM AUTHOR]

Cultured embryonic stem (ES) cells are continuous cell lines derived from 3- to 5-day-old embryonic blastocysts. Essentially an artifact of tissue culture, they can, under certain physiological conditions, sustain an undifferentiated state with the capacity to divide and renew themselves indefinitely while having the ability to differentiate into all cell types when so instructed by specific extracellular signals. An understanding of these fundamental properties and elucidation of the underlying mechanisms involved is important for implementation of potential stem cell-based therapies for human disease. [ABSTRACT FROM AUTHOR]

Stem cells are a subcategory of cells designated as "precursor" cells. Precursor cells provide the cellular building blocks to maintain the tissues and organs of the body throughout the life-span of an individual. Precursor cells also provide the cellular building blocks for tissue replacement and repair following injury. There are three basic categories of precursor cells: lineage-uncommitted pluripotent stem cells; germ layer lineage-committed ectodermal, mesodermal, and endodermal stem cells; and lineage-committed progenitor cells. These three categories of precursor cells are based on their life-span, the nature of their lineage commitment, their ability to form various differentiated cell types, and their programmed developmental lineage pattern (Fig. 1). [ABSTRACT FROM AUTHOR]

The two most basic properties of stem cells are the capacities to self-renew and to differentiate into multiple cell or tissue types (1-3). Generally, stem cells are categorized as one of three types: embryonic stem cells (ES), embryonic germ cells (EG), or adult stem cells. ES cells are derived from the inner cell mass of the blastula (Fig. 1). They proliferate indefinitely and can differentiate spontaneously into all three tissue layers of the embryo (4) and into germ cells as well (5-7). EG cells are derived from primordial germ cells (see (Fig. 1), a small set of stem cells that reside in the protected environment of the yolk stalk, so that they remain undifferentiated during embryogenesis. As with ES cells, EG cells have the capacity to differentiate into all three tissue layers (8). Adult stem cells are found in most tissues and in the circulation. They may have less replicative capacity than ES or EG cells and, until recently, were thought to have restricted developmental fates (9). This classification system omits a significant source of stem cells derived from the extraembryonic tissues (umbilical cord, placenta and amniotic tissues/fluids), which are derived from neither the adult organism nor the embryo proper. This review will describe studies of stem cells derived from extraembryonic tissues with an emphasis on cells derived from umbilical cord, their developmental origins, and relationships to other types of stem cells and potential in regenerative medicine. [ABSTRACT FROM AUTHOR]

Stem cells are a unique cell population in both biological and clinical contexts. Stem cells are defined by their function to reproduce themselves (self-renewal) and concurrently generate daughter cells that are committed to differentiation (1). The differentiation of stem cells leads to the production of all cell types in a given cell lineage. Furthermore, stem cells conduct this dual function for a lifetime, thereby continuously providing specialized cells that perform normal functions of self-renewing tissues/organs (e.g., bone marrow, intestinal epithelium; see ref. 2). Clinically, these characteristics of stem cells allow them to be a potentially powerful resource for various applications, such as regenerative medicine and gene therapy (3). Our ability to understand stem cell biology is therefore crucial for such practical applications. [ABSTRACT FROM AUTHOR]

Stem cells, which have a great capacity for self-renewal and can differentiate into at least one committed cell type, exist in embryonic and adult organisms of many phyla. Although stem cells of various types from mice and other lower organisms have been studied for many years, it was not until the derivation of stem cell lines from human embryos in 1998 (1,2) that the idea of stem cell-based therapies became widespread for the treatment of a range of disorders from Alzheimer's disease to type I diabetes. Efforts to generate insulin-producing islet cells from murine and human embryonic stem (ES) cells followed the establishment of these ES cell lines. In this review we will discuss the derivation procedures and growth characteristics of ES cell lines from these two species and the status of research to promote their differentiation into cells of the endocrine pancreas lineage. [ABSTRACT FROM AUTHOR]