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Implantation was perhaps the first therapeutic tool in regenerative medicine. Since the first tissue implants were launched, the economical meaning of treating degenerative disease, and the influence in health care costs for the elderly population, has become more apparent (1). It is also clear that tissue implant use fails, as the majority of implants do not integrate within the host tissue, die, or are no longer available after a period of time. Although implants may be mechanically durable and made of biologically inert materials, implants and their lack of biocompatibility accelerate the need for innovative means of regenerating loss or decayed tissue (2, 3). Alternatively, in the arena of the elderly, neurological and cardiac diseases will have major roles in the overall costs of health and consequent pharmaceutical, device, hospital, and clinical practices for the next 25 yr. The great therapeutic potential of stem cells in treating degenerative diseases can be rationalized, as cell therapy and tissue engineering may be considered the most relevant window of opportunity in health-related business for the dawn of the 21st century (4). Will cell therapy be a tailor-made process? Will autologous cell transplantation become a standard medical procedure? Will off-the-shelf cell treatments soon be packaged, prescribed, and routinely used in the hospital environment? [ABSTRACT FROM AUTHOR]

While the discovery of neural stem cells revolutionized the field of neural transplantation, ethical and funding limitations have made the search for alternative cell sources imperative for stem cell researchers. Bone marrow and umbilical cord blood both harbor a population of stem cells and transplantation studies in multiple models of brain injury and disease have demonstrated proof of principle for these cells as possible therapeutics. In this chapter, we discuss the characteristics of cells from bone marrow, umbilical cord blood and granulocyte colony stimulating factor exposed peripheral blood and summarize the recent literature on the use of these cells in experimental models of central nervous system injury and disease. We will discuss the neural potential of these hematopoietic cells and possible mechanisms underlying reported behavioral recovery. [ABSTRACT FROM AUTHOR]

The purpose of this chapter is to identify recent developments in health research methodology that might be useful for ensuring progress in cellular therapy for brain repair. Recently, commentators suggested that the need for rapid scientific and commercial successes has privileged approaches, which are inadequate for solving the problems inherent in the project of repairing the human brain. Critical analysis of recent clinical trials for the treatment of Parkinson's disease (PD) revealed a number of unresolved conceptual and methodological issues. These issues included: a lack of consensus concerning treatment goals, the absence of clearly defined effect sizes for clinical significance, and the weak communication of research findings for the accurate synthesis of evidence. A particular problem has been the lack of interest in collecting qualitative data regarding the experiences and values of patients participating in the research. It is recommended that the explicit adoption of so-called "evidence-based" approaches to research design, data collection, and analysis will ensure optimal outcomes for using stem cells for cellar therapies. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) hinders the delivery of potentially therapeutic drugs to the brain by restricting the diffusion of drugs from the vasculature to the brain parenchyma. One method to overcome the BBB is with cellular implants that produce and deliver therapeutic molecules directly to the brain region of interest. Immunoisolation is based on the observation that xenogeneic cells can be protected from host rejection by encapsulating, or surrounding, them within an immunoisolatory, semipermeable membrane. Cells can be enclosed within a selective, semipermeable membrane barrier that admits oxygen and required nutrients and releases bioactive cell secretions but restricts passage of larger cytotoxic agents from the host immune defense system. The selective membrane eliminates the need for chronic immunosuppression of the host and allows the implanted cells to be obtained from nonhuman sources. This chapter discusses cell immunoisolation for treating central nervous system (CNS) diseases, from concept to preclinical evaluation, in a wide range of animal models and relating to the clinical trials conducted to date. [ABSTRACT FROM AUTHOR]

The choroid plexus (CP) produces cerebrospinal fluid (CSF) and forms a portion of the physical structure of the CSF-blood barrier. More recently, the CP been implicated in other basic aspects of neural functioning, such as surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive cocktail of polypeptides for neuronal function and survival, and participating in repair processes following trauma. The CP also has a role in maintaining the extracellular milieu of the brain by actively modulating the chemical exchange between the CSF and brain parenchyma and by secreting numerous growth factors into the CSF. Preclinical and clinical studies in aging and neurodegeneration demonstrate anatomical and physiological changes in the CP, suggesting effects not only in normal development and pathological conditions, but also in potential endogenous repair processes following trauma. CP dysfunction in central nervous system (CNS) diseases, and the endogenous secretion of growth factors, indicates that transplantable CP might enable delivery of growth factors to the brain while avoiding the conventional molecular and genetic alterations associated with modifying cells to secrete selected products. Thus, this enables the possibility of replacing or transplanting CP as a means of treating acute and chronic brain diseases. This chapter focuses on the various functions of the CP, how these functions are altered in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma. [ABSTRACT FROM AUTHOR]

Neural transplantation is emerging as a viable long-term method to treat degenerative diseases of the nervous system. Unfortunately, the shortage of suitable donor tissue necessitates the development of novel approaches to enable transplantation on a widespread basis. Transplantable cells obtained from xenogeneic sources have shown considerable promise in preclinical animal models, as well as in a limited number of human trials conducted to date. Although animal-sourced tissue overcomes the shortage of available cells, transplant survival remains poor, and immunosuppressive regimens are suboptimal in improving graft viability, with deleterious side effects. One potential way of enabling xenotransplantation takes advantage of the immunoprotective capabilities of Sertoli cells, which are normally found in the testes, where they provide local immunologic protection to developing germ cells. In animal models, allogeneic and xenogeneic Sertoli cells survive and function for extended periods of time when grafted into the brain. Moreover, isolated Sertoli cells protect cografted dopaminergic neurons from immune destruction and reverse lesion-induced deficits in Parkinsonian rodents. This chapter discusses these benefits within the context of several potential underlying biological mechanisms. [ABSTRACT FROM AUTHOR]

This chapter reviews the cell transplantation strategies that have been explored as potential options in the treatment of pain and traumatic brain injury (TBI). As the goals of these two therapeutic targets are widely disparate, approaches have evolved along distinctive paths. Thus, although the provision of a local cellular source of pharmacologic analgesic molecules may be most appropriate in the management of chronic pain, central nervous system (CNS) repair after traumatic injury will most likely require replacement of lost neural populations and reestablishment of appropriate neurocircuitry to be maximally effective. The development of cellular strategies that would replace, or be used as, an adjunct to current clinical treatments for neuropathic pain have progressed over the past 30 yr. There are a variety of useful surgical and pharmacologic interventions, including electric stimulation, implantable mechanical pumps, and a myriad of drugs for pain relief, but cell and molecular technologies are a new frontier in pain medicine. The earliest cell therapy studies for pain relief tested adrenal chromaffin cells from rat or bovine sources that were placed in the subarachnoid space and functioned as cell minipumps, secreting a cocktail of antinociceptive agents around the spinal cord for peripheral nerve injury, inflammatory, or arthritic pain. These animal, and later clinical, studies suggested that the spinal intrathecal space was a safe and accessible location for cell grafts. A major problem remained: a lack of homogeneous expandable cell source to supply the antinociceptive agents. Cell lines that are either naturally immortalized or can be reversibly immortalized are the next phase for a practical homogenous source. These technologies have been modeled with various murine cell lines, where cells are transplanted that downregulate their proliferative or oncogenic phenotype either before or after transplant. Most recently, cell lines for pain have used molecular switches to remove the oncogenic sequence before grafting, to take advantage of the proliferative property induced by an oncogene for expansion, followed by its removal before grafting to make it safe, without the danger of tumor formation in the host. An alternate approach for current human cell lines is the use of neural or adrenal precursors, where their antinociceptive properties are induced by in vitro treatment with molecules that drive the cells to an irreversible neural or chromaffin phenotype. Although such human cell lines are at an early stage of investigation, their potential for clinical antinociception are enormous against the daunting problem of neuropathic spinal cord injury (SCI) pain. For TBI, early transplants using fetal neural tissue has more recently led to stem cell transplants and various manipulations, including the generation of immortalized neural stem cell lines, use of neurally differentiated embryonic stem cells and neurons derived from a human teratocarcinoma cell line, and nonneural sources, e.g., bone marrow and umbilical cord. Although the ideal goal of these grafts would be to replace neural cells lost to injury and to reintegrate within the host CNS circuitry, it is more likely that their beneficial effects (when observed) are attributable to the provision of trophic support. Thus, a promising approach in transplantation strategies for improved therapeutic outcomes following TBI may be to utilize grafted cells engineered to produce appropriate neuroprotective and trophic agents as vehicles for delivery to damaged CNS sites, similar to the approach taken in the cell-based delivery for pain management. [ABSTRACT FROM AUTHOR]

Stem cells exhibit the unique properties of continual self-renewal and the ability to differentiate into a variety of cell types with the appropriate inductive cues. In the past hematopoietic stem cells were identified in bone marrow that have the capability to differentiate into cells that are part of the blood system. The cells therefore are restricted to the types of cells they can become. Recently, other types of stem cells such as mesenchymal stem cells and multipotent adult progenitor cells have been isolated from bone marrow that have the ability to differentiate into a broader range of cell types. The potential of these bone marrow-derived stem cells to be used in treating neurological disorders is the focus of this chapter. [ABSTRACT FROM AUTHOR]

This chapter focuses on three new studies that used autologous (i.e., when the donor and recipient are the same individual) and heterologous (i.e., when the donor and recipient are different individuals) transplants of adult, bone-marrow-derived stem cells to counteract the behavioral deficits produced by intrastriatal injections of quinolinic acid (QA) in rats, a rodent model for Huntington's disease (HD). These studies support previous findings that have demonstrated that transplants of adult bone-marrow-derived stem cells can survive and integrate into the host tissue and can counteract functional deficits caused by CNS damage. In the initial study using this HD model, nestin-positive cells were observed 14 d after the transplant and GAD-positive cells were observed at 21 d posttransplant, a finding that supports the contention that adult bone-marrow stem cells possess the plasticity to transdifferentiate into neurons. However, because less than 1% of the cells expressed neuronal phenotypes, and because the functional recovery observed in all three studies occurred within 1 mo after transplantation, it is hypothesized that the ameliorative effects of the transplants were due to the production of neurotrophic factors that facilitated functioning of spared neurons, rather than through the replacement of lost neurons. When compared with transplants of heterologous stem cells, the transplants of autologous stem cells were more efficacious, at least for reducing QA-induced behavioral deficits. Because the use of autologous transplants in HD may prove unfeasible, if the mutant gene becomes expressed in the transplanted autologous stem cells, it may become critically important to find ways to reduce any adverse immunological response or other factors that may be limiting the efficacy of heterologous transplants, if this form of therapy is to become clinically viable for HD. In summary, the findings reported in this chapter support the contention that transplantation of adult, bone-marrow-derived stem cells has significant therapeutic potential as a treatment for HD, but research into how to prevent a possible immune reaction of the heterologous transplant may prove to be critical before this approach has clinical utility. [ABSTRACT FROM AUTHOR]

The use of neuroteratocarcinoma cells for transplantation in stroke has emerged as a strategy for cell replacement therapy and has begun its transition from laboratories to clinical settings. Procurement logistics and novel neuroprotective functions associated with these cells allow their use to serve as an efficacious alternative to the use of fetal cells as donor cell grafts for stroke therapy. However, the optimal transplantation regimen must still be determined. Specifically, the limitations of current stroke management reveal an urgent need to examine the efficacy of experimental treatment options, such as neural transplantation, to develop better therapies. This chapter discusses the characteristics of NT2N cells, the role of the host brain microenvironment and NT2N cell grafts, laboratory research and clinical trials for the intracerebral transplantation of NT2N cells in stroke, the mechanisms underlying the grafts' effects, and NT2N cell grafts and the need for immunosuppression. This chapter also highlights some of the most recent findings regarding NT2N cells. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited neurodegenerati of the CAG (cytosine-adenine-guanine) repeat sequence that encodes for glutamine residues. The disease manifests in the third and fourth decades of life, and death is imminent usually within 20 yr. Its pathology is marked by cell loss in the striatal nuclei. Following the marked cell loss, enlargement of the ventricles is observed, as well as cortical degeneration. The aim of neural transplantation is to replace the cells lost in the striatum as a result of the disease and to reform the damaged circuitry. Clinical trials using human fetal tissue have shown a proof of principle for neural transplantation as therapy for the disease. However, there are logistical and ethical issues associated with the current regime using human fetal tissue, and an alternative cell source is therefore required. This chapter outlines the various cell sources that are being explored as possible alternatives for use in neural transplantation for HD. [ABSTRACT FROM AUTHOR]

Neural transplantation research for Parkinson's disease has followed a circuitous and, at times, an unpredictable path. Based primarily on successful rodent studies, clinical trials using adrenal medullary tissue or fetal mesencephalic tissue were initiated throughout the world, but highly variable results in both transplant paradigms sent researchers back to the animal models for further study. Based on a then, newly available neurotoxin, MPTP was used in nonhuman primates to better model the neuropathology and behavior of Parkinson's disease. Using the MPTP, dopamine-depleted primate model, researchers have been able to address questions that were unanswered before advancing to clinical trials and which rodent models could not or did not answer. New investigations pursued questions regarding immunorejection, sources of dopamine-producing cells, transplant location, and even characteristics of the host. While this may give the impression that neural transplantation research had taken a step backward, the nonhuman primate model has helped to lay a foundation from which other transplant approaches could be compared before moving into clinical trials. Polymer encapsulated cells and neural progenitor cell lines are two such approaches that will be examined in the nonhuman primate model before being attempted in the Parkinson's patient population. While feasibility has been proven in the primate model, clinical applicability is still dependent on the creation of a stable source of donor cells. [ABSTRACT FROM AUTHOR]

Developing dopaminergic (DAergic) neurons that originate from aborted human embryos have been implanted into the brains of patients with Parkinson's disease (PD) and, in some cases, have successfully restored function. However, there are insufficient numbers of cells available to allow this therapy to become widely used. The limited amount of tissue from embryos may be circumvented by the use of cell lines that can be expanded in vitro for banking, then differentiated into DAergic neurons just prior to implantation into patients. Today, there are four main sources for such cell lines with future potential for banking and cell therapy for PD: human embryonic stem cells, human neural stem cells, human genetically immortalized stem/progenitor cells, and human adult-derived non-neural stem cells, such as bone marrow-derived stem cells. Currently, it is not possible to utilize these cell sources therapeutically for PD. The primary reasons are because it has not been feasible to effectively differentiate these cells into DAergic neurons and because the stability of phenotypic expression has been variable. This chapter describes methods to generate cells suitable for transplantation in PD in the future. The development of novel cell sources is described, along with an overview of the various types of stem cells that are suitable for grafting in PD. [ABSTRACT FROM AUTHOR]

Stem cell biology, construed in its broadest sense, has forced Medicine to view development and disease, and subsequent potential therapies, from an entirely different perspective (1-3). We have learned that there is a n inborn lasticity anThe Burnham Institute,,La Jolla,CAd flexibility "programmed" into the organism and its organ systems (1). The repository of this plasticity is thought to be the stem cell—the most primordial cell in the body and in any given structure. Nearly two decades ago, investigators began to identify cells with surprising plasticity and a propensity for dynamically shifting their fates within cultures obtained from developing and mature organs (1). The existence of such cells challenged the prevailing dogma that organs were rigidly and immutably constructed. Stem cells, as these plastic cells came to be termed, began to garner the interest of the developmental community, as well as that of the repair, gene therapy, and transplant communities. This interest arose when it was recognized that stem cells could be expanded in number and reimplanted into organs, where they would reintegrate appropriately and seamlessly, shift their fate in response to local cues to compensate for the absence of cells, express new genes, and in some cases, help promote functional improvement in disease models (4-13)( Fig. 1). Exploiting the power of a cell that presumably had a pivotal role in development for repair purposes is somewhat analogous to rebooting a computer or reseeding a lawn. Optimizing these natural processes is the primary focus of today's regenerative medicine. There have been a wide range of compelling studies conducted in animal models using various stem cells, including models of aging, spinal cord injury, stroke, parkinsonism, amyotrophic lateral sclerosis (ALS), cancer, multiple sclerosis, blood diseases, immunodeficiencies, enzyme deficiencies, myocardial infarcts, and diabetes. This chapter outlines investigations that are capturing the most attention and considers the current state of scientific understanding and controversy regarding the properties of embryonic and neural stem cells. Its objective is to provide a framework to appreciate the medical promise of this research and also to describe the challenges of translating fundamental stem cell biology into novel clinical therapies. [ABSTRACT FROM AUTHOR]