Alternative Tissue Sources

A desired characteristic of an alternative cell source is the generation of large, stable cell populations to circumvent the supply issue and to allow regular characterization to ensure the quality and character of the tissue, without the need for separate characterization of every collection. Second, tissue storage methods should be refined and validated to allow the cells to be delivered on demand to advance optimal clinical management of the recipient, rather than constraining both the...

Introduction

Recent placebo-controlled, randomized clinical trials (RCTs) failed to demonstrate clinically meaningful benefits for grafting embryonic cells in patients with Parkinson's disease (PD 1-3). Moreover, the emergence of late-onset, off-medication dyskinesias in two trials (1,3) resulted in the temporary cessation of clinical trials. Given that the research for the treatment of PD was the most advanced arm of the overall project of brain repair, current progress has not met original expectations...

Encapsulated Cell Lines And Neural Stem Cells

With new technologies, neural transplant studies for PD seem to have returned to where they began. Polymer encapsulation has given new life to adrenal medulla transplants, specifically to the chromaffin cells, which are isolated from the adrenal tissue and inserted into polymer spheres. The polymer spheres are porous to allow the exchange of dopamine or other small proteins. The size of the polymers' pores can be manipulated to prevent large-molecular-weight molecules (e.g., immunoglobulin G)...

Cp As A Biological Source Of Neurotrophic Factors

The CP is in an ideal location for distributing molecules both locally and globally to the brain. The CP possesses numerous specific transport systems, contains an array of receptors, and also serves as a major source of biologically active compounds. Choroid epithelial cells synthesize many proteins, e.g., TTR, transferrin, ceruloplasmin, cytokines, and growth factors, including TGF-a, TGF-P, basic fibroblast growth factor, nerve growth factor, glial-derived neurotrophic factor, neurotrophin...

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Parkinson's disease (PD), cell therapy, clinical trials of embryonic tissue transplantation, 32, 33, 62, 63 dopaminergic progenitor cell purification, 49, 50 dyskinesia induction, 48, 49, 63 embryonic stem cells, dopaminergic differentiation by genetic engineering, 42, 43 dopaminergic differentiation by soluble factors, 39, 41, 42 in vivo, 43-45 harvesting, 49 rodent model studies, 6 graft survival, 33 ideal cell characteristics, 33, 34 immune rejection, 49 mesenchymal stem cell...

Xenogenic Tissue

Xenotransplantation offers the opportunity of breeding animals for fetal striatal tissue donation under conditions where the supply can be regulated according to demand. The breeding stock is inbred, well-characterized, and controlled for pathogens, and tissue collection and preparation can be undertaken under standardized sterile GMP conditions. The most likely donor candidate is porcine tissue. The advantages are (1) the extensive experience of animal husbandry within this farm species (2)...

Bone Marrow As A Source Of Cells For Brain Repair

Hematopoietic and Nonhematopoietic Stem Cells Hematopoietic stem cells (HSCs) derived from bone marrow were first identified for their ability to reconstitute blood lineages they were subsequently shown to differentiate into skeletal and cardiac myocytes, endothelial cells, and hepatocytes. Surprisingly, bone marrow-derived HSCs have been recently described to trans-differentiate into neuroectodermic cell types, e.g., neurons and glial cells (3). Despite some skepticism regarding their capacity...

Abstract

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...

Conclusions And Future Directions

There is considerable promise of encapsulated cell therapy to treat a wide range of CNS disorders. Still, a number of research avenues exist that are incompletely explored and deserve attention prior to wide-scale clinical use of this technology. In some preclinical studies, the extent of diffusion from the implants appears to limit the therapeutic effectiveness of the encapsulated cells (51,58). Given the size of the human brain relative to the rodent and nonhuman primate brain, the potential...

Conclusion

Although the transplantation of NT2N cells has great potential for therapeutic efficacy in CNS disorders, concerns still remain regarding NT2N transplantation in a clinical setting. One recent study that raised such concerns found that embryonic cortical neurons and NT2N have different network properties. Neurons derived from the human NT2 cell line were found to form networks with a clustered neuritic architecture in vitro, whereas primary dissociated embryonic rat cortical neurons displayed a...

Preclinical Intracerebral Transplantation Of Nt2n Cells In Stroke

The rodent model of middle cerebral artery occlusion replicates many pathophysiological changes seen in clinical cerebral ischemia, leading to studies of treatment strategies for stroke. The potential efficacy of neural transplantation of NT2N neurons to correct the neurobehavioral deficits associated with cerebral ischemia have been elucidated by the use of this model. Data have shown that ischemia-induced behavioral dysfunctions are ameliorated by NT2N neuronal grafts as early as 1-mo...

Pd

Costs associated with PD include both direct and indirect expenses. Researchers recently determined that the US direct costs of PD are 16,634 per person yr for people who are covered by both Medicare and a private insurance policy. In 1997, researchers estimated that the annual US economic burden associated with PD was 25 billion. Through a recent multicenter collaboration, investigators calculated the direct medical costs associated with the treatment of PD among elderly people (average age,...

Whole Bone Marrow

Bone marrow transplantation (BMT) has been utilized for decades to repopulate cells in patients who received whole-body irradiation chemotherapy in the treatment of hematopoietic malignancies. However, only after the discovery that bone marrow cells transplanted into the brains of adult mice expressed neural antigens, such as glial fibrillary acidic protein (GFAP) (2), did investigators begin to systematically examine the neural differentiation of whole bone marrow in the CNS. After...

Cp In Development And Aging

The CP, which forms in the seventh week of gestation in humans, develops early in embryogenesis, thus indicating that the CP may help provide the maturing brain with a controlled extracellular environment. Even in the immature brain, the blood-CSF barrier is functional and limits passage of unwanted substances from CSF to the parenchyma. Although the CP is func tional early in development, its permeability appears to be suited for the embryonic brain by allowing low-molecular-weight compounds...

Cp And Neurogenesis

In the last 10 yr, it has become apparent that the brain is not static and immutable but possesses a considerable ability to generate new CNS cells from locally discrete populations of stem cells. The ependymal and subependymal layers of the lateral ventricles have received the greatest attention as stem cell sources, but it is interesting to note that the CP is largely an extension of these structures and also possesses remarkable neurogenic capabilities. Proliferative and immunocytochemical...

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Choroidal-cerebral calcification syndrome Hendra virus encephalitis Huntington's disease Leigh disease Listeriosis Atrophy of CP, decreased CSF production, diminished polypeptide synthesis, and metabolic activity Upregulation of lysyl oxidase in CP of SAO mice and in ALS patients CP of ALS patients has elevated SOD activity, as determined by enhanced Cu Zn-SOD staining Atrophy of CP, decreased CSF production, diminished polypeptide synthesis, and metabolic activity beyond that seen in...

Encouraging Human Experience With Pig Transplants

An Food and Drug Administration-approved US clinical phase I study is being conducted using neural xenotransplantation in 12 PD patients (18,19). This safety trial is focused on the unilateral transplantation of fetal pig mesencephalic neural cells into the putamen and caudate. Six patients received continuous systemic cyclosporine. An interim report at 12 mo listed no evidence of serious adverse events. Cultures were negative for bacterial and viral contamination, and no porcine endogenous...

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Embryoid body, dopaminergic neuron differentiation, 41 Huntington's disease transplantation sources, 93, 94 Embryonic stem (ES) cells, adult stem cell advantages, 118 culture, 4 definition, 34 Huntington's disease transplantation sources and markers, 92, 93 neural differentiation induction, Parkinson's disease cell therapy, advantages and limitations, 48 derivation, 39 dopaminergic differentiation by genetic engineering, 42, 43 dopaminergic differentiation by soluble factors, 39, 41, 42 in...

Outcome Measures

There are now a variety of standardized scales available for the measurement of functional changes in patients with neurological disorders (25). Leading researchers recognized that the progress of cellular therapies for neurological disorders would be enhanced if research groups used similar assessment procedures. Langston and colleagues (25) constructed the Core Assessment Program for Intracerebral Transplantation (CAPIT) to guide research in the field. The CAPIT-PD contains a battery of...

Fetal Neural Transplantation

In recent years, delivery of exogenous proteins into the central nervous system (CNS) has utilized a strategy of cellular and gene therapy. Researchers in this field have focused on finding a transplantable and transfectable cellular platform to serve as a local delivery system for gene products of therapeutic value (1-3). A continuous secretion of the gene product may be necessary to achieve a sustained impact from the application of a gene product to affected regions of the CNS. This...

Days

Recovery of thermal hyperalgesia and tactile allodynia after subarchnoid grafts of human neuronal cell lines in the excitotoxic model of SCI pain. Adult male Wistar Furth rats were spinally injected with quisqualic acid (QUIS), an excitoxic agent, in a rat model of SCI and chronic pain (239-242). Animals were left untreated or were injected with either NT2.17 GABA or NT2.19 5HT cells (1 x 106 cells injection) into the subarchnoid space at 2 wk (14 d) after QUIS. Animals were tested...

Study 2 Transplantation Of Mscs In A Unilateral Model Of Hd

In our second study, we assessed whether heterologous transplants of adult MSCs could reduce motor deficits in a unilateral QA rodent model of HD. The surgical procedures were similar to those used in our first study, but the MSCs were separated from the bone marrow that was aspirated from the femurs of six donor rats using magnetic cell-sorting procedures (VarioMACs Mitenyi Biotec) with CD90 (Thy-l)-tagged MSCs. The MSCs were plated and transferred through 20 passes during a 3-mo period before...

Cell Therapy Economical Implications

Although some investors claim that economical benefits from stem cell therapy are speculative (38), there appears to be great promise. Published data on the potential for new stem cell-based therapies clearly suggest a prospective for new and powerful medicinal use. More than 70 conditions have been identified as potential targets for stem cell therapy. These conditions vary from relatively rare conditions to cancer and heart disease, which afflicts millions and generates billions in spending....

Contents

Color 1 Current Views of the Embryonic and Neural Stem Cell Cell Replacement or Molecular Repair Roya Sabetrasekh, Yang D. Teng, Jitka Ourednik, Kook In Park, and Evan Y. 2 Developing Novel Cell Sources for Transplantation in Parkinson's Disease Nicolaj S. Christophersen, Ana Sofia Correia, Laurent Roybon, Jia-Yi Li, and Patrik Brundin 31 3 Neural Transplantation in the Nonhuman Primate Model of Parkinson's Disease Kimberly B. Bjugstad and John R. Sladek, Jr 61 4 Cell-Based Therapy for...

Mechanism Of Immunomodulation By Sertoli Cell Transplants

The mechanism(s) underlying the ability of Sertoli cells to protect themselves and cografted cells is not well understood. Unlike the brain and the anterior chamber of the eye, the native testes have excellent lymphatic drainage (38). Antigens grafted into the testes stimulate humoral and cellular immune response, indicating an intact afferent limb of the immune system (39). The efferent limb also appears to be intact, because intratesticular islet allografts can be destroyed in presensitized...

Info

April 1, Year Proj Proj Proj Proj Proj 2000 2005 2010 2015 2020 2025 2030 April 1, Year Proj Proj Proj Proj Proj 2000 2005 2010 2015 2020 2025 2030 Fig. 1. The number of senior citizens will double by 2030. The data above are in accordance with the World Health Organization forecasts. Thus, the number of individuals suffering from age-related neurodegenerative conditions, including cardiac disease, Alzheimer's disease, and Parkinson's disease (PD) will increase (22). In the case of heart...

Genetically Engineered Cells

A variety of cells may be engineered in vitro, either to produce molecules of potential importance for CNS release (e.g., in the form of polymer encapsulated cells, as below) or to alter the properties of a cell to render it useful for circuit reconstruction. Of course, these strategies are not necessarily mutually exclusive trophic factor support may be crucial for transplanted cells to survive and integrate in the host brain, and genetically engineering cells to release trophic factors in the...

Survival And Functional Recovery Of Xenografts In Preclinical Models

Likely, neural xenografts could function anatomically and behaviorally if their survival could be enhanced. Xenogeneic tissues mediate behavioral recovery in many animal models of neurodegeneration (7). In rodent models of PD, transplantation of fetal brain tissue obtained from mouse, hamster, rabbit, pig, and humans results in structural and functional recovery. Similarly, xenografts of fetal preoptic nuclei, superchiasmatic nuclei, and striatal neurons reverse genetic hypergonadism in mice,...

Normal Host Brain Microenvironment And Cell Grafts

Pioneering studies using NT2N neurons revealed that purified NT2N neurons survive, mature, and integrate well with the host nervous system following transplantation into the CNS of rodents (24-26). From a developmental cell biology perspective, such a transplantation setup enables the direct examination of growth and maturation of human neuronal cells in an in vivo CNS environment that otherwise could not be fully investigated in an in vitro setting. Compared to human fetal neurons, the use of...

Gcsfstimulated Peripheral Blood For Brain Repair

Similar to cord blood, peripheral blood progenitor cells (PBPCs) have been used during the last few decades as an alternative to bone marrow for hematogenic reconstitution. These cells are easily obtained by apheresis procedures after daily injections of the donor with granulocyte colony-stimulating factor (G-CSF 66), and their transplant leads to a faster engraftment and less therapeutic failure, compared to bone marrow transplants (67). Recently, researchers have reported that infusion of...

Potential Clinical Applications Of Bmscs In Neurologic Injury And Disease

Since the discovery that a subpopulation of cells within the adult bone marrow may be able to differentiate into neural lineages, BMSCs have become an appealing alternative to traditional donor populations, including fetal neural tissue, neural stem cells, and embryonic stem cells, which are encumbered by significant limitations. First and foremost, utilization of fetal brain and embryonic tissues is fraught with ethical concerns. Procurement of embryos for embryonic stem cells, fetuses for...

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Increased neuronal survival, better in rotorod Increase live span TP of MSCs in spinal cord Immature astrocytes Better in open field Injection of MSCs into distal stump IV injection of MSCs TP of MSCS in striatum Neurons, astrocytes Better in rotorod Schwann cells Improvement of sciatic Neurons, astrocytes Better in dot test Munoz-Elias et al., 2004 (56) Ohta et al., 2004 (60) Wehner et al., 2003 (62) Weimann et al., 2003 (63) Li et al., 2002 (67) Li et al., 2001a (68) Stroke, CX Stroke, CX...

The Goals For Cellular Therapies

The long-term goal of reconstructive neurosurgery is to provide a cure for patients with neurological disorders. Also, in degenerative conditions, such as PD or Alzheimer's disease, the expeditious use of cellular therapies might prevent the onset of disabling symptoms. The problem here is defining what constitutes a cure and prevention. For example, cure and prevention for a genetic condition (e.g., Huntington's disease HD ) refers to grafting cells that reverse or delay the signs and symptoms...

Nt2n Cell Grafts And Immunosuppression

Although the brain is perceived as an immunoprivileged site, neuronal graft rejection still persists. Indeed, the sustained motor and cognitive improvements noted in NT2N neuronal transplanted animals were only observed with systemic administration of cyclosporin A (CsA) immunosuppression (38-40). In contrast, behavioral recovery in the nonimmuno-suppressed animals transplanted with NT2N neurons began to diminish by about 2-mo posttransplantation. Moreover, histological analysis revealed...

Injured Host Brain Microenvironment And Cell Grafts

Because progressive neurodegeneration ensues after the onset of many neurological disorders, as exemplified in stroke, critically identifying a conducive host microenvironment seems to be a prerequisite for successful cell transplantation therapy. In stroke animal models, the reported NT2N neuronal graft survival rate of 15 (34) is a bit higher, compared to fetal cell grafts, but this rate is still low, considering that ischemic stroke is not limited to a specific cell population. Moreover,...

References

Freed, C., Greene, P., Breeze, R., et al. (2001) Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 344, 710-719. 2. Freeman, T. B., Watts, R., Hauser, R., et al. (2002) A prospective, randomized, double-blind, surgical placebo-controlled trial of intrastriatal transplantation of fetal porcine ventral mesencephalic tissue (neurocell-PD) in subjects with Parkinson's disease. Exp. Neurol. 175, 426. 3. Olanow, C. W., Goetz, C. G., Kordower, J. H., et al....

Traditional Views Of The Cp

The most recognized function of the CP is CSF production (13). CSF formation across species is generally proportional to the weight of the CP. In humans, CSF volume is 80-150 mL and forms at a rate of approx 500 mL per d. CSF production follows a circadian rhythm, with nighttime levels (0200 hours) doubling the levels produced during the daytime (14). As much as 30 of the CSF is formed at other sites, particularly under pathological conditions, including the ependymal lining of the ventricles...