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Parkinson's Disease and Stem Cell Treatment

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Abstract

Parkinson's disease is a neurogenerative disease characterized by a progressive loss of the dopaminergic neurones in the substantia nigra, pars compacta in the midbrain ( Borta & Hoglinger, 2006). Stem cells derived from embryos or fetal tissues have been introduced in the clinic as an alternative treatment for parkinson’s disease. Because of their self-renewal capacity and pluripotentiality, human embryonic stem cells are thought to hold enormus promise as potential replacement tissue in neurodegenerative disease such as Parkinson’s. Pluripotential embryonic stem cells, neural tissue derived stem and phenotype-specified progenitor cells have been investigated for their ability to generate neurons and glia, and the molecular mechanism by which they do so (Goldman & Windrem, 2006). Logistical issues, in particular the difficulty in obtaining ample supply of fetal ventral mesencephalic cells coupled with their poor graft survival, limit the clinical applicability of fetal dopamine cell transplants. This review evaluates human neural stem cells as a graft source for Parkinson's disease.
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Introduction

Parkinson's disease is a relatively common disorder of the nervous system that afflicts patients later in life with tremor, slowness of movement, instability and rigidity. Treatment of these cardinal features of the disease is a success story of modern science and medicine, as a great deal of disability can be alleviated through the pharmacological correction of brain dopamine deficiency. Unfortunately these therapies only provide temporary relief from early symptoms and do not halt disease progression. For that reason, neuroprotective and cell replacement strategies are being explored (Borta & Hoglinger, 2007). A major advance in the understanding of Parkinson's disease (PD) came when dopamine deficiency was discovered in the corpus striatum and substantia nigra (SN) of brains taken from patients. Later studies demonstrated the connection between the SN and the striatum, thus suggesting that dopaminergic cell loss in the SN directly leads to dopaminergic deficiency in the striatum. The determination that PD is a disease of dopamine loss led to the development of rational therapies aimed at correcting this deficiency. Experimental therapeutics of PD includes novel delivery systems, anti-apoptic strategies and implantation of genetically engineered cells, and stem cells (Jankovic, 2006).
Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease, in which neurons of the substantia nigra die and fail to provide the neurotransmiter, dopamine, to the striatum (Redmond et al, 2007). Neural stem cells possess high potencies of self-renewal and neuronal differentation. As the neural stem cells most primordial cells, the human neural stem cells have attributes that appear to promote anatomical and functional preservation and/or restoration in neurodegenerative diseases. Pluripotential embryonic stem cells, neural tissue derived stem and phenotype-specified progenitor cells have been investigated for their ability to generate neurons and glia, and the molecular mechanism by which they do so (Redmond et al, 2007). Some works focus on the potential utility of neural stem cells and progenitor cells as substrates for structural repair of the brain.
Embryonic stem cells as source of

Dopaminergic neurons

Stem cells are undeveloped cells capable of proliferation, self-renewal, conversion to differentiated cells, and regenerating tissues. There are two main types of stem cells, embryonic and nonembryonic. Embryonic stem cells are derived from the inner cell mass of a blastocyst, which forms several days after an egg is fertilized. If the blastocyst implants into the uterus, the inner cell mass will develop into a fetus, with the surrounding trophoblast developing into the placenta (Iacoviti et al, 2007). The cells in this line are pluripotent and will differentiate under appropriate culture conditions into the three lineages of: ectoderm, endoderm and mesoderm, from which all mature cells, will develop. Ectodermal cells are the source of neuronal cells such as those containing (releasing) dopamine, and are essential to treat Parkinson’s disease.
Umbilical cord matrix stems (UCMS) cells
Umbilical cord matrix stem (UCMS) cells have several properties that make them of interest as a source of cells for therapeutic use. For example, they can be isolated in large numbers, grow robustly and can be frozen/thawed, can be clonally expanded, and can easily be engineered to express exogenous proteins UCMS cells have genetic and surface markers of mesenchymal stem cells and appear to be stable in terms of their surface marker expression. UCMS cells express growth factors and angiogenic factors, suggesting that they may be used to treat neurodegenerative disease.
To test the therapeutic value of UCMS cells, undifferentiated human UCMS cells were transplanted into the brains of hemiparkinsonian rats that were not immune-suppressed. The PD model rats that received a human UCMS cell transplant showed a significant decrease in the number of rotations that was not seen in sham-transplanted animals and the PD animals that were not transplanted with UCMS cells all showed a progressive degradation (Weiss et al, 2006). The study concluded that, UCMS cells transplanted into normal rats did not produce brain tumors, rotational behavior, or a frank host immune rejection response and the UCMS cells could partially reverse the parkinsonian behavioral phenotype in rats. In summary, the umbilical cord matrix appears to be a rich, noncontroversial, and inexhaustible source of primitive mesenchymal stem cells and can be use as a treatment (Figure 2).
Human Neural Stem Cells
Recent studies have focused on the promising possibility that dopamine (DA) neurons can instead be generated from multi- potential stem or precursor. Because these cells can self- renew, they potentially provide an abundant supply of transplantable tissue. However, they also pose their own unique challenge; unlike fetal neurons, stem/progenitor cells must first be differentiated to express the appropriate DA phenotypic traits, either in culture or in the brain itself (Yang et al, 2007).
The goal of this study was to determine whether, under different growth conditions in vitro, human neural progenitor cells might be more easily persuaded to express DA enzyme tyrosine hydroxylase (TH) in the transplant. To do so, human neural progenitors (HNPs) were expanded in culture either as neurospheres or as a monolayer of attached cells and transplanted into 6-hydroxydopamine (6-OHDA)-lesioned rats in the undifferentiated state or following their predifferentiation into TH-expressing cells in culture. But, when these predifferentiated HNPs are transplanted into the brain TH staining is not observed, either because expression is lost or TH-expressing cells preferentially die. More studies are needed to move forward in the development of cell replacement therapies for Parkinson's disease.

Conclusion:
Studies indicate that stem cells treatment is very effective in Parkinson’s disease. But embryonic stem cells and fetus derived have significant problems that impede their adaptation into the clinics. It is very difficult to prepare large quantities of dopaminergic progenitors from fetal tissue, because of the small numbers of neural stem cells that may be purified from the first trimester midbrain, and the impracticality and controversial nature of sampling large number of abortuses (aborted fetuses) for this purpose. For that reason these treatments cause a moral and ethical issue.

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Figure 2. Effect of human umbilical cord matrix stem (hUCMS) cells on Parkinson’s disease (PD). (A) Percentage change after transplantation surgery in animals that received hUCMS cell or sham transplants.The number of rotations observed in the PD model rats that received an hUCMS cell transplant was significantly lower than the control PD rats that received a saline injection. (B): Inspection of the rotational behavior of individual PD model rats that received hUCMS cell transplants revealed two populations: one population decreased their rotations (responders); the other population did not.

References:
Redmond D, Bjugsta K, Teng YD, Ourednik V, Ourednik J, Wakeman D., Parsons Z.,Gonzalez R., Blanchard B., Kim S.U., Gu Z., Lipton S.A., Markakis E., Roth R., Elsworth J.D., Sladek J.R., Sidman R.L., and Snyder E.Y..(2007) Behavioral improvement in a primate Parkinson’s model is associated with multiple homeostatic effects of human neural stem cells. Contributed by Richard L. Sidman, May 2, 2007

Goldman1 S.A. and Windrem M.S.(2006). Cell replacement therapy in neurological disease. New York, NY 10021, USA Phil. Trans. R. Soc. B (2006) July 31 361, 1463–1475

Borta A. and Hoglinger G.(2007). Dopamine and adult neurogenesis.Jounal Journal of Neurochemistry, 2007, 100, 587-595.

Iacovitti L.,Donaldson A.E., Marshall C.E., Suon S., and Yang M.(2007) A prtocol for the diferentation of human embryonic stem cells into dopaminergic neurons using only chemically defined human additives: studies in vitro and in vivo. Brain Res. 2007 January 5; 1127(1): 19–25.

Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M., Merchav S., Luo Y., Rao M.S., Weiss G.M., Medicetty S., Bledsoe A.R., Rachakatla R.S. (2006). Human Umbilical Cord Matrix Stem Cells: Preliminary Characterization and Effect of Transplantation in a Rodent Model of Parkinson’s Disease.DOI: 10.1634/stemcells.2005-0330
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Jankovic J. (2006). An update on the treatment of Parkinson's disease.
Mt Sinai J Med. 2006 Jul;73(4):682-9. Review.
PMID: 16878274

Yang M, Donaldson AE, Marshall CE, Shen J, and Iacovitti L, (2007). Studies on the Differentiation of Dopaminergic Traits in Human Neural Progenitor Cells In Vitro and In Vivo. Cell trans. 2007 August 15; 13(5): 535-547

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