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 J
OURNAL
 
OF 
 Molecular Neuroscience
Editor-in-Chief:
I
LLANA
G
OZES
,
 
PhD
 J
OURNAL
 
OF 
 Molecular Neuroscience
Editor-in-Chief:
I
LLANA
G
OZES
,
PhD
Volume 24 Number 3, 2004 ISSN: 0895–8696
HumanaJournals.com
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This Issue is Dedicatedto Latest Developments in the Research onParkinson’s Disease
Guest Co-Editor: Daniel Offen,
P
h
D
This Issue is Dedicatedto Latest Developments in the Research onParkinson’s Disease
Guest Co-Editor: Daniel Offen,
P
h
D
 
Embryonic and Adult Stem Cells As a Source for Cell Therapyin Parkinson’s Disease
Yossef S. Levy, Merav Stroomza, Eldad Melamed, and Daniel Offen 
* 
Laboratory of Neurosciences, Felsenstein Medical Research Center, and Department of Neurology, Rabin Medical Center-Beilinson Campus, Petah Tiqva; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 
Received April 19, 2004; Accepted July 5, 2004
Abstract
The rationale behind the use of cells as therapeutic modalities for neurodegenerative diseases in general, andin Parkinson’s disease (PD) in particular, is that they will improve patient’s functioning by replacing the dam-aged cell population. It is reasoned that these cells will survive, grow neurites, establish functional synapses,integrate best and durably with the host tissue mainly in the striatum, renew the impaired wiring, and lead tomeaningful clinical improvement. To increase the generation of dopamine, researchers have already trans-planted non-neuronal cells, without any genetic manipulation or after introduction of genes such as tyrosinehydroxylase, in animal models of PD. Because these cells were not of neuronal origin, they developed withoutcontrol, did not integrate well into the brain parenchyma, and their survival rates were low. Clinical experi-ments using cell transplantation as a therapy for PD have been conducted since the 1980s. Most of these exper-iments used fetal dopaminergic cells originating in the ventral mesencephalic tissue obtained from fetuses.Although it was shown that the transplanted cells survived and some patients benefited from this treatment,others suffered from severe dyskinesia, probably caused by the graft’s excessive and uncontrolled productionand release of dopamine. It is now recognized that cell-replacement strategy will be effective in PD only if thetransplanted cells have the same abilities, such as dopamine synthesis and control release, reuptake, and metab-olizing dopamine, as the original dopaminergic neurons. Recent studies on embryonic and adult stem cells havedemonstrated that cells are able to both self-renew and produce differentiated tissues, including dopaminergicneurons. These new methods offer real hope for tissue replacement in a wide range of diseases, especially PD.In this review we summarize the evidence of dopaminergic neuron generation from embryonic and adult stemcells, and discuss their application for cell therapy in PD.
Index Entries:
Bone marrow stromal cells; dopamine; dopaminergic neurons; Parkinson
’
s disease; stem cells.
 Journal of Molecular Neuroscience
Copyright © 2004 Humana Press Inc.All rights of any nature whatsoever reserved.ISSN0895-8696/04/24:353
–
386/$25.00
 Journal of Molecular Neuroscience353Volume 24, 2004
Introduction
Parkinson
’
s disease (PD) is a well-characterizeddisease of the central nervous system (CNS).The dis-ease affects about 2% of the population over 50 yr ofage. The extrapyramidal signs and symptoms of PD(resting tremor, rigidity, hypokinesia, bradykinesia,etc.) result mainly from the degeneration and loss ofdopaminergic neurons of the nigrostriatal path-way. Current treatment regimens for PD consistprimarilyof pharmacological supplementation ofthe dopaminergic loss with dopamine (DA) agonistand levodopa (
L
-3-4-dihydroxyphenylalanine), aprecursor of DA. Levodopa, which can readily crossthe blood
–
 brain barrier (BBB), is the most effectiveagent controlling the symptoms of PD. Most
O
RIGINAL
A
RTICLE
*Author to whom all correspondence and reprint requests should be addressed. E-mail: doffen@post.tau.ac.il
 
354Levy et al. Journal of Molecular NeuroscienceVolume 24, 2004
Parkinson
’
spatients have a good initial response tolevodopa, but after a few years become subject toadverse effects, which include dyskinesia, fluctua-tions of efficacy (on
–
off effect), freezing, mentalchanges, and loss of efficacy.Functional replacement of specific neuronal pop-ulations through transplantation of neural tissue rep-resents an attractive therapeutic strategy for PD. Inthe late 1970s, Andrew Bjorklund and collaboratorsdemonstrated that the transplantation of embryonicDAneural tissue, obtained from the fetal ventralmesencephalon, could reverse the symptoms ofDAdepletion in the unilateral 6-hydroxydopamine(6-OHDA)-treated rat model of PD (Bjorklund andStenevi, 1979; Brundin et al., 1988). Encouraged bythese findings in animal models, Olle Lindvall andcollaborators, launched a clinical program in1984
–
1985 to attempt transplantation of embryonicneural tissues into the brains of PD patients. Clini-cal trials with transplantation of human embryonicmesencephalic tissue into the caudate and putamen(striatum) of PD patients were initiated in 1987, andabout 350 patients have since undergone transplan-tation (Lindvall and Hagell, 2002a). These clinicaltests showed that grafts of fetal ventral mesen-cephalon successfully survive and reduce motorsymptoms (Sauer and Brundin, 1991; Frodl et al., 1994;Lindvall, 1994; Nakao et al., 1994; Haque et al., 1997;Bjorklund and Lindvall, 2000; Okano et al., 2002).Although transplantation is a promising treatmentfor PD, it requires brains from about 5
–
10 fetuses foreven one PD patient, thus causing ethical and prac-tical problems, limiting its clinical application. Themammalian adult brain is a very plastic system thatis capable of incorporating transplanted stem cellsinto functional neurotransmission. In recent yearsthe questionable benefit and safety of this procedurewas raised as a control study pointing to the highrisk of adverse signs such as tardive dyskenesis(Freed et al., 2001, Freed, 2002; Olanow et al., 2003).The challenge of cell replacement in PD is huge, andefforts to find the best cell source are still being con-tinued with high priority. To overcome this problem,researchers are turning to stem cell biology for mate-rials to use in the therapeutic transplantation of PD.Many researchers have investigated the use of a widevariety of candidate cells as possible transplantationdonor cells for PD therapy. Our group has investi-gated bone marrow stromal cells (BMSCs) for exper-imental therapeutics in PD model animals (Levyet al., 2003a,b). However, the complete and coordi-nated induction of specific neuronal phenotype inmultipotent neural precursors in vitro has provedelusive. The initial success of levodopa treatment forPD suggested the feasibility of DAreplacement ther-apy by neural transplantation; and the small size ofstriatum (or caudate putamen in human beings),which becomes DAdenervated in PD, makes it aneasily accessible target for transplantation (Freemanet al., 1998). Transplantation of DA-producing tissuehas received considerable attention as an alternativetherapy that delivers DAdirectly to the striatum,sparing other tissues from adverse effects of DAstim-ulation and metabolism, and avoiding the drugpeaks and valleys of pharmacological administra-tion by providing a relatively constant source. Muchof the scientific efforts during the past 15 yr havetherefore had to provide proof of principle that (1)the grafted DAneurons can survive and form con-nections in the PD patient
’
s brain, (2) the patient
’
s brain can integrate and use the grafted neurons,and (3)the grafts can induce a measurable clinicalimprovement (Lindvall, 2003).Stem cells have the remarkable ability to exist invivo in a dormant, undifferentiated state and to self-propagate. Stem cells are not restricted to cell typesspecific to the tissue of origin, and so they are ableto differentiate in response to local environmentalclues from other tissues. This capability of self-renewal and differentiation has great therapeuticpotential in curing diseases. The ideal stem cells arepresent in the embryo, although recent studies pointto various sources of stem cells in several organs andmature tissues. Although stem cells possess greatpromise as a cure for diseases of the nervous system,methods of enriching and producing functional cellsmust be developed. Cell-replacement strategy will be effective in PD only if the transplanted cell hasthe same abilities, such as DAsynthesis and con-trol release, reuptake and metabolizing DA, as theoriginalDAneurons.Embryonic stem (ES) cells are pluripotent cells iso-lated from the inner cell mass, a cluster of a few hun-dred identical cells in the blastocyte, which is formedin the early stage of embryonic development. ES cellscan proliferate extensively in an undifferentiated stateand can provide an unlimited source of many tissuetypes. One advantage of using ES cells is their acces-sibility to genetic engineering, which permits the iso-lation and functional analysis of specific cell types(Kim et al., 2002). The use and growth of ES cells arenot without disadvantages, and the use of the fertil-ized egg raises ethical concerns and limitations. More-over, culture of these cells is complicated and needs
of 00

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reply05 / 09 / 2010
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