Stem Cell-Based Cell Therapy in
Neurological Diseases: A Review
Seung U. Kim1,2*and Jean de Vellis3
1Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia,
Vancouver, British Columbia, Canada
2Medical Research Institute, Chungang University School of Medicine, Seoul, Korea
3Mental Retardation Research Center, University of California Los Angeles School of Medicine,
Los Angeles, California
Human neurological disorders such as Parkinson’s dis-
ease, Huntington’s disease, amyotrophic lateral sclero-
sis (ALS), Alzheimer’s disease, multiple sclerosis (MS),
stroke, and spinal cord injury are caused by a loss of
neurons and glial cells in the brain or spinal cord. Cell
replacement therapy and gene transfer to the diseased
or injured brain have provided the basis for the develop-
ment of potentially powerful new therapeutic strategies
for a broad spectrum of human neurological diseases.
However, the paucity of suitable cell types for cell
replacement therapy in patients suffering from neurologi-
cal disorders has hampered the development of this
promising therapeutic approach. In recent years, neu-
rons and glial cells have successfully been generated
from stem cells such as embryonic stem cells, mesen-
chymal stem cells, and neural stem cells, and extensive
efforts by investigators to develop stem cell-based brain
transplantation therapies have been carried out. We
review here notable experimental and preclinical studies
previously published involving stem cell-based cell and
gene therapies for Parkinson’s disease, Huntington’s
disease, ALS, Alzheimer’s disease, MS, stroke, spinal
cord injury, brain tumor, and lysosomal storage diseases
and discuss the future prospects for stem cell therapy of
neurological disorders in the clinical setting. There are
still many obstacles to be overcome before clinical
application of cell therapy in neurological disease
patients is adopted: 1) it is still uncertain what kind of
stem cells would be an ideal source for cellular grafts,
and 2) the mechanism by which transplantation of stem
cells leads to an enhanced functional recovery and
structural reorganization must to be better understood.
Steady and solid progress in stem cell research in both
basic and preclinical settings should support the hope
for development of stem cell-based cell therapies for
C 2009 Wiley-Liss, Inc.
Key words: stem cell; embryonic stem cell; neural
stem cell; mesenchymal stem cell; cell therapy; gene
transfer; neurological diseases; transplantation
Stem cells are defined as cells that have the ability
to renew themselves continuously and possess pluripo-
tent ability to differentiate into many cell types. Two
types of mammalian pluripotent stem cells, embryonic
stem cells (ESCs) derived from the inner cell mass of
blastocysts and embryonic germ cells (EGCs) obtained
from postimplantation embryos, have been identified,
and these stem cells give rise to various organs and tis-
sues (Thompson et al., 1998; Shamblott et al., 1998;
Donovan and Gearhart, 2001; Marshak et al., 2001).
Recently, there has been an exciting development in
generation of a new class of pluripotent stem cells,
induced pluripotent cells (iPS cells), from adult somatic
cells such as skin fibroblasts by introduction of embryo-
genesis-related genes (Takahashi et al., 2007; Yu et al.,
2007; Park et al., 2008). In addition to ESCs and iPS
cells, tissue-specific stem cells could be isolated from var-
ious tissues of more advanced developmental stages such
as hematopoietic stem cells, bone marrow mesenchymal
stem cells, adipose tissue-derived stem cells, amniotic
fluid stem cells, and neural stem cells. Among these are
multipotent neural stem cells (NSCs) in developing or
adult mammalian brain with properties of indefinite
growth and multipotent potential to differentiate into
three major CNS cell types, neurons, astrocytes, and oli-
godendrocytes (McKay, 1997; Flax et al., 1998; Gage,
2000; Gottlieb, 2002; Kim, 2004).
Contract grant sponsor: KOSEF (to S.U.K.); Contract grant sponsor:
Canadian Myelin Research Initiative (to S.U.K.); Contract grant sponsor:
NIH; Contract grant number: HD-006576 (to J.d.V.); Contract grant num-
ber: HD004612 (to J.d.V.); Contract grant sponsor: NMSS (to J.d.V.).
*Correspondence to: Seung U. Kim, MD, PhD, Division of Neurology,
Department of Medicine, UBC Hospital, University of British Columbia,
Vancouver, British Columbia V6T2B5, Canada.
Received 10 October 2008; Revised 12 January 2009; Accepted 20
Published online 19 March 2009 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/jnr.22054
Journal of Neuroscience Research 87:2183–2200 (2009)
' 2009 Wiley-Liss, Inc.
In humans, the existence of NSCs with multipotent
differentiation capability has also been reported in embry-
onic and adult human brain (Brustle and McKay, 1996;
Sah et al., 1997; Flax et al., 1998; Kim, 2004). In a group
of cancer patients who had infusion of bromodeoxyuri-
dine (BrdU) for diagnostic purposes and later died, evi-
dence that new neurons are continuously being generated
in adult human CNS has been demonstrated (Erkisson
et al., 1998). Why, then, is there only limited capacity for
repair in adult CNS of patients suffering from injury or
diseases? It appears that the endogenous brain environ-
ment that is responsible for induction of NSC prolifera-
tion and consequent NSC differentiation into neurons is
not adequate in most of the diseased or injured brain.
Recently, continuously dividing immortalized cell
lines of NSCs have been generated by introduction of
oncogenes, and these immortalized NSC lines have
advantages for basic studies of neural development and
cell replacement therapy or gene therapy studies: 1) sta-
ble immortal NSC cells can be expanded readily in large
numbers in a short time; 2) immortalized NSC cells are
homogeneous, insofar as they were generated from a sin-
gle cell (single clone) via oncogene transduction; and 3)
stable expression of therapeutic genes can be achieved
readily (Renfranz et al., 1991; Snyder et al., 1992; Hosh-
imaru et al., 1996; Flax et al., 1998; Kim, 2004; Lee
et al, 2007a; Kim et al., 2008b). Immortalized NSCs
have emerged as a highly effective source for genetic
manipulation and gene transfer into the CNS ex vivo;
immortalized NSCs have been genetically manipulated
in vitro to survive, integrate into host tissues, and differ-
entiate into both neurons and glial cells after transplanta-
tion into the intact or damaged brain. We have previ-
ously generated immortalized cell lines of human NSCs
by infecting fetal human brain cells grown in primary
culture with a retroviral vector carrying the v-myc onco-
gene and selecting continuously dividing NSC clones.
Both in vivo and in vitro, these cells were able to differ-
entiate into neurons and glial cells and populate the
developing or degenerating CNS (Flax et al., 1998;
Kim, 2004; Lee et al., 2007a). Cell replacement and
gene transfer to the diseased or injured CNS with NSCs
have provided the basis for the development of poten-
tially powerful new therapeutic strategies for a broad
spectrum of human neurological disorders including
Parkinson’s disease (PD), Huntington’s disease (HD),
Alzheimer’s disease (AD), amyotrophic lateral sclerosis
(ALS), multiple sclerosis (MS), stroke, spinal cord injury,
and brain tumors (Brustle and McKay, 1996; McKay,
1997; Flax et al., 1998; Gage, 2000; Temple, 2001; Got-
tlieb, 2002; Kim, 2004; Lindvall et al, 2004; Goldman,
2005). There are still many obstacles to be overcome
before clinical application of cell therapy in neurological
disease patients is adopted: 1) it is still uncertain what
kind of stem cells would be an ideal source for cellular
grafts and 2) the mechanism by which transplantation of
stem cells leads to an enhanced functional recovery has
to be better understood. Steady and solid progress in
stem cell research in both basic and preclinical settings
should support the hope for development of stem cell-
based therapies for neurodegenerative diseases. This
review focuses on the utility of stem cells, particularly
NSCs, as substrates for structural and functional repair of
the diseased or injured brain and spinal cord.
Parkinson’s disease (PD) is characterized by an exten-
sive loss of dopamine neurons (DA) in the substantia nigra
pars compacta and their terminals in the striatum (Kish
et al., 1988; Agid,1991) and affects more than 500,000
people in the United States. Although the etiology of idio-
pathic PD is not known, several predisposing factors for
the dopaminergic depletion associated with the disease
have been suggested, including programmed cell death, vi-
ral infection, and environmental toxins. As an effective
treatment for PD, patients have been given L-dihydroxy-
phenyl alanine (L-DOPA), a precursor of dopamine, but
long-term administration of L-DOPA consequently pro-
duces grave side effects (Lang and Lozano, 1998a,b).
Since the late 1980s, transplantation of human fetal
ventral mesencephalic tissues into the striatum of PD
patients has been adopted as a successful therapy for
patients with advanced disease (Lindval et al., 1990; Ola-
now et al., 1996; Kordower et al, 1997a; Dunnett and
Bjorklund, 1999). However, this fetal tissue transplanta-
tion has grave problems associated with ethical and reli-
gious questions and logistics of acquiring fetal tissues. In
addition, recent reports have indicated that the survival of
transplanted fetal mesencephalic cells in the patients’
brains was very low, and it was difficult to obtain enough
fetal tissues for transplantation (Hagell et al., 1999). To
circumvent these difficulties, utilization of neurons with a
DA phenotype generated from ESCs, MSCs, or NSCs
could serve as a practical and effective alternative for fetal
brain tissues for transplantation. DA neurons were gener-
ated from mouse ESCs or mouse NSCs after treatment
with fibroblast growth factor 8 (FGF8) and sonic hedge-
hog (Lee et al., 2000; Hagell and Brundin, 2002; J.H.
Kim et al., 2002; T.E. Kim et al., 2003), overexpression
of Nurr1 (Wagner et al., 1999; Chung et al., 2002; Kim
et al., 2003), Bcl-xL (Shim et al., 2004), or coculture with
a mouse bone marrow stromal cell line (Kawasaki et al.,
2000). Neurons with a DA phenotype have been gener-
ated from monkey ESCs by coculturing with mouse bone
marrow stromal cells (Takagi et al., 2005) and also from
human NSCs derived from fetal brain (Redmond et al.,
2007), and behavioral improvement was seen in MPTP-
lesioned monkeys following intrastriatal transplantaiton of
these cells (Takagi et al., 2005; Redmond et al., 2007).
DA neurons were also generated from fetal murine mes-
encephalic progenitor cells and induced functional recov-
ery following brain transplantation in parkinsonian rats
(Studer et al., 1998).
Transplantation of NSCs in the brain attenuates
anatomic or functional deficits associated with injury or
disease in the CNS via cell replacement, release of spe-
cific neurotransmitters, and production of neurotrophic
2184Kim and de Vellis
Journal of Neuroscience Research
factors that protect injured neurons and promote neuro-
nal growth. Recently, we have generated continuously
dividing immortalized cell lines of human NSC from
fetal human brain cell culture via a retroviral vector
encoding v-myc (Kim, 2004; Lee et al., 2007a; Kim
et al., 2008b), and one of the immortalized NSC lines,
HB1.F3, induced functional improvement in a rat
model of PD following transplantation into the striatum
(Yasuhara et al., 2006).
Earlier studies have used gene transfer technology
to develop treatment for PD by transferring the tyrosine
hydroxylase (TH) gene, a rate-limiting step enzyme in
the catecholamine biosynthesis process, into certain cell
types and then implant these cells into the brains in PD
animal models (Wolff et al., 1989; Fisher et al., 1991;
Jiao et al., 1993; Anton et al., 1994; During et al.,
1994). However, gene transfer of TH using genetically
modified cells produced only partial restoration of be-
havioral and biochemical deficits in PD animal models,
because the cells utilized did not carry a sufficient
amount of tetrahydrobiopterin (BH4), a cofactor to sup-
port TH activity (Kang et al., 1993). Therefore, it is
necessary to transfer in addition the GTP cyclohydrolase
I (GTPCH1) gene, which is the first and rate-limiting
enzyme in the BH4 biosynthetic pathway (Bencsics
et al., 1996). Immortalized CNS-derived mouse NSC
line C17.2 was transduced to carry the TH gene and the
GTPCH-1 gene for production of L-DOPA, and fol-
lowing intrastriatal implantation behavioral improvement
was seen in 6-hydroxydopamine-lesioned rats (Ryu
et al., 2005). We have similarly engineered a HB1.F3
human NSC line to produce L-DOPA by double trans-
duction with cDNAs for human TH and GTPCHI, and
transplantation of these cells into the brain in a PD rat
model led to enhanced L-DOPA production in vivo and
induced long-term functional recovery (Kim et al.,
2006). A summary of preclinical studies of stem cell
transplantation in PD animal models in rats and monkeys
is shown in Table I.
Huntington’s disease (HD) is an autosomal domi-
nant neurodegenerative disorder characterized by invol-
untary choreiformic movements, cognitive impairment,
and emotional disturbances (Greenmayre and Shoulson,
1994; Harper, 1996). Despite identification of the HD
gene and associated protein, the mechanisms involved in
the pathogenesis of HD remain largely unknown, ham-
pering effective therapeutic interventions. Transplanta-
tion of fetal human brain tissue may serve as a useful
strategy for reducing neuronal damage in HD brain, and
a recent study has documented improvements in motor
and cognition performance in HD patients following
fetal cell transplantation (Bachaud-Le ´vi et al., 2000).
This trial follows previous reports on experimental HD
animals that positive effects of fetal striatal cell transplan-
tation ameliorate neuronal dysfunction (Nakao and
Itakura, 2000) and that striatal graft tissue could integrate
and survive within the progressively degenerated stria-
tum in a transgenic HD mouse model (Dunnett et al.,
1998). The latter study is consistent with results obtained
from HD patients indicating survival and differentiation
of implanted human fetal tissue in the affected regions
(Freeman et al., 2000).
A major limiting factor in the transplantation of
fetal striatal cells is the difficulty in supplying sufficient
amounts of embryonic striatal tissue and the concomitant
ethical issues associated with the use of human embry-
onic tissue. An ideal source of cell transplantation in HD
would be NSCs, which could participate in normal
CNS development and differentiate into regionally
appropriate cell types in response to environmental fac-
tors. In this regard, previous studies have shown that
NSCs isolated from embryonic or adult mammalian
CNS can be propagated in vitro and subsequently
implanted into the brain of animal models of human
McKay, 1996; McKay, 1997; Flax et al., 1998; Gage,
HD (Brustle and
TABLE I. Stem Cell-Based Cell Therapy in Experimental Parkinson Disease Models*
Reference Animal modelTransplanted cellsAdditional treatment Functional outcome
Studer et al., 1998
J.H. Kim et al., 2002
Hagell and Brundin, 2002
Takagi et al., 2005
factor score ;
Ryu et al., 2005Rat, 6-OHDA Immortalized NSC (mouse, C17-2)
S.U. Kim et al., 2006Rat, 6-OHDAImmortalized NSC (human, HB1.F3)Rotarod ;
Yasuhara et al., 2006
Redmond et al., 2007
Immortalized NSC (human, HB1.F3)
factor score ;
*ESC, embryonic stem cell; NPC., neural precursor cell; NSC, neural stem cell; BMSC, bone marrow mesenchymal stem cell; 6-OHDA, 6-hydroxy-
dopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TH, tyrosine hydrpxylase; GTPCH1, GTP cyclohydrolyrase-1.
Stem Cell Therapy in Neurological Diseases 2185
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