Review Article

http://mjiri.iums.ac.ir Medical Journal of the Islamic Republic of Iran (MJIRI)

Iran University of Medical Sciences

Stem cell-based approach for the treatment of Parkinson's disease

Parisa Goodarzi1, Hamid Reza Aghayan2, Bagher Larijani3, Masoud Soleimani4

Ahmad-Reza Dehpour5, Mehrnaz Sahebjam6, Firoozeh Ghaderi7, Babak Arjmand8

Received: 22 May 2013 Accepted: 21 April 2014 Published: 28 January 2015

Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative brain disorder which is around 1.5
times more common in men than in women. Currently, drug medications, surgery, and lifestyle changes are
common approaches to PD, while all of them focused on reducing the symptoms. Therefore, regenerative medi-
cine based on stem cell (SC) therapies has raised a promising hope. Various types of SCs have been used in
basic and experimental studies relevant to PD, including embryonic pluripotential stem cells, mesenchymal
(MSCs) and induced pluripotent SCs (iPSCs). MSCs have several advantages over other counterparts. They are
easily accessible which can be obtained from various tissues such as bone marrow, adipose tissue, peripheral
blood, etc. with avoiding ethical problems. Therefore, MSCs is attractive clinically because there are no related
ethical and immunological concerns . Further studies are needed to answer some crucial questions about the
different issues in SC therapy. Accordingly, SC-based therapy for PD also needed more complementary evalua-
tion in both basic and clinical study areas.

Keywords: Cellular therapy, Neurodegenerative diseases, Parkinson’s disease, Stem cell.

Cite this article as: Goodarzi P, Aghayan H.R, Larijani B, Soleimani M, Dehpour A.R, Sahebjam M, Ghaderi F, Arjmand B. Stem cell-
based approach for the treatment of Parkinson's disease. Med J Islam Repub Iran 2015 (28 January). Vol. 29:168.

Introduction sults in a reduction of a neurotransmitter

Parkinson’s disease (PD) is the first or called dopamine in the brain which is nec-
second most common neurodegenerative essary for regulating of body movement.
brain disorder after Alzheimer’s disease Clinical signs of PD appear when about
that affects the control of body movements 70% of the dopamine-producing neurons
(1, 2). First time PD was formally de- are damaged. Symptoms of PD include
scribed in "An Essay on the Shaking Pal- slow physical movements (bradykinesia),
sy," published in 1817 by a London physi- shaking (tremor), muscle stiffness (rigidity)
cian named James Parkinson (3). It is re- and postural instability (impaired balance
sulted from the degeneration of dopamine- and coordination), and pain (4-7). PD is
producing nerve cells in the substanti- about 1.5 times more common in men than
anigra, a region in the mesencephalon that in women, and its prevalence increases
controls movement. This degeneration re- with age. It affects about 1%–2% of the

____________________________________________________________________________________________________________________
1. MSc, Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, School of Nursing and Midwifery, Iran Univer-
sity of Medical Sciences, Tehran, Iran. [email protected]
2. MD, PhD, Chronic Diseases Research Center, Endocrinology and Metabolism Research Institute & Brain and Spinal Cord Injury Research
Center, Tehran University of Medical Sciences, Tehran, Iran. [email protected]
3. MD, Endocrinology and Metabolism Research Center , Endocrinology and Metabolism Research Institute, Tehran University of Medical sci-
ences, Tehran, Iran. [email protected]
4. PhD, Hematology Department, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran. [email protected]
5. PhD, Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. [email protected]
6. BSc, Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran. [email protected]
7. BSc, Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran. [email protected]
8. (Corresponding author) MD, PhD, GMP-Compliant Stem Cell Facility, Endocrinology and Metabolism Research Center, Endocrinology
and Metabolism Research Institute & Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Shariati Hospital,
North Kargar, Tehran, Iran. [email protected],
 Stem cell therapy and Parkinson’s disease

population over 70 years of age (8). The ferase (COMT) inhibitors (19). All of these
causes of PD are still unknown, however a treatments have some considerable side ef-
number of researchers believe that it devel- fects such as wearing off phenomena, mo-
ops in response to a combination of certain tor fluctuation, and abnormal movements as
genetic and non-genetic factors (9). dyskinesia. On the other hand, DBS as a
surgical treatment has some serious limita-
Current treatments for Parkinson’s dis- tions. It is costly and generally considered
ease for late stage disease without dementia.
There is currently no cure for PD thus; Furthermore, it can produce cognitive dis-
several treatments have focused on reliev- orders, which may be permanent (8). As
ing the symptoms (10). Accordingly, cur- current therapeutic approaches for PD only
rent treatments include the use of oral prep- provide symptomatic relief with serious
arations of L-3,4-dihydroxyphenylalanine limitations therefore, some alternative
(L-DOPA) and dopamine receptor agonists, treatments such as regenerative medicine
apomorphine in more serious cases, contin- and stem cells (SCs) therapy are necessary
uous intestinal infusion of L-DOPA, and (20-22). There are several types of (stem)
deep brain stimulation (DBS) in subthalam- cells that have been investigated as poten-
ic nucleus and globus pallidus by using tial candidates for cellular therapy in vari-
surgically implanted electrodes (11). There- ous neurological disorders such as spinal
fore, pharmacological treatments are based cord injury, multiple sclerosis, stroke, and
on the uptake of levodopa (L-DOPA) and PD, including embryonic pluripotential
inhibition of dopamine degrading by using SCs, fetal or adult SCs (hematopoietic and
dopamine agonists and also dopamine de- mesenchymal SCs), iPSCs from different
grading enzymes inhibitors. Today, dopa- sources, and human fetal ventral mesence-
mine receptor agonists are used as the first phalic (hfVM) tissue that contains nigral
choice to delay the starting of L-DOPA. dopaminergic cells (23-29). Different types
Furthermore, they will be useful in ad- of stem cells have been investigated for
vanced stage of PD as adjunct therapy with treatment of PD with specific advantages
L-DOPA. Their mechanism of action is and disadvantages (Table 1). The purpose
stimulation of presynaptic and postsynaptic of this review is to describe various sources
dopamine receptors. Levodopa as a known of SCs that are candidate for treatment of
medication for PD treatment has been used PD.
to relieve the effects of dopamine deficien-
cy. Unfortunately, its therapeutic effect is Embryonic stem cells (ESCs)
reduced after around 3-5 years (8, 12-15). These are “pluripotent cells” derived from
As well, there are some other medications the inner cell mass of a blastocyst (2, 32)
that are used for PD for instance; Bromo- and can differentiate into any type of cell in
criptine, Pramipexole, Ropinirole, anticho- the body for instance, nigral dopaminergic
linergic medications (e.g., Benztropine), neurons (33-35). On the other hand, human
monoamine oxidase B inhibitors (MAO-B- ESCs are a source of dopamine neurons for
I), Amantadine, and DBS which stimulates transplantation in PD (36, 37). It has been
the part of brain affected by PD (16, 17). demonstrated that, embryonic pluripotential
MAO-B-I can stabilize the dopamine levels stem cells-derived dopaminergic neurons
in the synaptic cleft. Selegiline and Rasa- generate functional recovery after trans-
giline are two irreversible MAO-B inhibi- plantation into the striatum of PD in animal
tors that catalyse the oxidative deamination models (38). However, there are some seri-
of active amines and cause prolonged do- ous concerns about the use of these cells for
pamine activity (18). Also, here are some treatment of PD or other neurodegenerative
other types of Levodopa degradation in- diseases. Tumor formation is one of the
hibitors such as catechol-O-methyl trans- most important adverse effects which can

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 P. Goodarzi, et al.

Table 1. Advantages and disadvantages of stem cell types used in Parkinson’s disease (11, 26, 30, 31)
Type of stem cell Advantages Disadvantages
Embryonic stem cell (a) Highly proliferative/pluripotent (a) Risk of tumor formation
(ESCs) (b) Able to form all three germ layer (b) Ethical issues
(c) Generate dopaminergic neurons (c) Genomic instability
(d) Transplantation survival/some degree of functional
recovery

Induced pluripotent (a) Unlimited PD patient-specific cells/autologous (a) Risk of tumor formation
stem cells (iPSCs) transplantation (b) In autologous transplantation risk
(b) Transplantation survival/some degree of functional of susceptibility to the
recovery original pathology of the patient
(c) Minimized immune reactions and ethical issues

Mesenchymal stem (a) Improve motor performance in mice (a) Modest clinical improvement
cells (MSCs) (b) No reported adverse effects in humans in humans
(c) A realistic cell source for regenerative medicine
(d) Easily accessible from different tissues

Fetal brain neural (a) Lower risk of tumor formation and immune (a) Limited differentiation in vivo
stem cells (fNSCs) rejection in comparison with ESCs (b) Partial effect in PD-like symp-
(b) Ability to differentiate into neurons, astrocytes, toms
oligodendrocytes, and dopamine neurons (C) Risk of GIDs
(d) Ethical issues
(e) Histocompatibility concerns (f)
limited supply

be avoided by cell sorting, prolonged dif- (NSCs) are considerable candidates for
ferentiation and subsequently exhaustion in transplantation therapy in neurodegenera-
vitro before transplantation (11, 39-42). tive diseases (53), there are some limita-
Several animal studies have shown a mild tions on using of them such as potential
to moderate improvement in PD symptoms problems of cell regulation, ethical issues,
after transplantation of ESCs or neural stem and probability of tumorigenicity. Accord-
cells differentiated from embryonic plu- ingly, several studies showed that MSCs
ripotential stem cells (38, 43-45). have a high therapeutic potential against
neurological diseases, without the men-
Mesenchymal stem cells (MSCs) tioned limitations. In addition, MSCs are
MSCs are multipotent cells which can be readily accessible, isolated and expanded
commonly isolated from bone marrow. easily with no risk of rejection (54). MSCs
Bone marrow-derived mesenchymal stem have low immunogenic properties due to
cells (BMSCs) are the most well studied the lack of MHC-II (55). Furthermore, they
MSCs. Additionally, there are some other have protective effects on dopaminergic
MSCs sources, such as umbilical cord, neurons loss in animal models and human
dermis, adipose tissue, peripheral blood, (56-64). Some experimental studies eluci-
etc. (29, 31, 46-48). They have potentially dated that MSCs are potentially useful as
self–renewal property with differentiation vectors for treating a variety of central
capacity into a variety of cells such as oste- nervous system disorders (65). These find-
oblasts, chondrocytes, myocytes, adipo- ings also revealed MSCs ability to trans-
cytes, fibroblasts, neurons, and also dopa- differentiate into special neurons which is a
minergic neurons (48-50). MSCs can pro- substantial factor for treating neurodegen-
tect injured tissues to generate a wide spec- erative disorders. Some clinical transplanta-
trum of cells, for instance, dopamine neu- tion trials are performed by using MSCs for
rons, which can renew damaged or lost treatment of PD. For instance, autologous
cells in PD (31, 51, 52). Although, it has BMSCs were used in a clinical trial in
been demonstrated that embryonic pluripo- which patients followed for up to 36
tential stem cells and neural stem cells months after transplantation. This trial

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 Stem cell therapy and Parkinson’s disease

showed partial improvement with no tumor rotid body is located in the bifurcation of
formation or other side effects. Although common carotid artery and has some do-
MSCs have been promising candidate for paminergic cells as an alternative treatment
treatment of PD, more clinical studies are in PD (76-78). Likewise, sympathetic gan-
needed regarding MSC transplantation and glion tissue from cervical and thoracic
its safety and efficacy (31). sympathetic trunk can be implanted into the
striatum in PD (79). In addition, adrenal
Induced pluripotent stem cells (iPSCs) medullary tissue as a source of dopaminer-
iPSCs are usually derived from adult so- gic neurons is another choice for treatment
matic cells, such as fibroblasts by overex- of PD with limited benefits (80).
pressing self-renewal and pluripotency fac-
tors (Oct4, Sox2, Klf4, and Myc) (66, 67). Conclusion
Besides pluripotency and self-renewal Current treatments and medications of PD
properties, iPSCs have some advantages as try to relieve motor symptoms by providing
a source for cell-replacement therapies. For dopamine substitutes or dopamine receptors
instance, the opportunity to obtain the re- agonists and also in advanced PD patients,
programmed cells directly from the pa- apomorphine, continuous intestinal admin-
tients, thus potentially reducing the risk of istration of L-Dopa, and DBS (19, 81). Alt-
transmissible infections and immune reac- hough these treatments have some effects
tions following cellular therapy (68). Ra- on controlling symptoms, their adverse ef-
ther, using iPSCs in basic and clinical re- fects are considerable. Additionally, they
searches has no ethical limitations. In other cannot replace or regenerate the lost dopa-
words, for treatment of PD, patients own minergic neurons. While, cellular therapy
somatic cells can be differentiated into a using stem cells extracted from different
pluripotent state to produce dopaminergic sources such as, hfVM tissue can provide
neurons which could be transplanted into dopaminergic neurons regeneration, re-
the patient’s brain (69, 70). iPSCs are coun- placement, and reinnervation and also
terparts of embryonic pluripotential stem symptomatic relief lasting for several years
cells in morphology, proliferation, surface following transplantation in some cases that
antigens, and ability to differentiate into were able to withdraw from L-DOPA ther-
three germ layer cells (71). Several basic apy (11, 18, 19, 26, 82). Therefore, it is the
and clinical investigations elucidated prom- time to apply a novel and more effective
ising role of iPSCs in regenerating dopa- treatment for PD by cellular therapy and
minergic neurons as the underlying factor regenerative medicine. Nowadays, stem
in treatment of PD. Transplantation of these cell therapy has turned into an attractive
cells into the striatum ameliorated PD field of science for researchers and conse-
symptoms (10, 11, 31, 72, 73). Although, quently stem cells have been optimized to
the use of iPSCs has various advantages, use for treatment of various neurological
the risk for tumor formation is a serious disorders based on their potential to differ-
obstacle to use these cells in clinical trans- entiate into neural cells. In particular, these
plantation trials. Accordingly, it is needed cells could be induced to generate dopa-
to minimize this risk and the probability of minergic neurons for an effective treatment
genetic mutations before translating iPSCs of PD (31). Although, there are no good-
related basic science into clinical setting in established inclusion criteria for patient se-
PD (11, 74, 75). lection, several clinical trials have intro-
duced criteria to include the PD patients in
Other tissue sources their trials (83). For instance, some studies
Different tissues were used for treatment have included patients with at least 2 fea-
of PD including; carotid body, sympathetic tures of PD (tremor, rigidity, or bradykine-
ganglion neurons, and adrenal medulla. Ca- sia), good response to L-dopa, and intact

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 P. Goodarzi, et al.

higher mental functions (84) and also a imental researches to the clinical transplan-
minimum of 7 years of treatment, the pres- tation trials in various diseases including,
ence of intractable problems (more ad- neurological disorders and PD. On the oth-
vanced stages), taking L-dopa for several er hand, embryonic pluripotential stem
years and established L-dopa induced dys- cells, iPSCs, and also fetal stem cells have
kinesia (8). In addition, more precise inclu- some valuable properties in comparison
sion criteria have been introduced in some with adult MSCs for instance, pluripotency
ongoing clinical trials. For instance, a clini- and self-renewal capacity, which introduce
cal trial has described the inclusion criteria them as a considerable source for research
as below; and future cellular therapies. Of course,
- Males and females aged 18-80 years. various ethical problems and safety con-
- Current diagnosis of PD with motor cerns (e.g. tumorigenesis), are needed to
complications according to standard crite- overcome by performing further investiga-
ria. tions in both fields (11). Generally, against
- Responsiveness to dopa agonists. the promising clinical potential of (stem)
- Stage 2.5, 3 & 4 based-on HOEHN & cell based therapies, there are also potential
YAHR staging. risks. Some of the considerable risks of
- Stable medications for 60 days prior to stem cell based therapies include; 1) trans-
the surgery. plantation site reactions, 2) immune re-
- No gross atrophy or any other patholo- sponse to the transplanted cells, 3) biodis-
gy of brain in MRI. tribution/ectopic grafting, 4) unintended
- Montgomery-Asberg Rating Scale differentiation into another cell type, 5) tu-
(MADRS) less than 19 for depression. morigenicity, and 6) lack of functional
- No significant cognitive impairment characteristics (30). As it has been de-
(MMSE > 21) (85). scribed, there are various cell or stem cell
Obviously, better realizing the underlying sources that have been used for treatment
basic and cellular mechanisms of PD could of PD, but the most successful clinical trials
help scientists to explicate safe and effi- have applied hfVM tissue to treat PD (26).
cient stem cell-based approaches to over- Therefore, we are trying to explain more
come side effects such as uncontrolled dif- details of the characteristics, complications,
ferentiation and growth which can induce and different aspects of this treatment in
tumor formation. Although, it is elucidated comparison with other types of cellular
that dopaminergic neurons generated from therapies. Following implantation of hfVM
stem cells can be the best candidate for tissue, survival of grafted dopaminergic
treatment of PD, It is needed to understand neurons, has been shown in the PD pa-
more about the basic etiology of PD, also tients’ brain striatum using positron emis-
dopaminergic cell differentiation, regenera- sion tomography (PET), and histopatholog-
tion, and function. MSCs have several ad- ical methods (86, 87). Dopaminergic grafts
vantages over embryonic pluripotential can be functionally integrated into neural
stem cells. iPSCs, and neural stem cells, for circuitries in brain (87). Additionally, it has
example, they can be obtained from pa- been demonstrated that, afferent and effer-
tients for auto even allo-transplantation ent synaptic connections can be established
(31). Moreover, MSCs are easily accessible between grafted and host neurons. Long-
that can be obtained from different types of term survival of the implanted grafts have
tissues such as bone marrow, adipose tis- been reported several years (more than 10
sue, peripheral blood, etc. with no ethical years) after transplantation (86,88) with
problems (86). Accordingly, it seems that acceptable function and restoring dopamine
MSCs are the ideal candidate and maybe release in the PD patient’s brain (87). Al-
ready to translate from the basic and exper- ternatively, following stem cell transplanta-
tion, dopamine restoring could be provided
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 Stem cell therapy and Parkinson’s disease

by two different paths; 1) in vitro pre- PD needs additional transplantation of sero-

differentiation of stem cells toward dopa- tonergic neurons to relieve nonmotor symp-
minergic neurons prior to transplantation, toms (88). There are various trials that have
2) In vivo differentiation toward dopamin- been performed in the mentioned arena us-
ergic neurons after implantation into the PD ing stem cells or hfVM tissue grafts. In
patient’s brain (86). Consequently, HfVM some of them the grafts or cells have been
tissue transplantation has some complica- implanted unilaterally (84) and in others
tions such as producing Lewy bodies after bilaterally (83, 86, 88, 89) in different parts
transplantation and graft-induced dyskine- of the brain such as putamen (86, 88, 89),
sias (GID) (26, 87). Furthermore, there sublateral ventricular zone (83, 84), and
were lack of homogeneity of effects in ini- caudate nucleus (88). Additionally, in these
tial clinical trials and also they caused GID trials, the number of transplanted stem cells
as a considerable adverse event in a sub- was 1-2 million cells/Kg of body weight
group of patients (11). Accordingly, the (83,88). Eventually, results of experimental
most serious complication after hfVM tis- studies suggest future (stem) cell-based ap-
sue transplantation is GIDs which can be proaches to PD, while there are remained
treated with DBS in the globus pallidus several fundamental questions about the
(87). Various studies showed that GIDs are stem cells’ mechanism of action, adverse
caused by the hfVM graft-derived sero- effects, the best cell source for dopaminer-
tonergic hyperinnervation. These investiga- gic neurons, as well ethical and safety con-
tions supported some evidence-based strat- cerns particularly about embryonic pluripo-
egies for avoiding GIDs following treat- tential stem cells and iPSCs (11, 86).
ment of PD using hfVM tissue or stem Therefore, stem cell-based therapies for PD
cells. As the hfVM tissue contains both do- are still in its infancy and performing more
paminergic and serotonergic cells, thus experimental researches as well clinical
minimizing the serotonergic portion of the trials is crucial for advancement of
graft is seriously suggested to reduce occur- knowledge in this arena (86).
rence of GIDs. On the other hand, during
processing and preparation of dopaminergic Acknowledgements
neurons from different sources of stem The authors would like to acknowledge
cells, depletion of serotonergic neurons Seyed Hassan Emami-Razavi, Abbas No-
should be considered as a rule. In addition, rouzi-Javidan, Fereshteh Mohamadi-Jahani,
stem cell expansion and long-term storage Hanieh Rostamabadi, and Maryam Kavousi
of the grafts before transplantation could for their considerable assistance.
reduce the dopaminergic/non-dopaminergic
ratio, thus avoiding cell manipulation or
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