Stem cells in Parkinson’s disease:
an update
Seema Gollamudi
Seema Gollamudi
Introduction
Parkinson’s disease (PD) is the
second most common neurodegenerative disease in the world after Alzheimer’s
disease (AD). About one percent of people over 60 years of age suffer from PD. Although most
cases of PD are sporadic, about 5–10 percent of patients have familial PD (fPD)
following an autosomal-recessive or -dominant inheritance pattern [1]. These two inherited forms appear to
have different pathologies. Patients with autosomal-dominant fPD typically show
extensive formation of Lewy bodies in different parts of the brain unlike
patients with autosomal-recessive fPD [1]. The symptoms of PD
arise due to loss of dopamine (DA) producing neurons in the substantia nigra
(SN). Although ten
different subtypes of DA-ergic neurons have been identified in the whole brain,
only three of them (A8, A9, and A10) reside in the midbrain [2]. The loss of the pigmented A9 DA-ergic
neurons of the ventrolateral pars compacta which control movement give rise to
the symptoms of PD [3].
The
most common symptoms of PD include bradykinesia, rigidity, tremor and postural instability
[4]. At advanced
stages of the disease, cognitive defects and behavioral problems may arise
including dementia. The neurochemical changes are the loss of DA in the striatum
due to loss of nigrostriatal axon terminals. The current treatments include a
combination of carbidopa/levodopa, use of dopamine agonists, surgical lesion
and deep brain stimulation. The prolonged use of levodopa increases the risk of
developing dyskinesias. Some of the other treatments of PD being developed in
clinical trials are use of plant derived substance PYM50028 cogane to promote
expression of endogenous neural growth factors, gene therapy by viral vector
mediated delivery of enzymatic machinery for DA synthesis to striatum,
continuous drug delivery and greater physiological stimulation of DA receptors
for better delivery systems for levodopa and the adenoassociated virus (AAV)
delivery of neuturin/trophic factors [5]. Current
pharmacological drugs only provide symptomatic relief but do not retard the
disease progression.
The clinical symptoms of PD do not
appear until 60-80% of the neurons have degenerated. Attempts to replace the
lost DA neurons in SN using fetal ventral mesencephalic grafts have proved
efficacious in some PD trials [6-8].
There is evidence that placement of graft tissue in the striatum is beneficial while
grafting such cells to the SN was of no benefit [9]. It has been
shown that α-synuclein (SNCA) pathology can even be found in the graft,
although this does not negate the motor benefits that they offer some
individuals with PD over many years [10, 11]. There are
several scientific and ethical considerations to be considered by the PD
patients before their participation in any stem cell related therapy [12]. The first cell therapy
studies in animal models of PD were performed in 1970s in rats using fetal rat DA
containing neurons as donors with the aim of restoring striatal DA levels [13,
14]. After the initial transplantation
of mesencephalic tissue from rat embryo to rats, further steps included
transplantation of mesencephalic DA-ergic neurons, taken from mouse embryos or
human fetuses, into DA-ergically denervated striatum of recipient rats or
MPTP-monkeys [15]. The
transplants survive, reinnervate the striatum, and generate adequate
symptomatic relief lasting as long as sixteen years following transplantation
in some patients [16-19].
Stem cells have the
benefit of being able to grow indefinitely and providing an unending supply of
cells which can be differentiated into numerous cell types for the study of
disease pathophysiology and mechanism, genetic correction and transplantation
into humans and animal models. Somatic cell reprogramming to produce neurons for
neurological disorders has gained significant attention due to its tremendous
potential [20]. Transplantation of DA producing
neurons into the striatum of PD patients can provide symptomatic relief given
that the striatum is sufficiently re-innervated. Various cell sources have been
tested in cell replacement studies in PD, including fetal ventral midbrain
tissue, embryonic stem (ES) cells, fetal and adult neural stem (NS) cells and,
induced pluripotent stem (iPS) cells [21]. Fibroblasts
or NS cells from patients can be efficiently
reprogrammed into iPS and subsequently differentiated into DA neurons [22]. Mouse and
human fibroblasts can be not only be directly reprogrammed into DA-ergic
neurons using appropriate neural factors [23], but NS
cells or fibroblasts can also be converted into iPS cells in
culture via viral transduction of four transcription factors: Oct4, Sox2, Klf4,
and c-Myc [24-27]. These iPS
cells make it possible to bypass human ES cells, to treat patients with their
own somatic cell-derived stem cells, and thereby avoiding immune rejection
caused by patient-donor cell incompatibility [28]. In a study comparing
iPS cells with human ES cells it was proved that the two had similar genomic
stability, transcription profiles, pluripotency, and DA-ergic neuron
differentiation capacity [29].
Several groups have succeeded in
generating DA-ergic neurons from iPS cells [28-31]. In PD models,
iPS cell derived DA-ergic neurons were shown to integrate into the striatum
with behavioral improvements comparable to those observed using ES cell-derived
DA neurons in both rat [28-30] and mice
[32]. The advantages of stem cell
technology outweigh the disadvantages. Consequently, cell replacement by
using human fetal mesencephalic tissue [33, 34] or ES/iPS cell
derived DA-ergic neurons [35-37] remains an
important therapeutic strategy; however, several practical limitations exist,
such as shortage of cell sources, variations in outcomes, adverse effects, and
socio-ethical issues [16]. Therefore, stem cell technologies
have recently arisen as highly promising tools that can provide an abundant source
of cells that can be used for experimental transplantation studies in PD. We provide
here an update on the current status in the stem cell research for PD disease modelling
and therapeutics.
Criteria
of stem cell selection
A stringent panel of assays can determine
that putative human ES/iPS cells are pluripotent [38]. These assays
include teratoma formation, embryoid body formation, changes in DNA methylation
patterns, and expression of pluripotent markers. A subset of phenotypic markers specific
to the development of midbrain DA neurons includes the transcription factors
pitx3, lmx1a, ngn2, msx1, girk2, and nurr1 [39]. These markers can be used to track
cellular development and isolate specific populations as multipotent progenitor
cells mature into postmitotic A9 subtype-specific DA-ergic neurons that express
DA transporter and vesicular monoamine transporter as well as the enzymes
aromatic amino acid decarboxylase and tyrosine hydroxylase (TH)
[39].
Some of the other criteria for
assuring pluripotent stem cell quality for cell therapy are normal chromosomal
structure, minimal de novo mutations associated with neural cell
transformation or DA-ergic neuron function and a high yield of A9 DA-ergic
neurons [40]. In addition for successful stem cell
based therapy in PD, the grafts should (a) exhibit a regulated release of DA
and molecular, electrophysiological, and morphological properties similar to
those of SN neurons [41, 42]; (b) enable
survival of more than 100,000 DA neurons per human putamen [43]; (c) reestablish the DA network within
the striatum and restore the functional connectivity with host extra-striatal
neural circuitries[44]; (d) reverse the motor deficits
resembling human symptoms in animal models of PD and induce long lasting and
major symptomatic relief in PD patients; and (e) produce no adverse-effects
such as tumor formation, immune reactions and graft-induced dyskinesias (GIDs).
Studies of fetal midbrain graft have
suggested that better outcomes could be obtained if the graft consisted of
well-differentiated A9 DA-ergic neurons [42, 45, 46], the most severely
damaged neuronal type in PD [47]. The A9 DA-ergic neurons are a
determinant factor for achieving synaptic formation with host tissues and
better behavioral recovery [46]. Both
ES cells and iPS cells, can provide an enriched population of therapeutically
relevant A9 DA-ergic neurons needed for treating PD patients [28,
31, 48-53]. Non-A9 DA-ergic neurons survived
transplantation but provided modest behavioral improvements when grafted in
animal models of PD [54-56]. Standardized differentiation
protocols yield consistent numbers of DA-ergic neurons across high-quality human
iPS cell lines [25,
30]. Recent differentiation protocols use
developmental patterning via a midbrain regionalized floor plate neural
progenitor cell stage to differentiate authentic A9 and A10 DA-ergic neurons [52,
57]. Both studies report
efficient DA release in vitro and in vivo after transplantation
by a large fraction of human A9 DA-ergic neurons and exceptional functional
integration leading to improved motor function without uncontrolled cell proliferation
after grafting into animal models of PD [52,
57].
Stem
cell based disease modelling of PD
The purpose of modelling PD using
stem cells enables us to get a mechanistic insight into the disease mechanism
due to the different PD gene mutations, disease development and progression and
gene function. Differentiation and maturation of the ES cells and iPS cells
enable the study of disease phenotypes during development and aging for PD
modelling [58]. Several iPS cell lines have been
generated from fibroblasts of patients carrying several known PD-related
mutations, namely SNCA [59, 60], PTEN
induced putative kinase 1 (PINK1) [61], parkinson
protein 2, E3 ubiquitin protein ligase (parkin) (PARK2) [62] and leucine-rich
repeat kinase 2 (LRRK2) [63, 64].
Neurons induced from iPS cell lines
from a SNCA triplication PD patient had higher levels of SNCA and lower levels
of ẞ-synuclein (SNCB) and γ-synuclein (SNCG) as compared to neurons
differentiated from healthy control iPS cells [59]. In order to
accurately model PD, a panel of isogenic disease and control cell lines from human
ES cells and human iPS cells were developed by genetically modifying single
base pairs in the SNCA gene by combining zinc-finger nuclease (ZFN)-mediated
genome editing and iPS cell technology [26]. Patient
derived human iPS cells carrying the A53T (G209) SNCA mutation followed by the
correction of this mutation or, alternatively, by generating either the A53T
(G209A) or E46K (G188A) mutation in the genome of wild-type human ES cells
comprised the panel of cell lines [26].
Patient-derived iPS cell lines carrying G2019S
mutation in LRRK2 were generated by independent groups. One mutant cell line,
had dysregulated expression of several genes, which were under control of extracellular-signal-regulated
kinase 1/2 (ERK). When the mutation was genetically corrected, the mutant
phenotype was rescued in differentiated neurons [65]. In the iPS
cells carrying the G2019S mutation, there was an increase
in ERK phosphorylation and the multiple PD-associated phenotypes were
ameliorated by inhibition of ERK. Neurons differentiated from iPS cell
line carrying a G2019S mutation in LRRK2 gene were also found to be more
susceptible to oxidative stress [63]. The neurons
had increased levels of SNCA and oxidative stress response proteins MAO-B and
HSPB1 and were more sensitive to caspase-3 activation caused by exposure to
hydrogen peroxide, MG-132 and 6-OHDA [63].
In mutant NS cells derived from PD
LRRK2 (G2019S) patients derived iPS cells, an increased susceptibility to
proteasomal stress as well as passage-dependent deficiencies in clonal
expansion and neuronal differentiation were observed [66]. Progressive
deterioration of nuclear architecture in mutant iPS cells (NSCs-LRRK2 G2019S)
but not in wild-type NSCs (NSCs-wt) was observed, which compromised clonal
expansion, impaired neural differentiation and increased susceptibility to
proteasomal stress. Disease phenotypes could be rescued by targeted correction
of the LRRK2 (G2019S) mutation with its wild-type counterpart in PD-iPS cells
and recapitulated upon targeted knock-in of LRRK2 (G2019S) in human hES cells. Knock-in
ES cells highlighted a role for LRRK2 in the nuclear architecture
and as a potential novel organelle affected in PD [66].
In one study, DA-ergic neurons were
generated from 7 idiopathic PD patients, 4 familial PD patients carrying the
G2019S mutation in the LRRK2 gene, and 4 healthy controls [64]. All had a similar ability to give rise
to DA-ergic neurons. When cultured for over 2.5 months to mimic aging in
vitro, only the DA-ergic neurons differentiated from sporadic PD or G2019S
mutant LRRK2 PD developed fewer and shorter neurites and a significant increase
in apoptotic cells which are signs of neurodegeneration. Further evidence
pointed to a compromised authophagy in the DA-ergic neurons derived from PD
patients [64]. In a different study, LRRK2 mutant iPS neurons
derived from familial PD patients have been associated with increased
sensitivity to oxidative stressors, such as 6-hydroxydopamine or
1-methyl-4-phenylpyridinium (MPP+), hydrogen peroxide or rotenone [63, 65].
Increased sensitivity to oxidative
toxins have also been reported with iPS cell derived neurons that harbor PD associated
homozygous recessive mutations in PINK1 [58], or a familial inherited triplication of
the SNCA gene [65].
Studies in
human iPS cell derived neuronal models of PD have revealed mechanistic details
about PD etiology, such as mitochondrial alterations, and how these may lead to
pathological features of the disease [61, 62]. iPS cell derived
neurons with mutations in PINK1 have been reported to display mitochondrial
function abnormalities, defective mitochondrial quality control, and altered
recruitment to mitochondria of exogenously transduced PARKIN [67]. PARKIN-deficient
iPS cell derived neurons from familial PD patients did not appear to show frank
mitochondrial defects, suggesting potential redundancy [62], although in
another study, PARK2 iPS cell derived neurons showed
increased oxidative stress and enhanced activity of the nuclear factor
erythroid 2-related factor 2 (Nrf2) pathway [68].
iPS cell derived neurons, but not fibroblasts or iPS cells, exhibited abnormal
mitochondrial morphology and impaired mitochondrial homeostasis [68].
Areas of interest would be to
explore why the DA-ergic neurons are prone to a higher level of intrinsic
oxidative stress, which predisposes the cells to damage in the context of PD
familial genetic mutations and to explore how the environmental toxins
predispose these cells to degenerate and develop strategies to prevent it.
Stem
cell based therapeutics for PD
Neural stem cells have been reported
to have a number of properties that might make them useful for brain repair [69]. However, it has proven difficult to
differentiate these cells into legitimate A9-subtype midbrain DA-ergic neurons
in vitro, and speculation still continues as to their DA-ergic capacity in
vivo post transplantation, thus limiting their preclinical and clinical
application [70]. Numerous cell
types have been reprogrammed into DA-ergic neurons for transplantation studies.
One of the earliest studies involved transplantation of undifferentiated ES
cells which were able to differentiate into DA-ergic neurons with concomitant
clinical improvements in parkinsonian rats [48].
Most transplantation
studies using mouse ES cells showed significant improvement of
parkinsonian rats in the rotational test
[71, 72], whereas
grafts with human ES cells showed only partial [55, 56] or even no [73] improvement. Rodent
and human ES cells derived DA-ergic neurons have been shown to survive
transplantation into the striatum of PD rats and generate some degree of
functional recovery, however the survival of ES cell derived DA-ergic neurons
post-transplantation is relatively low [35,
51, 55, 56, 73]. A major concern with using ES
cell-derived DA-ergic neurons for transplantation in PD patients is the risk of
adverse effects such as tumor formation which have been reported in rats [55,
73].
In another study iPS cell derived
neural cells were derived from 2 asymptomatic individuals and 3 familial PD
patients carrying the recessive homozygous Q456X mutation in PINK1, the
dominant homozygous G2019S mutation in LRRK2 and the heterozygous R1441C
substitution in LRRK2 and 2 healthy subjects not carrying these mutations [74]. A gradual
increase in sensitivity to cellular stress was seen as the cell type analyzed
became functionally closer to the vulnerable cell types in the PD patient's
brain. Cellular vulnerability associated with mitochondrial function in iPS
cell derived neural cells from PD patients and at-risk individuals could be
rescued with coenzyme Q10, rapamycin or the LRRK2 kinase inhibitor GW5074 [74].
Human retinal pigment epithelial
(hRPE) cells have the characteristics of neural
progenitor cells and can be induced to
differentiate into DA-ergic neurons. In one clinical
trial, cells from postmortem human eye tissue were cultured in vitro
and implanted in PD postcommissural putamen with stereotactic operation in 12
patients with PD [75]. Eleven patients showed
improvement in the primary outcome measure at 3 months post-treatment.
Positron emission tomography (PET) revealed increased DA release during the
first 6 months. It is now therefore suggested that hRPE cells, might serve
as a useful source of DA-ergic neurons for neural graft in the treatment for PD.
A highly efficient and specific
induction of cells with neuronal characteristics, without glial
differentiation, from both rat and human bone marrow stromal cells was
developed using gene transfection with Notch intracellular domain (NICD) and
subsequent treatment with bFGF, forskolin, and ciliary neurotrophic factor [76].
Intrastriatal transplantation of these GDNF-treated cells in a 6-OHDA rat model
of PD, resulted in integration of TH+ and DAT+ cells and functional recovery
in motor behaviors in apomorphine-induced rotational
behavior and adjusting step and paw-reaching tests [76]. Long term
survival of transplanted cells and restoration of motor function was also found
after autologous engraftment of A9 DA-ergic neuron-like cells induced from
mesenchymal stem cells (MSCs) in affected portions of striatum in
hemiparkinsonian macaques [77]. For seven months DAT
expression remained above baseline levels whereas for nine months cells
positive for DAT and other A9 DA-ergic neuron markers were consistently
demonstrated in the engrafted striatum [77].
Noninvasive intranasal (IN) delivery of MSCs to the brains of unilateral
6-OHDA-lesioned rats resulted in the appearance of cells in the olfactory bulb,
cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord [78]. It was efficacious in increasing
% survival of implanted neurons, % of proliferative neurons and improvement of
motor functions. The potential advantage of IN delivery of stem cells is that
it is a safe and non surgical alternative for stem cell therapy. Human and rat MSC
have been effectively transplanted into PD models with improvement of
behavioral deficits and survival of grafts and DA-ergic differentiation of the transplanted progenitors [79-82].
When embryonic neural progenitor
cells were transplanted in the host striatum, they not only survived for at
least three weeks after transplantation but also differentiated into DA (TH+)
and medium size spiny (DARPP-32- positive) neuronal phenotypes [37]. They could functionally integrate
in the striatum and ameliorate motor deficits as indicated by the statistically
significant decrease of contralateral rotations after apomorphine treatment [37]. Human tNSCs (trophoblastic neural stem
cells) isolated from preimplantation embryos in women with ectopic pregnancy have
been successfully transplanted intracranially into lesioned striatum of acute
and chronic PD rats and found to improve
behavioral deficits and neuropathology [83]. DA-ergic
neurons were also found to be regenerated in these mice in their nigrostriatal pathway
at 18-weeks. Neuronal-primed adipose mesenchymal stromal cells
(ASCs) derived from rhesus monkey (rASCs) combined with adenovirus containing
neurturin (NTN) and tyrosine hydroxylase (TH) (Ad-NTN-TH) were implanted into
the striatum and SN of MPTP lesioned hemi-parkinsonian rhesus monkeys and found
to integrate and ameliorate behavioral symptoms [84]. The advantage of using ASCs is that
they are readily available and can be obtained and used with neither ethical
nor immune-reactive considerations, as long as they are of autologous tissue
origin. Clinical trials
for PD have transplanted cell preparations dissected from the human fetal
ventral midbrain; [11,
19, 42, 85-89]. Of note, ESC-derived oligodendrocyte
progenitors are already being used for spinal-cord injury in the first
FDA-approved clinical trial using a pluripotent derived progenitor cell [88].
In another recent clinical trial fetal-derived neural precursor cells have been
used for Batten disease, a rare, fatal pediatric disorder [89].
Conclusions
and future directions
Although the advantages of using iPS
cells are numerous compared to ES cells, certain standards need to be met for a
successful outcome. A successful, clinically competitive stem cell based therapy
in PD needs to produce long lasting symptomatic relief without side effects
while counteracting PD progression. Prior to entering clinics with stem
cell-derived DA-ergic neurons, cell populations must be characterized
thoroughly both in vitro and in vivo. This is necessary to ensure
that the A9 midbrain DA-ergic neurons phenotype can functionally integrate,
release DA and provide the symptomatic relief needed. Future studies will need
to focus on i) the mechanisms of action and integration of the human stem cells
in the parkinsonian brain ii) correction of familial PD gene mutations for
autologous transplantation iii) transplantation of iPS cells or DA-ergic
neurons several years prior to onset of the disease based positive biomarker
results as a preventive measure iv) non surgical alternative strategies to
introduce stem cells to the brain v) Developing iPS cells which can target multiple
diseases at the same time vi) genetic interaction and complementation studies
between genes using mutant iPS cells and/or knockout mouse lines vii)
functional studies by generating gene knockouts, knockins and conditional
knockout models in iPS/ES cell lines.
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