PBPrimate BiologyPBPrimate Biol.2363-4715Copernicus PublicationsGöttingen, Germany10.5194/pb-4-185-2017Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectivesWiannyFlorenceflorence.wianny@inserm.frVezoliJulienjulien.vezoli@esi-frankfurt.deUniv Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, FranceErnst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, 60528 Frankfurt, GermanyFlorence Wianny (florence.wianny@inserm.fr) and Julien Vezoli (julien.vezoli@esi-frankfurt.de)11October2017421852139June201725August201731August2017This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/This article is available from https://pb.copernicus.org/articles/4/185/2017/pb-4-185-2017.htmlThe full text article is available as a PDF file from https://pb.copernicus.org/articles/4/185/2017/pb-4-185-2017.pdf
In order to calibrate stem cell exploitation for cellular therapy in
neurodegenerative diseases, fundamental and preclinical research in NHP
(nonhuman primate)
models is crucial. Indeed, it is consensually recognized that it is not
possible to directly extrapolate results obtained in rodent models to human
patients. A large diversity of neurological pathologies should benefit from
cellular therapy based on neural differentiation of stem cells. In the
context of this special issue of Primate Biology on NHP stem cells, we
describe past and recent advances on cell replacement in the NHP model of
Parkinson's disease (PD). From the different grafting procedures to the various
cell types transplanted, we review here diverse approaches for
cell-replacement therapy and their related therapeutic potential on behavior
and function in the NHP model of PD.
Introduction
The term Parkinson's disease (PD) makes reference to an ensemble of
neurodegenerative conditions affecting several parts of the brain (Braak et
al., 2006). PD is defined by the presence of
α-synuclein
positive inclusions into cell bodies and dendrites of monoaminergic cells, associated
with the principal pathologic characteristic which is progressive death of
pigmented cells of the substantia nigra pars compacta (SNpc), i.e.,
nigrostriatal dopaminergic (DA) neurons. These DA neurons disappear with an
annual estimated rate of 1 % in parkinsonian patients compared to
0.5 % in healthy subjects (Scherman et al., 1989). Characteristic
clinical signs appear late, i.e., when neuronal death exceeds the threshold of
70–80 % of nigrostriatal denervation and 50–60 % of neuronal death
in SNpc (Agid, 1991). However, PD diagnosis is mainly clinical and based on a
characteristic motor phenotype, i.e., bradykinesia, resting tremor, muscular
rigidity, postural instability and freezing of gait. The presence of these
motor troubles is used for the primary diagnosis of a parkinsonian syndrome;
additional exclusion–inclusion criteria allow clinicians to differentiate
between several forms of parkinsonism including PD – e.g., clinical motor
symptoms generally have unilateral onset in PD (Chia and Liu, 1992). Several
possible treatments are currently available for both early and late stages of
the disease. However, PD remains incurable and those palliative therapies
give rise to complications after several years of treatment. At present,
symptomatic treatments of PD involve mainly L-DOPA (levodopa, L-3,4-dihydroxyphenylalanine) therapy for correcting motor
symptoms and deep brain stimulation reserved for a subpopulation of patients.
Nonetheless, these therapeutic approaches are not fully satisfactory because,
even if movements are better controlled, they (i) do not cure the source of
these motor and non-motor symptoms, (ii) do not prevent the disease
progression and (iii) lead in the long term to behavioral troubles (e.g.,
impulse control disorders) at a significant rate (Destee, 2005).
A better comprehension of the physiopathology of PD and the establishment of
new therapies requires an in-depth investigation of early stages of the
disease, including pathophysiological characterization of (i) evolving non-motor
symptoms, (ii) the restructuring of the central nervous system induced by DA lesion
initiation and (iii) non-motor behavioral manifestations of the disease. Early
onset of cognitive troubles linked to PD is now recognized (Yang et al.,
2016), and they are in part due to fronto-striatal loop dysfunction (Brown and
Marsden, 1990; Raskin et al., 1990; Owen et al., 1992) that can degenerate
into psychological and behavioral troubles, e.g., dementia, with psychiatric symptoms being
identified in 40–80 % of patients presenting cognitive deficits (Greene
et al., 1993; Oikonomou and Paparrigopoulos, 2015). Early sleep and circadian disorders have been increasingly
observed in the majority of patients
(Adler and Thorpy, 2005), concerning many physiologic circadian rhythms
(Bruguerolle and Simon, 2002). Thus, it appears essential to precisely study
the evolution of neuronal reorganization at play during early stages of the
disease for the identification of new therapeutic targets and also to
characterize the multiparametric impact of therapeutic treatment on motor
and non-motor aspects of PD.
The study of behavioral, physiological, anatomical and biochemical
consequences of DA neuronal death in the basal ganglia was greatly facilitated
by the availability of neurotoxins capable of inducing a highly selective
death of DA neurons in animals, e.g.,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine
(6-OHDA) for primate and rodent models (Burns et al., 1983; Langston and
Ballard, 1984; Riachi et al., 1988; Lange, 1990; Forno et al., 1993;
Nerobkova et al., 1996; Asakawa et al., 2016; Franke et al., 2016).
These animal models of PD have been and are still essentials for the
development and amelioration of new therapeutic strategies. It is now well
acknowledged that testing in nonhuman primate (NHP) models is a safe and
requisite preclinical step before any translation to the clinic of brain
transplantation. NHPs are more appropriate than non-primates for in vivo
screening, because of their relative closeness to humans, notably regarding
brain organization. In particular, primates share precise cortical development
phases and associated compartmental growth of inter-areal connections (Kennedy
and Dehay, 2012); late frontal lobe development, both phylogenetically and
ontogenetically; compartmentalization of meso-frontal projections according
to a mediolateral gradient (Williams and Goldman-Rakic, 1998; Raghanti et al.,
2008); and functional organization of cortical and subcortical striatal
afferents (Haber, 2003). All these features are critically involved in the
evolution and manifestation of PD at different stages.
The low-dose MPTP monkey model (Bezard et al., 1997) is the model of choice
for translational study because it presents a parkinsonian syndrome
characterized by all critical aspects of PD, including a slow progressive
evolution of symptoms, e.g., it replicates the typical motor symptoms used for
primary clinical diagnosis of parkinsonism with response to classical DA
therapy (Stephenson et al., 2005), characteristic pattern of nigrostriatal
denervation observed in PD patients (Gibb and Lees, 1991; Perez-Otano et al.,
1994), early and long-lasting non-motor symptoms (Poewe, 2008; Vezoli et al.,
2011; Fifel et al., 2014; Swallow et al., 2016), and increased
α-synuclein expression in the pigmented cells of the SN (substantia nigra; Purisai et al.,
2005). However, even if those inclusion bodies appears in the same sites as for
Lewy bodies in PD, e.g., SN, they do not express typical Lewy body features
as found in human PD patients (Forno et al., 1993).
MPTP rodent models have been useful to unravel mechanisms underlying DA
neuron loss; however, their DA system and sensitivity to MPTP vary highly
across species (Jossan et al., 1989; Sundstrom and Samuelsson, 1997) and
differ from primates (Johannessen et al., 1985). One explanation is that
rodents express extremely small amounts of neuromelanin (DeMattei et al.,
1986), which is abundant in human brainstems and is proposed to have a role in
long-lasting toxicity of MPTP in primates (Jackson-Lewis and Przedborski,
2008).
The NHP MPTP model hence reproduces a large repertoire of motor and
non-motor impairments found in PD patients and is thus perfectly suited for
a multiparametric evaluation of the therapeutic efficacy of cell transplant
as well as for developing and refining techniques for improving integration of
grafted cells and minimizing potential side effects of the graft. Here we
focus on preclinical investigations done in the gold standard NHP MPTP model
(Emborg, 2007; Potts et al., 2014). We provide a non-exhaustive review of
different procedures using transplantation of various cell sources as a
therapeutic approach in the NHP MPTP model of PD and provide an update on
linked therapeutic behavioral and functional outcomes.
The grafted cells: types and characteristics
The first attempts to treat PD with cell replacement date back to the early
1970s, with the idea of reestablishing striatal DA transmission and restoring a
regulated release of DA in the striatum. Two different cell sources for auto-
and allografts (adrenal medullary tissue and ventral mesencephalic region of
fetuses respectively) paved the way for brain repair through cell
transplantation. Adrenal medulla grafts which contained chromaffin cells that
synthesized DA were grafted in 6-OHDA rats as an alternative source of
catecholamine-producing cells (Freed et al., 1981; Stromberg et al., 1985)
with the benefit of avoiding ethical and immunological issues linked to the
graft of fetal tissue. Even if testing in the 6-OHDA NHP model returned
minimal survival of transplanted adrenal medullary tissue (Morihisa et al.,
1984), it was rapidly followed by first clinical trials in the few patients
reporting clinical improvement (Lindvall et al., 1987; Madrazo et al., 1987).
However, grafts in larger cohorts of PD patients returned rather
unsatisfactory results, calling for more careful investigations at the
preclinical level (Sladek Jr. and Shoulson, 1988).
Fetal ventral mesencephalon
The fetal ventral mesencephalon (fVM), which generates DA neurons during
development, constituted another promising candidate for cell grafting. In
the late 1970s, transplantation of rodent fVM tissue into
the lateral ventricle adjacent to the putamen of 6-OHDA-lesioned rats as an
alternative to L-DOPA treatment was first performed (Perlow et al., 1979) and showed that fVM
tissue could survive, innervate the host striatum, release dopamine and reverse many
of the behavioral deficits in this PD model. The functional and behavioral
outcome of brain transplantation was then investigated further in 6-OHDA rats
for several years until the first trial of transplanting human fetal DA
neurons was performed in the same rodent model (Brundin et al., 1986). At the
time, testing of fVM striatal grafts on the recently developed NHP MPTP model
(Burns et al., 1983) returned satisfactory results, with behavioral recovery
in monkeys exhibiting mild to severe parkinsonism (Redmond Jr. et al., 1986;
Sladek Jr. et al., 1988; Annett et al., 1990, 1994, 1995; Taylor et al., 1991;
Starr et al., 1999; Collier et al., 2002),
confirming trials in the rodent model of PD. First clinical trials (Lindvall
et al., 1988) were again initially promising (Lindvall et al., 1990) but
were later held back due to efficiency concerns following studies with a larger
number of patients and randomized, double-blind, placebo-controlled protocols
(Freed et al., 2001; Olanow et al., 2003) that showed no significant
difference between grafted patients and placebo, with several patients
developing graft-induced dyskinesia.
Nevertheless, retrospective analyses and
reports on those clinical trials of fVM striatal grafts
demonstrated their efficiency either clinically (Kefalopoulou et al., 2014),
histologically (Li et al., 2016), behaviorally (Gordon et al., 2004) or
functionally (Politis and Piccini, 2010). Based on all these evidences, a new
clinical trial of fVM transplantation has been started on a cohort of
patients with improved grafting procedures and selection of patients (Moore
et al., 2014) with the aim of preparing for the move to stem-cell-based
transplantation in humans while waiting for preclinical investigation
reports in animal models.
The development of the MPTP NHP model of PD contributed enormously to the
standardization of the methodology, due to the possibility of studying large
cohorts of monkeys – in particular, in determining the optimal stage of the
donor fetuses (Sladek Jr. et al., 1993b; Elsworth et al., 1996), the conditioning
of the grafted sample, the site of transplantation (Collier et al., 2002) and
the mechanism of graft-induced recovery (Bankiewicz et al., 1990). More
recently, transplantation methods and sites of placement of the transplanted
cells were revisited and refined in the NHP model (Redmond Jr. et al., 2008;
Kordower et al., 2017).
All the transplantation studies performed with fVM in NHPs were based on the
assumption that fVM was enriched in immature DA neurons, although most of
the studies were performed without any detailed analyses of the cellular
content of the grafted tissue. However, fVM contains a heterogeneous population
of cells whose composition fluctuates during development and comprises a
relatively low proportion of DA progenitors divided in two subtypes:
(1) progenitors that will give rise to A9 neurons of the SNpc that express the
G-protein-gated inwardly rectifying K+ channel, GIRK2;
and (2) progenitors that
will give rise to A10 neurons of the ventral tegmental area
which express the calcium binding
protein, CALBINDIN (Thompson et al., 2005). A9 neurons are the essential
functional components for recovery of motor function in rodent models of PD
(Kuan et al., 2007; Grealish et al., 2010). Apart from DA progenitors, fVM
also contains a high diversity of radial glial cells; other types of
progenitors, including serotonin, GABAergic and oligodendrocyte precursors; and
non-neural cell types, such as endothelial cells, pericytes and
microglial cells (La Manno et al., 2016). This variability in tissue
composition as well as other issues, including limited availability of fetal
brains and ethical concerns associated with the use of aborted fetal
tissues, make it very difficult to generalize this cell therapy approach.
Progress in the field of stem cells brings hope that this type of
cell therapy could be generalized to treat PD patients. A number of
pluripotent stem cells (PSCs) have been tested in NHPs, isolated either from
early stage embryos (embryonic stem cells, ESCs) or from reprogrammed
somatic cells (induced pluripotent stem cells, iPSCs). PSCs have the capacity
to become any cell types in the body, including dopaminergic progenitors and
neurons. They thus constitute an infinite source of cells for transplantation
into PD patients.
We will now focus on the transplantable DA cell types generated from primate
PSCs, which represent the closest to clinical application. Human ESCs (Kriks
et al., 2011; Daadi et al., 2012; Doi et al., 2012; Grealish et al., 2014;
Gonzalez et al., 2015, 2016; Chen et al., 2016) and monkey
ESCs (Kawasaki et al., 2002; Sanchez-Pernaute et al., 2005; Takagi et al.,
2005; Xi et al., 2012) were first used, recently followed by human iPSCs
(Kikuchi et al., 2011; Kriks et al., 2011; Sundberg et al., 2013; Doi et al.,
2014) and monkey iPSCs (Morizane et al., 2013; Sundberg et al., 2013; Wang
et al., 2015).
DA neurons isolated from primate PSCs or by direct reprogramming of
somatic cells
Various protocols available for the generation of DA neurons from human and
NHP PSCs were adapted from those developed with mouse ESCs (Kawasaki et al.,
2000; Lee et al., 2000; Watanabe et al., 2005). Early protocols aimed at
first inducing neural differentiation of PSCs generally by culturing the PSCs
with stromal cells (PA6 cells or MS5 mouse lines) or in the presence of
medium conditioned by these cells (Takagi et al., 2005). Other protocols for
neural differentiation involved suspension cultures to generate embryoid
bodies and culture in serum-free medium (Roy et al., 2006; Iacovitti et al.,
2007). These protocols enable a significant enrichment of the population into
neural progenitors that expressed NESTIN, SOX1,
PSA-N-CAM (polysialylated neural cell adhesion molecule),
PAX6 and SOX2
(Kawasaki et al., 2002; Ben-Hur et al., 2004; Perrier et al., 2004; Park et
al., 2005; Sanchez-Pernaute et al., 2005; Takagi et al., 2005; Vazin et al.,
2008; Doi et al., 2012).
Midbrain DA specification of these neural precursors can then be induced by
addition of FGF8, a mid- and hindbrain organizing morphogen, and SHH, a
ventralizing morphogen (Perrier et al., 2004; Zeng et al., 2004; Park et
al., 2005; Yan et al., 2005; Yang et al., 2008; Cooper et al., 2010; Doi et
al., 2012), and/or by treatment with FGF2 and FGF20 – a secreted protein that
enhances the survival of primary DA neurons (Ohmachi et al., 2000; Takagi et
al., 2005; Morizane et al., 2013). Characterization of the cells showed that
DA neurons express midbrain DA neuron markers such as NURR1 and LMX1A, LMX1B,
FOXA2, OTX2, CORIN, PITX3, factors that control specification and
differentiation of midbrain DA neurons during mouse development (reviewed in
Arenas et al., 2015), and GIRK2, which is the A9-specific marker (Thompson et
al., 2005). They also express tyrosine hydroxylase (TH), and the dopamine
transporter (DAT), and they produce dopamine, confirming that they are
functional DA neurons (Kriks et al., 2011; Kirkeby et al., 2012; Arenas et
al., 2015).
Although these methods enabled efficient DA differentiation, the cultures
usually comprise a high percentage of glial cells and multiple neuron
subtypes, such as GABAergic, cholinergic and serotonergic neurons (Emborg et
al., 2013b; Morizane et al., 2013). Complete and robust midbrain specification
was recently obtained via a floor plate
intermediate stage from human
(Kriks et al., 2011; Xi et al., 2012; Sundberg et al., 2013) and NHP PSCs (Xi
et al., 2012; Hallett et al., 2015; Wang et al., 2015), using a modified
dual-SMAD
inhibition protocol (BMP/TGFβ inhibition; Chambers et al.,
2009) and activation of Wnt signalling, an essential pathway in DA neuron
development in the mouse (Castelo-Branco et al., 2003,
2004; Joksimovic et al., 2009) and in humans (La Manno et al., 2016).
Combining suspension culture with dual-SMAD inhibition, Wnt and SHH
activation also led to robust VM differentiation, with correct midbrain
GIRK2+ A9 and CALBINDIN+ A10 phenotypes, similar to fVM content (Kirkeby
et al., 2012; Morizane et al., 2013; Doi et al., 2014; Grealish et al., 2014;
Chen et al., 2016).
Most of the protocols to generate DA neurons from primate PSCs assume that
primate VM development follows the same sequences of events and thus
expresses the same set of specific markers as in rodents (recently reviewed in Arenas
et al., 2015). However, major differences in human and rodent ventral
midbrain development have recently been identified (La Manno et al., 2016).
In light of these results, studies have been engaged to develop and refine
the existing protocols and tools to generate DA neurons from primate PSCs
in vitro that better mimic their in vivo counterparts. In this line,
identification of a set of new markers of human mesencephalic DA progenitors
(EN1, SPRY1, PAX8, CNPY1 and ETV5) enabled Kirkeby and collaborators to
develop a differentiation protocol that leads to increased yield of DA
progenitors from human ESCs (Kirkeby et al., 2017). These markers enable
proper prediction of the resulting DA neuron content in the graft and will
enable further standardization of DA differentiation protocols from PSCs.
These last generation of PSC-derived DA progenitors are produced under
careful Good Manufacturing Practice (GMP) laboratory conditions (Kirkeby et al., 2017) and bare authentic fVM
features: they are able to reinnervate the lesioned striatum and function
with equal potency to fVM tissue upon striatal transplantation in the PD
rodent brain (Kriks et al., 2011; Doi et al., 2014; Grealish et al., 2014;
Chen et al., 2016). Based on recent preclinical in vivo assessments mostly
performed in the rodent model and more recently in the NHP model, several
clinical trials have been recently launched worldwide using human ESC DA
cells, such as the European trial “STEM-PD” (Kirkeby et al., 2017).
DA neurons can also be generated by direct reprogramming of somatic cells
such as mouse and human fibroblasts, using overexpression of different
transcription factors and midbrain-specific factors such as LMX1A, ASCL1, NURR1,
BRN2, FOXA2, NGN2, SOX2 and MYT1L (Caiazzo et al., 2011; Pfisterer et al., 2011a, b;
Liu et al., 2012). These induced DA (iDA) cells led
to reduction of motor symptoms when transplanted in the striatum of PD rodent
models (Kim et al., 2011; Liu et al., 2012; Dell'Anno et al., 2014; Rivetti
di Val Cervo et al., 2017) and represent an interesting cell source that
still needs to be pre-validated in the NHP model.
The intended application of reprogrammed cells (either iPSCs or iDA cells)
and their derivatives is autologous transplantation. However, their isolation
and deep characterization usually needs several months, which constitutes an
important drawback when considering that transplantations have to be done
when the system is still reparable. Furthermore, because they are derived
from PD patients, they may present genetic and epigenetic alterations and
may be more susceptible to the pathological processes induced in PD.
Neural stem cells
Multipotent neural stem cells (NSCs) present several advantages over DA
progenitors or neurons. They constitute homogeneous cell populations that can
be expanded on a very large scale and extensively characterized, and they can
be kept as frozen stocks that are ready to use for transplantation. This
ensures high levels of batch-to-batch consistency and enables optimal
traceability of the grafted cells. Another advantage of NSCs is that they are
capable of giving rise to neuronal and non-neuronal progenies, such as
astrocytes and oligodendrocytes. They are thus potentially capable of
responding
and adapting to the host environment, making them one of the best candidates to
restore a functional equilibrium in the nigrostriatal system (Redmond Jr. et al.,
2007).
Human NSCs have been isolated from fetal brains (Flax et al., 1998; Sun et
al., 2008; Wakeman et al., 2009) or from PSCs (Gonzalez et al., 2016) through
adaptation of the protocol used to derive mouse NSCs (Conti et al., 2005;
Pollard et al., 2008). They express the stem cell markers NESTIN, SOX2,
VIMENTIN and MUSASHI; are karyotypically normal; and can be amplified for long
periods of time in culture without losing their properties (Redmond Jr. et al.,
2007; Bjugstad et al., 2008; Wakeman et al., 2014; Gonzalez et al., 2015,
2016). Following testing for various contaminants (virus,
mycoplasma, bacteria, etc.), they constitute working cell banks
prepared under GMP-grade conditions (Gonzalez et al.,
2015, 2016). NSC lines can further be carefully preselected
for transplantation on the basis of their capacity to differentiate into DA
progenitors in response to DA induction in vitro and to give rise
to various neuronal and glial cell types upon transplantation into different
regions of the mouse brain in vivo (Redmond Jr. et al., 2007).
Human NSCs have shown very promising results upon injection in SN and
striatum of MPTP monkeys (Redmond Jr. et al., 2007; Bjugstad et al., 2008;
Gonzalez et al., 2015, 2016). Although transplantations of
human cells into the brain of NHPs bring crucial information, NSC safety and
efficiency within an NHP species still need to be confirmed. This would imply
the isolation and deep characterization of NHP NSC lines that are still
sparse (Wianny et al., 2011).
Other cell types
Autologous neural cell ecosystems (or ANCE) represent an interesting
alternative for autologous transplantation. These cells are derived from the
adult monkey cortex; they do not require genetic modification and can be
expanded in only a few weeks in vitro (Brunet et al., 2009; Bloch et
al., 2014). They do not express specific DA markers, but progenitor markers
such as GFAP (glial fibrillary acidic protein),
NEUROFILAMENT, VIMENTIN and NESTIN (Brunet et al., 2009). It is
still unclear whether these cells are able to differentiate into DA neurons
(Bloch et al., 2014). They showed very good survival and integration upon
auto transplantation in striatum and SN of the PD NHP brain, which is associated with
behavioral recovery (Bloch et al., 2014). However, this system needs careful
characterization in the NHP model to evaluate its usefulness in future
clinical application.
Human retinal pigment epithelial (hRPE) cells may constitute another suitable
cell type for transplantation in PD. They are isolated from the inner layer
of the retina of postmortem fetal eyes and produce L-DOPA as a precursor of
their characteristic eumelanin pigment through the activity of TH. They can
be easily expanded in culture and stored as frozen stocks, allowing
extensive characterization and testing before transplantation. hRPE cells
attached to gelatin microcarriers (GM) show enhanced survival and improve motor
deficits after striatal grafts in rodents (Subramanian et al., 2002; Cepeda
et al., 2007) and in NHP models of PD (Watts et al., 2003; Doudet et al.,
2004). RPE-GM are currently
used in human PD patients under the name of Spheramine
(Titan Pharmaceuticals, Inc.). The mechanism of action of RPE cells may not
be the production of dopamine, but constant in situ release of low
physiological level of levodopa, which may stimulate DA synthesis from
surviving DA neurons.
In 2011, the results of the first randomized, double-blind,
placebo-controlled trial of RPE cell transplantation in PD patients showed
that hRPE cells provided no antiparkinsonian benefits over sham surgery (Gross
et al., 2011). Optimal therapeutic benefit could be reached after
administration of low doses of levodopa. These results have been recently
confirmed in NHPs where unilateral striatal transplantation of hRPE-GM was
not sufficient to completely reverse the motor symptoms of induced
parkinsonism (Peng et al., 2016). Studies performed in the NHP model will be
crucial to refining the characteristics of these RPE cells used for
transplantation, in particular the optimal age of the donors. Fetal hRPE
cells indeed showed higher survival than those obtained from neonatal donors,
at least in the rat PD model (Peng et al., 2016; Russ et al., 2017). The NHP
model may also help in evaluating the therapeutic effect of other sources of
hRPE cells and other formulations of microcarriers to increase cell survival
(Falk et al., 2012).
Cell labeling
As far as xenografts are concerned, human-grafted cells are easily
distinguished from the host primate brain using human-specific markers, such
as the human cytoplasmic markers hCy (Daadi et al., 2012) and STEM121 (Kriks
et al., 2011; Gonzalez et al., 2015; Chen et al., 2016). In contrast,
localizing the NHP cells upon transplantation in NHP models necessitates
labeling cells before grafting.
fVM tissue cannot be labeled prior to transplantation; its progenies are
thus commonly detected by simple TH immunofluorescent staining. This strategy
enables locating the transplanted tissue, but the migration of the grafted
cells and connection with host TH+ cells cannot be monitored (Taylor et
al., 1991; Sladek Jr. et al., 1998). Furthermore, the high density of DA neurons
in the core graft often precludes accurate counting (Brundin et al., 1986;
Sladek Jr. et al., 1998). As previously mentioned, the developing human VM also
contains others types of progenitors that may not give rise to TH+ neurons
(La Manno et al., 2016). Thus, TH+ labeling may underestimate the variety
of progenies arising from fVM grafts.
In contrast to fVM tissue, NSCs, DA progenitors and DA neurons can easily be
labeled in vitro, prior to grafting. This was originally performed
through incorporation of BrdU (bromodeoxyuridine; Takagi et al., 2005; Redmond Jr. et al., 2007,
2008). The disadvantage of this labeling is that not all
cells become labeled with BrdU, leading to underestimation of cell survival
(Takagi et al., 2005; Redmond Jr. et al., 2007). With the emergence of new
technologies, cells are now frequently labeled with fluorescent proteins
(GFP or RFP) after electroporation of a GFP-expressing plasmid and antibiotic
selection (Morizane et al., 2013), or lentiviral infection (Gonzalez et al.,
2016). Although the efficiency and stability of the labeling were not always
documented, this type of labeling remains essential to assess the migration
and facilitates visualization of neurite extension of the grafted cells
(Gonzalez et al., 2016). The fluorescent dies PKH26 and PKH67 can also be
cited (Bloch et al., 2014; Wolff et al., 2015), but their propensity to fade
overtime makes them inappropriate for long-term labeling.
So far, GFP and RFP labeling seems most appropriate for evaluating integration
and differentiation rates of grafted cells. However, some studies reported
GFP-induced cytotoxicity (Liu et al., 1999; Detrait et al., 2002) and, more
recently, dose-dependent toxicity in DA neurons in rats after cytoplasmic GFP
transfection (Klein et al., 2006; Ansari et al., 2016). While this toxicity
seems to be more associated with the level of expression of this reporter
gene in transfected cells, this should be carefully taken into account while
evaluating the efficacy of GFP-expressing transplant in NHPs.
It is noteworthy that senescent cells found in the aged and degenerative
brain produce autofluorescence that interferes with detection of specific
fluorescent signals, implying rigorous manual tracing analyses of
transplanted cells in the case of fluorescent labeling (Spitzer et al.,
2011; Salmonowicz and Passos, 2017).
Noninvasive methods developed for tracking cells in real time after grafting
might also help to improve the design of future clinical cell
transplantation. A nice example is cell labeling with superparamagnetic iron
oxide (SPIO)
nanocomposites, which allow cell tracing in living animals using
MRI (Guzman et al., 2007).
Survival, differentiation and integration of the grafted cellsNumber of grafted cells and survival
In studies performed with fVM, transplanted cells in the striatum consist of
small pieces of fVM tissue (1 to 2 mm3; Elsworth et al., 1996;
Collier et al., 1997; Leranth et al., 1998; Redmond Jr. et al., 2013)
or cell suspensions that are usually not unicellular (Annett et al., 1994,
1995). The amount of grafted fVM tissue per monkey is the
equivalent of 2–3 fetuses, which does not allow for precise determination of
the number of transplanted cells (Table 1a). Consequently, the
survival rate is also difficult to precisely evaluate. In contrast,
single-cell suspensions of NSCs, DA progenitors or neurons enable precise counting
of the transplanted cells, and 1 to 10 million of cells were usually injected
per monkey brain (Table 1a).
Looking back on several decades of transplantation studies in MPTP NHPs, it
appears that the survival rate of transplanted DA neurons is disappointing,
with generally more than 90 % of the cells dying after transplantation
(Table 1a; Sanchez-Pernaute et al., 2005; Redmond Jr. et al., 2007; Doi et al., 2012;
Emborg et al., 2013a; Wang et al., 2015).
It is noteworthy that early DA neurons tend to survive better upon grafting
in the brain of PD monkeys than do terminally differentiated DA neurons, as
previously shown in rodents (Brundin et al., 1986). For example, VM tissue
isolated from early stage fetuses showed a higher survival rate than that of
older stage fetuses (Sladek Jr. et al., 1993b; Elsworth et al., 1996; Collier et
al., 2002), as was previously shown in rodents (Fricker et al., 1997; Torres
et al., 2007; Torres et al., 2008). Similarly, early DA progenitors derived
from primate PSCs (D21–D28 neurospheres) produced larger grafts (Kikuchi et
al., 2011) and showed a higher survival rate (Takagi et al., 2005; Wang et
al., 2015) than did late DA neurons (D42 neurospheres; Sanchez-Pernaute et
al., 2005; Takagi et al., 2005; Kikuchi et al., 2011; Doi et al., 2012;
Emborg et al., 2013a). Nevertheless, the survival rate never exceeded 5 %.
In contrast to DA neurons, uncommitted neural cells show a much higher
survival rate that is generally close to 10 % for NSCs (Redmond Jr. et al.,
2007; Bjugstad et al., 2008; Gonzalez et al., 2015, 2016)
and over 40 % in the case of autografts of immature neural cells derived
from the adult cortex (ANCE; Bloch et al., 2014). The higher survival rate
of immature cells, as compared to that of terminally differentiated neurons,
could be explained by their multipotent features, which allow them to best
adapt to environmental fluctuations. They also exhibit minimal neurite
outgrowth and may thus be less sensitive than differentiated cells to
mechanical stress during their isolation and transplantation procedure.
Interestingly, increasing the number of grafted cells did not improve cell
survival proportionally in MPTP NHPs, regardless of their origin (fVM or PSC
derivatives; Sladek Jr. et al., 1998; Bjugstad et al., 2008; Bloch et al., 2014;
Hallett et al., 2015; Gonzalez et al., 2016). It has been hypothesized that a
high cell number might induce host rejection in the case of
allotransplantation and that it may also exhaust the supply of neurotrophic
factors that are present in low amounts in the adult diseased brain.
Grafted cells characteristics pre-graft.
(a): Grafted cellcharacteristicspre-graft.GraftedOriginDevelopmentalCharacteristicsGrafted numberLabelingRecipientGraftedReferencescell typedifferentiation stagespeciessitesFetal fVMfVM (NHP)E74 (cell suspension)not shown1 VM/brain (2 µL/site)NOmarmosetCdN, Put, NAccAnnett et al. (1994, 1995)fVM (NHP)late fVMnot shown1 VM/brainNOAFGstriataRedmond Jr. et al. (1986)fVM (NHP)E40–E50 & latenot shown1 VM/brain (1 mm3 pieces)NOAFGCdNSladek Jr. et al. (1993b);gestation(6 sites/brain)Elsworth et al. (1996a)fVM (NHP)E44–47not shown1/6 VM/site (6 sites/brain)NOAFGCdN or PutElsworth et al. (1996b);Collier et al. (1997)fVM (NHP) & co-graftsE41–47not shown1/6 VM/site (1–2 mm3 pieces)NOAFGCdN or PutSortwell et al. (1998)fVM/embryonic striatumfVM (NHP)E40–42not shown2 VM/brain (6 sites/brain)NOAFGstriatumSladek Jr. et al. (1998)fVM (NHP)E43–47not shown1/2 VM/brainNOAFGSNCollier et al. (2002)fVM (NHP)E44–45not shown1.5 VM/siteNOAFGPutKordower et al. (2017)fVM (NHP)transfected with AAV5-not shownnot shownNOAFGCdN and PutRedmond Jr. et al. (2013)hu-GDNF vectorfVM (NHP)E40not shownmultiple sites (1 mm3)NOAFGCdNLeranth et al. (1998)fVM (NHP)E42 to E45 (cellnot shown1.5 fVM/brainNOAFGCdN or PutRedmond Jr. et al. (2008)suspension/solid pieces)fVM (NHP)various stagesnot shown4 to 6 sites/brain (1 mm3)NOAFGCdNTaylor et al. (1991)fVM (NHP; early/late)E38–44; E80–165not shown6 sites/brain (1 mm3)NOAFGCdN or PutTaylor et al. (1996)fVM (NHP)E45–47; E52–54not shown1/2 VM/SN and 1 VM/striatumNOAFGPut and SNSladek Jr. et al. (2008)fVM (porcine)not shownnot shown10 VM (1 mm3)NOcynoPutAaron-Badin (2016)(CTLA4-Ig expression)NSCsfetal brain (human)NSCs at early passages (13GW)Stable karyotype, proliferating SOX2+,106 cells/siteBrdU, LacZAFGCdN, SNRedmond Jr. et al. (2007);NESTIN+, VIMENTIN+, MUSASHI+Bjugstad et al. (2008)Screened in vivo in micefetal brain (human)NSCs (multilayeredStable karyotype, proliferating NESTIN+,not shownBrdU, GFPAFGCdN, PutWakeman et al. (2014)and AAV-GDNF injectionsadherent network NSCs)GFAP+, SOX2, GFAP+,-βIII-tubulin+, BLBP+, DCX+parthenogenetic hESCsNSCs (cGMP grade, current GMP)Euploid karyotype, proliferating SOX2+,10 × 106 GFP+GFP, RFPAFGCdN, Put, SNGonzalez et al.NESTIN+, MUSASHI+, CD133+, OCT4-,cells (4 sites left)(2015, 2016)SSEA4 free of mycoplasma and viral10 × 106 RFP+contaminantsadipose stem cells (NHP)DA neurons (combinedβIII-tubulin+, NEFM+, MAP-2+,2 × 106 cells/siteBrdUrhesusCdN, Put, SNZhou et al. (2013)with adenovirus expressingNESTIN+, TH+, PITX3+,(3 sites/hemisphere)neurturin and TH)LMX1B+, MSX1+, FOXA2+
Continued.
(a): Grafted cellcharacteristicspre-graft.GraftedOriginDevelopmentalCharacteristicsGrafted numberLabelingRecipientGraftedReferencescell typedifferentiation stagespeciessitesDA neuronshESCs GFP+DA neuron (day 25)FOXA2+, βIII-7.5 × 106 cells/GFPrhesusCdN, PutKriks et al. (2011)tubulin+, LMX1A+, NURR1+,brain (3 sites/hemisphere)PITX3+, TH+; novel DAmarkers (TFF3, TTR, EBF1, EBF3)hiPSCsDA neurons (neurospheres:βIII-tubulin+ (85 % TH+ at day 42)4.8 × 106 cells/brainNOcynoPutKikuchi et al. (2011)day 28 and day 42 ±DA differentiation)hESCsDA neurons (neurospheres:Decreased LMX1A and EN14.8 × 106 cells/brainNOcynoPutDoi et al. (2012)day 14–day 28 and day 35–42)expression and increased NURR1+and percentage of TH+ cells fromearly to late neurosphereshESCsDA neurons (from NSCs)βIII-tubulin+, TH+,1 × 106 cells/siteGFPAFGCdN, SNDaadi et al. (2012)NURR1+, PITX3+, FOXA2+ESCs (NHP)DA neurons (day 41–44βIII-tubulin+, TH+, BF1+5 × 106 cells/brainNOcynoPutSanchez-PernauteDA differentiation)et al. (2005)ESCs (NHP)DA neurons24 % TH+, PAX2+, PTX3+,3–6 × 105 cells/sideBrdUcynoPutTakagi et al. (2005)(day 21 neurospheres)NURR1+, LMX1B+ release DA.iPSCs (NHP)DA neurons (day 42)βIII-tubulin+ (37 %;2.5 × 106 cells/brainGFPrhesusCdN, Put, SNEmborg et al. (2013a)GABA+, 49 %; TH+ 16 %/.(2.5 × 105 in SN)GIRK2+/FOXA2+/CALBINDIN)S-100β+ (16 %),NESTIN+ (50 %)iPSCs (NHP)DA neurons (day 30)FOXA2+/TH+/βIII-5 × 106/siteNOcynoPutSundberg et al. (2013);tubulin (> 3 %),(4 sites unilateral)Hallett et al. (2015)TRA-1-81-, TRA-1-60-iPSCs (NHP)DA neurons (day 18–22)βIII-tubulin+, TH+, FOXA2+,not shown, Ren et al. (2013) =GFP/FeridexcynoCdN, PutWang et al. (2015)NURR1+, GIRK2+5 × 106 cells/brainnanoparticlesiPSCs (NHP)DA neurons (day 28)βIII-tubulin+ LMX1A, FOXA24.8 × 106cells/brainGFPcyno, no MPTPPutMorizane et al. (2013)(8 × 105/tract)Other cell typeshuman retinahuman levodopa-not shown65–100 × 103 cells/NOrhesusCdN, PutPeng et al. (2016)producing RPE cellssite (5 sites/brain) unilateralNHP (females)PKH26 endometrium-not shown4 × 106 cellsPKH26AFGCdNWolff et al. (2015)derived cells(2 sites) unilateralbone marrow (NHP)GDNF-MSCsCD73+, CD105+, CD90+,5 × 106/brainFeridexcynoCdN, Put, SNRen et al. (2013)CD106+, Stro-1+. Multipotent.nanoparticlescarotid bodies (NHP)striatal carotid bodynot shownnot shownNOcynoPutLuquin et al. (2011)cell aggregates3 mm3 of DLPFCcultured cortical brainshown in Brunet et al. (2009)2–4 × 105/sitePKH67AFGCdN, Put, SNBloch et al. (2014)of same monkeycells (“ANCE”)(b): Grafted cellcharacteristicspost-graft.GraftedDevelopmentalSurvivalLocalizationCharacteristicsOvergrowthInflammationReferencescell typedifferentiation stageproliferationmicrogliaactivationFetal fVME74 (cell suspension)300–3800 TH+ cells/brainTH+TH+not shownnot shownAnnett et al. (1994, 1995)late fVMnot shownTH+TH+not shownnot shownRedmond Jr. et al. (1986)E40–E50 & late gestation3500 TH+ cells/site (E44)TH+early fVM led tonot shownnot shownSladek Jr. (1993b);550 TH+ cells/site (E49)increased DA in the DA-depletedElsworth et al. (1996)CdN (host derived); no DA increasewith late stages fVME44–47not shownnot shownTH+ 5–10 % increasednot shownnot shownElsworth et al. (1996);dopamine transporter/control.Collier et al. (1997)Enhanced oxidative metabolism(cytochrome oxidase activity)E41–4711 500 cells/brainTH+TH+, synaptophysinnot shownnot shownSortwell et al. (1998)E40–428000 DA neurons/VM,TH+TH+, dopamine transporternot shownnot shownSladek Jr. et al. (1998)donor doubling number ofgrafted cells does notproportionally increasecell survival
Continued.
(b): Grafted cellscharacteristicspost-graft.GraftedDevelopmentalSurvivalLocalizationCharacteristicsOvergrowthInflammationReferencescell typedifferentiation stageproliferationmicrogliaactivationE43–471000 TH+ (late VM)NOTH+not shownnot shownCollier et al. (2002)10 000 TH+ (early VM)E44–45up to 100 000 TH+TH+TH+, GIRK2+, CALBINDIN+not shownminimal neuro-Kordower et al. (2017)inflammatory response(LN3/GFAP staining)transfected with AAV5-not shownNOTH labeling illustrations,not shownnot shownRedmond Jr. et al. (2013)hu-GDNF vectorstriatal punches analyzedfor DA and GDNF concentrationE40not shownTH+TH+ grafted cells acts via synaptic contactsnot shownnot shownLeranth et al. (1998)on host neurons. The synaptic targets aredendrites and somata of host neuronsE42–E45 (cell12 000–60 000 survivingTH+TH+, GIRK2+, CALBINDIN+not shownstronger glial reactionRedmond Jr. et al. (2008)suspension/solid pieces)TH+ cells similar solid/cell suspension and CdN/Putto solid graftvarious stages< 500 TH+ cells/graftTH+TH+not shownno sign of rejectionTaylor et al. (1991)E38–44; E80–165up to 18 000 TH+ cellsTH+TH+ early fVM: increased DAnot shownnot shownTaylor et al. (1996)levels and neuritic extensionsE45–47; E52–541500–6000 TH+ cells/graftTH+TH+/DAT+not shownnot shownSladek Jr. et al. (2008)10 000 TH+ cells in theSN when striatal graftclosest to the SNnot shownnot shownTH+TH+, NF70+, GFAP+ increased (18F)F-L-not shownweak IBA1/CD68/GFAP inAaron-Badin (2016)L-DOPA fixation with CTLA4-Igimmunosuppressed animalsNSCsNSCs at earlyup to 10 % surviving cell TH+:BrdU labeling/few neurons (3 % βIII tubulin+),NOno microglial activationRedmond Jr. et al. (2007);passages (13 GW)< 1 % of grafted cellsβGal stainingfew TH+ cells GFAP+, GDNF+ migration(18F-DPA714 binding)Bjugstad et al. (2008)NSCs (multilayered adherent16–41 mm3 graft TH+:eGFP< 20 % NESTIN+, 80 % NEUROFILAMENT+,NOno microgliaWakeman et al. (2014)network NSCs)< 1.1 % of grafted cellsno MAP2 and no DA differentiation;few GFAP+; GDNF not sufficient toinduce DA differentiationNSCs (cGMP grade)10 % RFP+ cells engrafted TH+:GFP or RFPTH+, GIRK2+, VMAT2+, synaptophysin+;NOno microglia or hostGonzalez et al.1.85 % of grafted cellshigher DA neuron innervation (TH fibermicroglia (IBA-1).(2015, 2016)density) in striatum (low dose of cells)DA neurons (combinedvery low (few BrdU+ cells)BrdU labelingnot shownnot shownnot shownZhou et al. (2013)with adenovirus expressingneurturin and TH)DA neuronsDA neuron (day 25)not shownGFP human-TH+, FOXA2+not shownpersistent inflammation (IBA1+)Kriks et al. (2011)specific SC-121DA neurons (neurospheres: day 28 andsmaller graft size with day 42; TH+:NONURR1+,VMAT2+, DAT+, GIRK2+,low (< 1 % KI67+)not shownKikuchi et al. (2011)day 42 ± DA differentiation)1.25 % (day 28) 5.25 %PITX3+; CALB+; Improved DA differentiationday 28 > D42 grafts(day 42) of grafted cells(TH+) in day 42 graftsDA neurons (neurospheres:smaller grafts with day 14 grafts;TH+ and DAT labeling39 % NeuN+ (8 % TH+,< 1 % KI67+ cells; decreasednot shownDoi et al. (2012)day 14–28 and day 35–42)13 000–18 000 TH+ cells/sideVMAT2+, AADC+, PITX3+); other neuronstumorigenicity for day 42 grafts(< 0.75 %TH+)mostly GABAergic; increased DA synthesis (PEThigher DA yield with day 42analysis of [18F] L-DOPA uptake) in thegrafts compared to host striatum(linked to behavioral improvement)DA neurons (from NSCs)TH+: 10 % of the grafted cellsGFP human-TH+; GIRK2+; CALB+; synaptophysin; serotonin-not shownnot shownDaadi et al. (2012)specific nucleiDA neurons (day 41–44TH+ cells: < 0.1 % of the grafted cellsNOTH+, DAT+, AADC, few serotonergic,NOmicroglia (CD68+).Sanchez-PernauteDA differentiation)(3300 TH+/brain); graftfew DCX+ neuroblasts.et al. (2005)volume: 5.4–14 mm3Increased F18 fluorodopaDA neurons (day 218000 total cells/side (1.3–2.7 %)BrdU labelingTH+, DAT+, high percentage of GABA+NOnot shownTakagi et al. (2005)neurospheres)4300 TH+cells/brain (0.4 %)neurons, few serotonergic;(underestimated due to BrdU labeling)GIRK2+ CALB+DA neurons (day 42)less than 1.5 % total survivalGFPMAP2+ (63 %), GFAP+(22 %),NO (KI67-/OCT4-/NANOG-/low inflammatory reactionEmborg et al. (2013a)MBP+ (10 %); majority of MAP2+SOX17-/BRA-)and reactive microgliaare GABA+; few TH+DA neurons (day 30)13 000 TH+ cells/putamen:TH+/FOXA2+TH+/FOXA2+/βIII tubulin + cellsNOlow inflammatory reactionSundberg et al. (2013);functional improvementHallett et al. (2015)DA neurons (day 18–22)20 000 TH+ cells whole brainMRITH+; FOXA2+; NURR1+;NO (KI67-)NO (IBA1-)Wang et al. (2015)(0.4 % if 5 millions were grafted)GIRK2+; serotonin-
Continued.
(b): Grafted cellscharacteristicspost-graft.GraftedDevelopmentalSurvivalLocalizationCharacteristicsOvergrowthInflammationReferencescell typedifferentiation stageproliferationmicrogliaactivationDA neurons (day 28)autologous: 4400 TH+ cells/GFP+TH+ (higher number in autografts)not shownweaker immune rejection (lower nb ofMorizane et al. (2013)tract (0.5 % of grafted cells)CD45+ CD8+, CD3+ cells) and activatedallogeneic: 2200 TH+/tract(GIRK2?, CALB?), FOXA2+,microglia (11C-PK11195 uptake;NURR1+, DAT+, GFAP+IBA1+) in autologous graftsOther cell typeshuman levodopa-not shownNOGlucose metabolismnot shownnot shownPeng et al. (2016)producing RPE cells(18F-FDG PET imaging)PKH26 endometrium-derived cellsvery lowPKH26TH+, (GIRK2?, CALB?)not shownnot shownWolff et al. (2015)GDNF-MSCsnot shownMRIincreased host DA levels, 5-HT innot shownno activation ofRen et al. (2013)striatum/SPECT imaging (TRODAT1 uptake)astrocytes andno increase in host DA neuron survivalmicrogliastriatal carotid bodypoor (80–100 TH+ cells/NOTH+not shownnot shownLuquin et al. (2011)cell aggregatesinjection TH+site)cultured cortical brainSN (20–50 %), CdN (30–40 %),PKH67increased TH+ cells in grafted animalsnot shownBloch et al. (2014)cells (“ANCE”)Put (10–20 %)(originating from the graft?)
Grafted cell survival can be improved through implantation of micrografts or
cells over several sites within striatum or SN of NHPs (Table 1a; Collier et al., 2002;
Redmond Jr. et al., 2007; Gonzalez et al., 2015, 2016; Hallett et al., 2015), confirming earlier rodent studies (Nikkhah et al.,
1994). Another strategy to increase cell survival of grafted cells involves
delivery of neurotrophic factors combined with cell transplantation (Elsworth
et al., 2008; Redmond Jr. et al., 2013). In this context, glial cell-derived
neurotrophic factor (GDNF) is one of the most widely tested neurotrophic
factors, and it is well known to promote survival of DA neurons in vitro
(Lin et al., 1993) and in vivo in different animal models of PD
including NHPs, where it prevents degeneration of DA neurons (Kordower et al.,
2000; Grondin et al., 2002; Elsworth et al., 2008). The neurotrophic actions
of GDNF in PD have been extensively described elsewhere (Duarte et al., 2012;
Sullivan and Toulouse, 2011; d'Anglemont de Tassigny et al., 2015).
Neurexophilin 3 (NXPH3), a synapse-related peptide, may be also be used in
combination with cell grafts for promoting cell survival. It was recently
shown to support survival of mouse iPSC-derived DA neurons in vitro
and in vivo, when combined with grafted cells (Nishimura et al., 2015).
Number of TH + cells required for functional
recovery
Despite the low-cell surviving rate of the grafted cells, several studies showed
behavioral improvement upon cell grafting in MPTP NHPs (Table 2). This
suggests that a minimal restoration of normal DA innervation in the striatum
is sufficient for functional recovery, as previously shown in the rodent
model (Grealish et al., 2014). However, a certain threshold of TH+ cell
dose is needed to improve PD motor symptoms and was estimated to be
approximately 10 000 TH+ cells per brain, whether derived from ESCs (Doi et
al., 2012) or from iPSCs (Hallett et al., 2015; Wang et al., 2015). A lower
number of TH+ cells led to poor dopamine reinnervation and no functional
recovery (Sanchez-Pernaute et al., 2005; Hallett et al., 2015). Considering
that the monkey striatum is 5 to 7 times smaller than the human striatum (Yin
et al., 2009), these results are in accordance with those obtained in humans,
where 100 000 dopamine-producing cells isolated from fVM were necessary to
reach optimal functional outcome (Lindvall, 2013).
Characteristics and outcomes of the graft.
SpeciesNumberGrafted cellsGrafted sitesImmuno-Survival timeFunctional outcomeRef.graftedsuppressionXenograftAFG22human NSCsCdN/SNno or C or CPA4–8 monthsmotor score reduced byRedmond Jr. et al. (2007);half at month 2 post-graftBjugstad et al. (2008)rhesus2DA cells from hESCsCdN/PutC1 monthno report of motor score evolution,Kriks et al. (2011)no quantificationcyno1neural progenitorsPutFK5066 monthsno improvement in reaching taskKikuchi et al. (2011)from hiPSCsnor in neurological score; increasingFDOPA uptake between months 3–6post-graft; no significant changein DAT binding vs. pre-graftcyno9DA cells from hESCsPutFK50712 monthssignificant motor recoveryDoi et al. (2012)from month 3 post-graft only incases grafted with late (d42) DA cells;FDOPA uptake significantly correlatedwith degree of motor recoveryAFG4DA cells from hESCsCdN/SNCPA2 monthsno report of motor score evolutionDaadi et al. (2012)and no quantificationAFG10NSCs from hfVM andCdN/Put (GDNF)CPA1.5 and 11 monthsasymptomatic monkeys; someWakeman et al. (2014)AAV-GDNF injectionsSN (hfVM-derived NSCs)directional outgrowth ofgrafted cells but no proof ofnigrostriatal reconstructionAFG2NSCs from human ESCsCdN/Put/SNC14 weeksasymptomatic monkeysGonzalez et al. (2015)AFG12NSCs from human ESCsCdN/PutCPA6 and 12 monthsspontaneous motor recovery in non-grafted group;Gonzalez et al. (2016)faster, more pronounced recovery and increasedDA, HVA in low-cell vs. high-cell groupcyno12porcine fVM – solid blocksPutCPA1–48 months2–6 fold increased locomotor activityAaron-Badin et al. (2016)at month 6 post-graft vs. pre-graft andsignificant increase in FDOPA uptake ratio(grafted vs. non-grafted side)rhesus6human levodopa-producingstriatumno48 monthssignificant reduction in motor score (4/5 cases)Peng et al. (2016)RPE cellsat month 6 post-graft; motor recovery maintainedup 48 months post-graft; no change in glucosemetabolism post-graft but PRP decreasedin grafted vs. non-grafted sideAFG22human NSCsCdN/SNno or C or CPA4–8 months∼ 50 % reduction in motorRedmond Jr. et al. (2007);score at month 2 post-graft; migrationBjugstad et al. (2008)of NSC-derived TH+ cells tocontralateral non-grafted SNAllograftrhesus2DA cells from hESCsCdN/PutC1 monthno report of motor score evolutionKriks et al. (2011)and no quantification
Continued.
SpeciesNumber graftedGrafted cellsGrafted sitesImmuno-Survival timeFunctional outcomeRef.suppressionAFG2fVM – solid blocksstriatano69 daysparkinsonian score significantly reducedRedmond Jr. et al. (1986)at 69 days post-graft and CSF-HVA concentrationat 40–80 % of baseline (non-grafted MPTPcases ∼ 20 % of baseline)AFG7fVM – solid blocksCdNno7–8 monthsfull recovery of motor score and healthyTaylor et al. (1991)behavior at month 7–8 post-graft;no recovery in shamAFG3fVM – solid blocksCdNno14 weeksno report of motor score evolutionSladek Jr. et al. (1993b)post-graft; in some grafts a 4 to 14-foldincrease in DA concentration vs.lesioned non-grafted striatumXenograftmarmoset6fVM – cell suspensionCdN/Put/NAccno6 monthssignificant reduction in rotationalAnnett et al. (1994)behavior at month 3 post-graft correlatingwith number of surviving striatal TH+ cells;no improvement in cognitive taskmarmoset9fVM – cell suspensionCdN or Putno10–12 monthsbetter recovery of rotational behaviorAnnett et al. (1995)for Put grafted cases vs. CdN graftedcases at month 3 post-graftAFG16fVM – solid blocksCdN or Putno9 monthssevere parkinsonian cases CdN-graftedTaylor et al. (1995)show more than 50 % reductionon motor score at month 9AFG20fVM – solid blocksCdNno18 monthsonly early stage fVM donor induce 50 %Elsworth et al. (1996a)reduction in parkinsonian score coherent with∼ 15–35 % increase in DA concentrationnear grafts vs. non-grafted striatumAFG3fVM – solid blocksCdN or Putno9 months∼ 10 % increase in DATElsworth et al. (1996b)binding and DA concentration neargrafts location accompanied byslight behavioral improvementAFG4fVM – solid blocksCdN or Putno8 monthsno report of motor score evolution post-graftCollier et al. (1997)AFG10fVM – solid blocksCdN or Putno6 monthsno report of motor score evolution post-graftSortwell et al. (1998)AFG8fVM – solid blocksstriatumno?no report of motor score evolution post-graftSladek Jr. et al. (1998)AFG2fVM – solid blocksCdNno3 monthsasymptomaticLeranth et al. (1998)monkeysAFG10fVM – solid blocksSNno6 monthssignificant but slight reduction inCollier et al. (2002)parkinsonian score at month 5–6 post-graft associated with modest increasein DA concentration in ventrolateral Putcyno1ESC-derived DA cellsPutno7 monthsno report of motor score evolution post-graft;Sanchez-Pernaute et al. (2005)∼ 0.1 % survival on averageSanchez-Pernaute et al. (2005)
Continued.
SpeciesNumber graftedGrafted cellsGrafted sitesImmuno-Survival timeFunctional outcomeRef.suppressioncyno6ESC-derived DA cellsPutC14 weeks50 % reduction in motor scoreTakagi et al. (2005)after week 8 post-graft; FDOPA uptakesignificantly increased at week 14 vs. shamAFG6fVM – solid blocksPut/SNno11, 20 and 36 weeksasymptomatic monkeysSladek Jr. et al. (2008)AFG20fVM – solid blocksCdN or Putno10 months> 50 % reduction inRedmond Jr. et al. (2008)or cell suspensionmotor score after month 10 post-graftfor severe and moderate cases;significant increase in healthy behavior score;cell suspension grafts led to reduced GFAP+cells in all cases and increased TH+ cellsat Put only; Put grafts better correlatewith motor improvement than CdN graftsrhesus9neuronal-primed ASCsCdN/Put/SNno12 monthsstable significant recovery in bothZhou et al. (2013)and/or adenovirus expressingmotor score and rotational behaviorneurturin and THin combined group only at month 2 post-graft;qualitative increase in striatal DAT levels at week 16post-graft only in combined group;coherent higher TH+ cells in SN of combined groupAFG13fVM – solid blocks and/CdN/Putno9 monthsrecovery in motor score for all grafted vs.Redmond Jr. et al. (2013)or AAV5-hu-GDNF vectorsham at month 1 post-graft; combined graftcases almost fully recovered at month 2 post-graft in fVM only group and not completein vector only groupAFG16PKH26 endometrium-CdNno1 monthasymptomatic monkeys; ∼ 30 %Wolff et al. (2015)derived cellsincrease in HVA concentration ingrafted vs. non-grafted sideAutograftrhesus4NSCs derived fromCdN/SNno5 monthsno quantification reported;Xu et al. (2010)MSCs and/or hTHmore reduction in motor score in casesreceiving hTH-NSCs and higher DAT levelscyno7CBCAPutno12 monthsno quantification reported for motor score,Luquin et al. (2011)max recovery at month 6 post-graft;FDOPA uptake significantly largervs. sham at month 12cyno1DA cells from iPSCsPutno12 monthsno quantification reported;Sundberg et al. (2013)no change in motor score nor daytimeactivity pre- vs. post-graftrhesus3DA cells from iPSCsCdN/Put/SNno6 monthsno quantification reported;Emborg et al. (2013a)no obvious behavioral recovery norPET changes for VMAT2 binding
Continued.
SpeciesNumber graftedGrafted cellsGrafted sitesImmuno-Survival timeFunctional outcomeRef.suppressioncyno8DA cells from iPSCsPutno3–4 monthsno MPTP treatment; about twiceMorizane et al. (2013)the number of surviving cellsin auto- vs. allograftscyno6GDNF-expressing MSCsCdN/Put/SNno8 weeksMPTP given after grafts; neuroprotectionRen et al. (2013)against MPTP for motor function of limbcontralateral to grafted side; DAT increasein grafted side vs. non-grafted sidecyno3DA cells from iPSCsPutno12–24 months1/3 case recovered daytime activity,Hallet et al. (2015)as well as hypokinesia and increased DATlevel in grafted side after month 6 post-graftAFG6ANCECdN/Put/SNno6 monthsonly one case that received twice the amountBloch et al. (2014)of cells per site did not recover; 2 cases offull and 2cases of partial motor recoveryin 200 days post-graftcyno1DA cells from iPSCsCdN/Put/SNno6 monthsmotor recovery (significantly differentWang et al. (2015)from non-grafted group) at week 6–8and week 22–24 post-graft
The required number of surviving TH+ cells to reach functionality may also
depends on the severity of DA loss. Indeed, imaging studies have shown that
parkinsonian monkeys that recovered from motor symptoms following
MPTP treatment show about 30 % more striatal DAT levels (Vezoli et al.,
2014), about 20–35 % more striatal (fluorodopa) FDOPA uptake and 10–20 % more
TH+ nigral cells than monkeys displaying stable parkinsonian motor symptoms
(Blesa et al., 2012). In more severely affected monkeys, more graft-derived
dopamine may be necessary to reverse parkinsonian behavior. On the contrary,
in less affected monkeys, the host nigrostriatal DA system may still be
capable of displaying a regenerative response after transplantation, and a lower
cell number might then be necessary (Elsworth et al., 1996).
Progenies of the grafted cells in the host brain
The principal focus when analyzing the graft composition is on DA neurons.
The most widespread marker of DA neurons is tyrosine hydroxylase, the
enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine,
which is the first step in the biosynthesis of dopamine. However, TH is also involved
in the synthesis of other catecholamines such as epinephrine and
norepinephrine. The identity of DA neurons is thus usually refined by
studying the expression of DAT through immunostaining analyses
(Sanchez-Pernaute et al., 2005; Takagi et al., 2005; Kriks et al., 2011;
Hayashi et al., 2013; Morizane et al., 2013) or measurement of the binding
potential of 11C-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (11C-CFT) at
the dopamine nerve terminals (Hayashi et al., 2013; Hallett et al., 2015). The
graft content is occasionally further analyzed through staining for GIRK2
and CALBINDIN to highlight the presence of A9 and A10 DA neurons
respectively (Kikuchi et al., 2011; Kriks et al., 2011; Sundberg et al., 2013;
Wang et al., 2015).
As previously mentioned, PSC dopaminergic differentiation in vitro leads to
variable amounts of TH+ DA neurons, as well as to other types of neurons,
astrocytes and in certain cases neural progenitors. Accordingly, the content
of the grafts from PSC-derived DA neurons is variable, with a usually high
proportion of MAP2+ neurons, from which only a small proportion expresses
TH (Takagi et al., 2005; Doi et al., 2012; Emborg et al., 2013a). A9 type DA
neurons generally maintained their original A9 characteristics upon grafting
(Hayashi et al., 2013; Wang et al., 2015). Non-negligible amounts of other
types of neurons (GABA+ and SEROTONIN+), GFAP+ astrocytes and MBP+
oligodendrocytes are also found in the grafts (Emborg et al., 2013a).
NSCs, isolated either from fetuses or PSCs, generally poorly differentiated
into TH+ neurons and principally gave rise to glial cells or
undifferentiated neural progenitors when transplanted in MPTP-treated NHPs
(Redmond Jr. et al., 2007; Bjugstad et al., 2008; Wakeman et al., 2014; Gonzalez
et al., 2015, 2016). These non-neuronal cells may be
involved in the reestablishment of adequate homeostasis in the lesioned
brain, as previously suggested (Redmond Jr. et al., 2007). More recently,
high-throughput RNA sequencing analyses enabled in-depth characterization of the
grafts and showed that hNSC grafts induced the expression of genes and
pathways that have been previously reported to be downregulated in PD
(Gonzalez et al., 2016).
Axonal outgrowth and migration in the host brain
One of the critical issues of cell therapy in PD is the capacity of the
transplanted cells to grow axons and reinnervate the DA-denervated host
striatum over distances that are relevant for the size of the human brain.
The adult brain has been suspected of no longer being capable of eliciting and
directing axonal outgrowth from the SN to the striatum. Grafted cells have
thus often been placed ectopically into the striatum, which is the site of lost
dopaminergic input (Annett et al., 1994, 1995; Elsworth et
al., 1996; Sanchez-Pernaute et al., 2005; Takagi et al., 2005; Kriks et al.,
2011; Daadi et al., 2012; Doi et al., 2012; Morizane et al., 2013; Sundberg
et al., 2013).
When transplanted in the lesioned rodent striatum, DA neurons from human fVM
and PSCs show extensive reinnervation of striatal and extra-striatal target
structures (Brundin et al., 1986; Sanchez-Pernaute et al., 2005; Thompson et
al., 2005; Kirkeby et al., 2012; Grealish et al., 2014), and, when grafted in
the SN, they project axons over long distances and reinnervate the relevant
A9 and A10 host target structures (Grealish et al., 2014), as was observed
for rodent DA neurons (Thompson et al., 2009).
In contrast, their capacity to reinnervate distant targets seems rather
limited in the NHP brain, with TH+ fibers extending only a few millimeters
into the host (Sladek Jr. et al., 1998; Collier et al., 2002; Takagi et al.,
2005; Kriks et al., 2011; Emborg et al., 2013a), although this parameter was
often not extensively documented (Elsworth et al., 1996; Sanchez-Pernaute et
al., 2005; Takagi et al., 2005; Kikuchi et al., 2011; Daadi et al., 2012; Doi
et al., 2012; Hayashi et al., 2013; Morizane et al., 2013; Sundberg et al.,
2013; Hallett et al., 2015; Wang et al., 2015). fVM grafts performed either
in the CdN or in the putamen induce increased TH innervation of the
non-grafted ipsilateral nucleus (Redmond Jr. et al., 2008), suggesting that they
could potentially extend long neurites. However, direct innervation of the
remote striatum from SN grafts has not been observed in these species
(Collier et al., 2002; Daadi et al., 2012; Emborg et al., 2013a; Ren et al.,
2013; Bloch et al., 2014).
To promote reinnervation of the nigrostriatal circuitry, multiple
intrastriatal and intranigral fVM grafts have been used as “bridge grafts”
that attract the growth of neurites from grafted DA neurons in the rat
(Mendez et al., 1996, 2000) and NHP models
(Sladek Jr. et al., 1993a, 2008). Using this strategy, fVM
grafts placed in the SN extended neurites over long distance preferentially
to striatal co-grafts, suggesting that axon guidance cues are still present
in the lesioned brain to guide the growing axons from the grafted DA neurons
to their appropriate targets.
The nature of these guidance cues is still poorly known in the lesioned NHP
brain. Several molecules such as the NETRIN, SLIT, EPHRIN and SEMAPHORIN families of
secreted proteins, whose axon guidance activities have been extensively
studied in the nervous system, have been shown to affect embryonic DA axons
and may be involved in the regulation of axonal outgrowth of transplanted
cells in the lesioned NHP brain. NETRIN-1 attracts whereas SLIT-2 repels
rodent midbrain DA neurons in vitro and in vivo (Lin et al., 2005;
Li et al., 2014), and both proteins affect human PSC DA neuron outgrowth
in vitro (Cord et al., 2010). Signaling through the EPHRIN family
receptor EphB1 and ligand EPHRIN-B2 is involved in the regulation of axonal
growth of developing DA neurons in rodents (Yue et al., 1999; Sieber et al.,
2004). EphA4 receptor and EPHRIN-B2 ligand are expressed in the adult NHP
brain, including the CdN, putamen and SN (Xiao et al., 2006), and may play a
role in directing axonal outgrowth of grafted cells. SEMAPHORINs are
expressed in the rodent striatum and may be involved in the establishment of
DA projections from the midbrain to the striatum during embryonic development
(Hernandez-Montiel et al., 2008; Kolk et al., 2009; Torre et al., 2010). SHH
signalling is involved in DA axon pathfinding and determination of the
structural diversity of the DA projections during rodent development and may
also promote axonal growth of grafted cells (Hammond et al., 2009). Whether
these guidance cues persist in the adult or lesioned NHP brain is still
unknown.
In addition to its action on DA neuron survival, GDNF also stimulates
outgrowth of DA neurons after lesion or grafting in the rodent (Sinclair et
al., 1996; Sautter et al., 1998; Wilby et al., 1999; Zhang et al., 2013) and
NHP brain (Elsworth et al., 2008; Redmond Jr. et al., 2009; Wakeman et al.,
2014). Combination of GDNF and NETRIN-1 was found to support directed
long-distance growth of DA axons from rodent fVM grafts (Zhang et al., 2013).
However, recent studies showed that GDNF delivery combined with fVM graft did
not lead to increased functional improvement in the PD NHP model (Redmond Jr. et
al., 2013), highlighting the need to clarify the benefit of GDNF delivery in
this context.
Besides axonal outgrowth, migration of the transplanted cells is also
involved in the reinnervation of the lesioned striatum over long distances.
In the rodent model, transplanted primate DA neurons extensively migrate, even
reaching the contralateral hemisphere (Sanchez-Pernaute et al., 2005). In the
NHP model, the sparse data available suggest that migration of DA neurons is
limited, as judged by the lack of expression of the migrating neuroblast marker,
doublecortin (Sanchez-Pernaute et al., 2005). In contrast to DA neurons,
primate NSCs show widespread migration throughout the MPTP-lesioned NHP brain
(Redmond Jr. et al., 2007; Bjugstad et al., 2008; Brunet et al., 2009; Gonzalez
et al., 2016) as was previously shown in various rodent models (Fricker et
al., 1999; Guzman et al., 2007). In particular, NSC progenies were observed
migrating along the nigrostriatal pathway, from the caudate to the putamen
(Bjugstad et al., 2008; Gonzalez et al., 2016). The phenomenon of migration
of immature cells is exemplified by unilateral injections, where the grafted
cells were found migrating to the opposite hemisphere (Bjugstad et al., 2008;
Brunet et al., 2009). Interestingly, human NSCs spontaneously and
preferentially migrate to the region of cellular loss over long distances in
the lesioned PD NHP brain (Bjugstad et al., 2008), suggesting that migration
is not a random event. The signals that direct NSC migratory pattern in the
MPTP model are not known. Progenies of human NSCs express the chemokine
receptor CXCR4, suggesting that chemokine-dependent mechanisms are involved
in the regulation of their migration (Imitola et al., 2004; Kelly et al.,
2004; Chang et al., 2013).
Immature cells develop very slowly in the host environment, and this may take
several months before they generate terminally differentiated progenies,
including fully functional mature DA neurons that extend projections in the
nigrostriatal pathway. Studies of axonal outgrowth and cell migration are
thus more appropriate in the NHP model, which allows long-term analyses as
well as studies to assess the capacity of grafted cells to innervate the host
brain over sufficiently long distances to provide good innervation of the
remote putamen in primates.
Neurotrophic support and interaction with the pathological brain
From the earlier transplantation studies of adrenal medullar cells (Madrazo
and Franco-Bourland, 1991) to the most recent studies of NSCs and DA neuron
transplantation (Redmond Jr. et al., 2007), the functional effects of grafted
cells were hypothesized to be obtained not exclusively by a cell-replacement
mechanisms but also through diffuse release of neurotrophic stimuli and
neuroprotective support on host circuitry (Li et al., 2005; Redmond Jr. et al.,
2007; Bloch et al., 2014; Gonzalez et al., 2015, 2016;
reviewed in Martino and Pluchino, 2006). NSCs can express and produce in situ
a wide array of transmembrane and trophic molecules capable of promoting
tissue repair. GDNF and BDNF are expressed in glial cells derived from the
grafted NSCs, in both the rodent and NHP models, and may provide trophic
support to the pathological host milieu (Redmond Jr. et al., 2007; Gonzalez et
al., 2015).
Close physical associations have commonly been observed between grafted cells
and host cells, indicating intercellular relationships. For example, DA
neurons from transplanted fVM tissue or isolated from PSCs establish synaptic
contacts with host striatal neurons by targeting dendrites and somata of
spiny neurons (Leranth et al., 1998), as visualized by synaptophysin staining
(Sortwell et al., 1998; Daadi et al., 2012; Wang et al., 2015).
Differentiated progenies of hNSCs were also found in close contact with host
TH+ neurons that showed increased cell body size as compared to DA neurons
of the lesioned brain (Bjugstad et al., 2005; Redmond Jr. et al., 2007; Gonzalez
et al., 2015).
Overgrowth and tumor formation
One major concern with regard to the use of PSCs-based therapy is the risk of
overgrowth or development of tumors. In the NHP model, tumor formation or
overgrowth was generally not detected following transplantation of
PSC-derived DA neurons (Sanchez-Pernaute et al., 2005; Takagi et al., 2005;
Emborg et al., 2013a; Sundberg et al., 2013; Hallett et al., 2015; Wang et
al., 2015) or immature NSCs, as judged by the negative staining for Ki67, a
marker of proliferative cells (Table 1b; Redmond Jr. et al., 2007; Bjugstad et al., 2008;
Gonzalez et al., 2015, 2016). As
expected, pluripotent nuclear (OCT4, NANOG) and membrane markers (TRA-1-81,
TRA-1-60, SSEA4) were also not found in these grafts (Emborg et al., 2013a;
Morizane et al., 2013; Gonzalez et al., 2015; Wang et al., 2015).
Proliferating cells have occasionally been detected after transplantation of
hiPSC-derived DA neurospheres (Kikuchi et al., 2011; Doi et al., 2012).
However, prolonged PSC DA differentiation in vitro enabled a drastic
reduction of tumorigenicity (Doi et al., 2012) as previously shown in the rat
(Brederlau et al., 2006).
However, depending on the protocol used to obtain DA neurons, the population of
grafted cells may still contain immature proliferating cells that may, in some
cases, be incapable of differentiating in the host tissue and eventually form
tumors in vivo. The possibility of uncontrolled growth of the grafted cells
in vivo should still be a matter of concern. This highlights the need for
deep characterization of the grafted cells and long-term preclinical
studies in the NHP model to validate the safety of each cell type.
Impact of the immune status of the host brain
The brain has long been positioned as immune privileged, but it is now well
established that this privilege is not absolute and that immunological
rejection processes can occur in the CNS (Lindvall, 1989; Cicchetti et al.,
2003; Louveau et al., 2015). Transplanted tissue or cells might thus be
recognized as foreign, leading to their rejection after transplantation in
the brain. Fetal VM tissue expresses MHC antigens that can elicit an immune
response in the case of host mismatch (Widner et al., 1989). Expression level
of MHC molecules is low in human PSCs and NSCs (Drukker et al., 2002; Vagaska
et al., 2016) but can rapidly be induced in inflammatory conditions or
following differentiation in vitro (Drukker and Benvenisty, 2004;
Vagaska et al., 2016).
Xenografts in the MPTP-treated NHPs have thus usually been performed under
immunosuppression (Table 2). In the immunosuppressed environment,
transplanted cells elicit only weak immune reaction, with minimal glial
scarring and host IBA1+ microglia around the graft core (Redmond Jr. et al.,
2007; Kikuchi et al., 2011; Kriks et al., 2011; Daadi et al., 2012; Doi et
al., 2012; Gonzalez et al., 2015, 2016; Aron Badin et al., 2016).
In the case of allografts in NHPs, immunosuppression has exceptionally been
used, and, when evaluated, immune response or inflammatory reaction was
generally found to be weak (Table 1b).
However, direct comparison of allo- and autografts of iPSCs in healthy NHPs
reported immune reaction in allografts, with the presence of host microglial
cells that expressed MHC-II, IBA1+ cells, CD45+ leucocytes and CD8+
killer T cells in the grafts (Morizane et al., 2013). In contrast, in the
case of autotransplantation, the immune reaction was only minimal with rare
reactive microglial cells and a low number of MHC-II-expressing cells. TH+
cell survival rate was also higher in autografts than in allografts with
immunosuppression and led to functional recovery (Sundberg et al., 2013;
Hallett et al., 2015; Wang et al., 2015).
These recent studies suggest that immunosuppression can only be withdrawn in
the autologous models (Emborg et al., 2013b; Morizane et al., 2013; Sundberg
et al., 2013). Direct comparison of autograft and allografts in the lesioned
NHP brain might ultimately confirm the efficacy and safety of autologous
iPSC-derived or iDA cells.
Functional and clinical outcomes
In marmosets (Callithrix jacchus), parkinsonism can be modeled with MPTP,
6-OHDA or also through overexpression of α-synuclein (Yun et al., 2015).
The MPTP model reproduces typical neurotransmitter loss; unilateral 6-OHDA
lesions allow evaluation of the asymmetry of motor symptoms, such as rotational
behavior; α-synuclein overexpression in the midbrain mimics the slow
onset of motor symptoms and allows for the investigation of the so-called presymptomatic
period before appearance of characteristic motor symptoms. Only the MPTP and
6-OHDA models have been used to assess cell-replacement therapy. In 1988,
MPTP-treated marmosets (cumulative dose 11.3 mg kg-1 over 3 days,
intraperitoneal) subsequently received unilateral and bilateral fVM grafts
(Fine et al., 1988). Spontaneous locomotor activity as well as
amphetamine-induced hyperactivity were increased in grafted monkeys compared
to MPTP-treated controls and sham-grafted animals, suggesting graft-derived DA
release into grafted striatum. In subsequent studies conducted by Dunnet and
collaborators using 6-OHDA to induce hemiparkinsonism, symptoms were assessed
with a battery of motor tasks including rotational behavior (spontaneous and
amphetamine-induced). They showed that, 3 months after fVM grafts in
the caudate nucleus (CdN), putamen (Put) and nucleus accumbens (NAcc), there was
a significant reduction in rotational behavior (both spontaneous and
amphetamine-induced) that correlated with the number of TH+ cells counted
in the striatum. However, no improvement in the cognitive task was observed
(Annett et al., 1994). In the follow-up experiment (Annett et al., 1995) it
was shown that, after 3 to 6 months following fVM tissue grafts in Put only,
animals had better motor recovery compared to those that received fVM grafts
in CdN only. They finally showed that only fVM grafts derived from the youngest
donor age were efficiently reducing amphetamine-induced rotations (Annett et
al., 1997).
Experiments done in African green monkeys (Cercopithecus aethiops sabaeus)
all rely on the model developed by Redmond and collaborators (MPTP intramuscular,
IM, at 0.2 to 2.15 mg kg-1 typically injected every day over a 5-day
period) and are all produced with his collaboration. This was the first team
to induce efficient recovery of MPTP-induced parkinsonism with fVM grafts
(Redmond Jr. et al., 1986), and they have been very prolific in that effort (see
Table 1). Work from this lab has shown through very careful and detailed
motor score evaluation that full motor recovery is seen 7–8 months after fVM
grafts into CdN, but not in sham-operated animals (e.g., grafts into
cortex; Taylor et al., 1991). A subsequent study (Elsworth et al., 1996)
showed not full recovery but instead slight improvement on the clinical motor scale.
They additionally described that, at the fVM graft sites, DA concentration was
increased compared to the non-grafted side, sham-operated or control MPTP-treated
cases (10–12 % of DA concentration of control animals compared to less
than 1–2 % of controls in other cases). Collier and colleagues (2002)
showed slight but significant behavioral improvement after transplant of fVM
cells into rostral SN of both severely and moderately parkinsonian monkeys
5–6 months post-graft (Collier et al., 2002). This slight improvement was
correlated with a slight but significant increase in DA concentration
confined to the medial–lateral putamen. Later Redmond and collaborators
demonstrated that fVM grafts done in the putamen result in a better correlation
with motor improvement than those done in CdN and that the GFAP+ area was
reduced following cell suspension compared to solid graft of fVM (Redmond Jr. et
al., 2008). In 2013, they compared fVM grafts in combination with human GDNF
vector or not (Redmond Jr. et al., 2013). This study demonstrated that
behavioral recovery was accompanied by a 3-fold increase in DA concentration
in animals receiving fVM+vector compared to fVM only, whereas animals
receiving vector only did not recover. Bloch and collaborators (Bloch et al.,
2014) performed bilateral autotransplantation of prefrontal cortex biopsies
(ANCE) in CdN, Put and SN (2–4 × 105 cells per site) of parkinsonian African
green monkeys (5 MPTP dose of 0.45 mg kg-1, 82 days prior to grafts).
All animals grafted with living cells recovered from motor symptoms (within
200 days post-graft), including one case that received disrupted cell grafts
but with 1.5 % surviving cells, except for the animal that received twice
the amount of cells which did not show any improvement. Postmortem analyses
showed an average of 30 % cell survival, with better survival rate in SN
(∼ 40 %) followed by CdN (∼ 30 %) and Put
(∼ 20 %). Striatal TH+ cells at the grafted sites were higher in
all animals grafted with living cells compared to sham-grafted animals
(∼ 20 to 70 % of non-MPTP-treated controls). The most recent study
used symptomatic MPTP monkeys with some additionally rendered dyskinetic with
levodopa treatment and showed that bilateral putaminal grafts of fVM did not
lead to graft-induced dyskinesia (Kordower et al., 2017). Redmond and
collaborators also tested xenografts of human fVM tissue. In 2007, they
transplanted undifferentiated human NSCs derived from fVM tissue (hfNSCs)
unilaterally in SN and bilaterally in the CdN (1–9 × 106 cells per
site) of African green monkeys receiving a cumulative MPTP dose of either
2.25 mg kg-1 (severe parkinsonism) or 1.75 mg kg-1 (motor
asymptomatic). Severely parkinsonian monkeys showed a significant recovery of
motor symptoms compared to sham-operated ones within the first 2 months
post-graft. Those animals presented cell migration such that the percentage
of donor-derived TH+ cells was the same between grafted and non-grafted SN
(∼ 7 % of total TH+ population), as well as the DA concentration.
Additionally, the proportion of cells with α-synuclein aggregates
decreased to less than 20 % after hfNSCs grafts compared to more than
80 % in non-grafted MPTP-treated animals (Redmond Jr. et al., 2007). They
later confirmed that implanted hfNSCs migrated along the nigrostriatal
pathway toward SN (Bjugstad et al., 2008). Gonzalez and collaborators (2016)
tested hpNSC grafts in CdN and Put of severely parkinsonian monkeys (MPTP
2.15 mg kg-1 IM over 5 days) with different concentrations of cells
(1 and 2 million cells per site, with low and high dose respectively) and triple
immunosuppression (Gonzalez et al., 2016). They showed that animals
transplanted with a low dose of cells displayed faster and greater recovery
than those transplanted with a higher dose and had significantly reduced motor
scores 12 months post-grafts. The low-dose group also presented higher levels
of DA and metabolite concentrations than high-dose and MPTP-lesioned control
groups.
In rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys, MPTP is administered either acutely, leading to rapid
nigrostriatal lesion and expression of motor symptoms, or chronically over
weeks to months, inducing a progressive DA lesion and slowly evolving
non-motor and motor symptoms. The main difference between these models is
that acute MPTP models induce a topography of the DA lesion different than
that produced by chronic MPTP intoxication, following which the ventral
striatum is the most preserved structure (Perez-Otano et al., 1994)
comparable to what is observed in PD patients (Gibb and Lees, 1991).
Sanchez-Pernaute and collaborators grafted DA cells derived from ESCs (cyno-1
line) in the anterior and posterior part of the right Put of one parkinsonian
cynomolgus monkey after repeated intravenous MPTP injections
(0.3 mg kg-1, once a week for 16 weeks). This monkey did not show
asymmetry of motor scores after unilateral graft (values not reported;
Sanchez-Pernaute et al., 2005). During the same period Takagi and collaborators
grafted bilaterally neural progenitors derived from ESCs in the Put of
parkinsonian cynomolgus monkeys after repeated intravenous MPTP injections
(0.4 mg kg-1 twice a week for a month on average). They showed that
grafted monkeys (treated daily with cyclosporine) started to recover motor
symptoms 4 weeks post-graft (significantly different from the sham-grafted group)
and stabilized after week 10 (Takagi et al., 2005). Accordingly,
fluorodopa uptake in the putamen was significantly increased in ESC-grafted animals compared to sham-operated ones.
Kikuchi and collaborators (2011)
bilaterally transplanted neural progenitors derived from human iPSCs
(105 cells per site) in the Put (6 sites per hemisphere) of one cynomolgus monkey
12 weeks after MPTP intoxication (0.4 mg kg-1 intravenous, IV, twice a week until
persistent motor symptoms) and with immunosuppression. The graft size
(estimated from anatomical MRI scans) increased tremendously from month 1 to
month 12 post-graft. PET-scan binding values of a tumor tracer (FLT,
3′-deoxy-3′-[18F]-fluorothymidine) also
constantly increased, and, while still below control values, some Ki67+ cells
were found in the graft showing proliferation of immature cells
(< 1 %). Neither improvement in neurological score nor in reaching
task performance could be seen. Doi and collaborators (2012) bilaterally
transplanted hESC-derived neural progenitors at different stages (D14 and
D28 floating spheres, D35 and D42 attached spheres) into the Put of
parkinsonian cynomolgus monkeys (0.4 mg kg-1 MPTP IV until
persistent motor symptoms). The D14 grafts contained up to 30 % of
Ki67+ cells, and the uptake ratio of PET tracer (FLT) used to detect brain
tumor was also substantially higher than control, indicating tumorigenicity,
whereas D42 grafts contained less than 1 % of Ki67+ cells and an FLT
uptake ratio comparable to control. However, even if FDOPA uptake was
correlated with the neurological score change after graft, there was no
significant recovery compared to sham-injected controls (Doi et al., 2012).
Zhou and collaborators grafted rhesus neuronal-primed adipose stem
cells (ASCs) combined or not with gene transfection of neurotrophic factor
and TH in CdN, Put and SN of hemiparkinsonian rhesus monkeys after single
intracarotid MPTP injection (0.6 mg kg-1). Animals showing stable
apomorphine-induced rotational behavior for more than 12 months were used
for transplantation. Only the combined group showed stable signs of recovery
(significant reduction in motor score, i.e., close to non-MPTP-treated
controls, and, in apomorphine-induced rotational behavior) as well as increased levels
of striatal DAT 4 months post-graft (no quantification). A progressive
recovery was observed in the group transplanted with neuronal-primed ASCs
only, and, coherently, the TH+ immunoreactive cells counted in the SN
were 15 % of
the intact side. TH+ cells rose to 30 % of the intact side in the combined
group, thus providing evidence that about 30 % of TH+ cells in the SN
is enough to induce stable recovery (Zhou et al., 2013). Xu and
collaborators (2010) performed autografts of NSCs derived from BMSCs and
transfected or not with human gene coding for TH in CdN and SN
(1.5–3 × 106 cells per site) of hemiparkinsonian monkeys 6 weeks following
1-month intoxication with intracarotid perfusion of MPTP
(1.2 mg kg-1; Xu et al., 2010). Hemiparkinsonian monkeys transplanted
with NSCs showed behavioral improvement with better amelioration in clinical
score for groups transplanted with NSCs modified to express human TH (no
report of scores or degree of recovery). Five months following grafts,
striatal FDOPA uptake and DAT levels were tested and showed respectively an
increase of grafted side compared to control lesioned monkeys and higher
values of DAT levels for grafted group with NSCs expressing hTH (qualitative,
no values or statistical tests reported). EGFP+ and TH+ double-labeled
cells were found in SN of all grafted groups, with higher proportion in
grafted group with NSCs expressing hTH (no values reported for cell counts).
Some years later, MSCs modified or not to express GDNF were grafted
unilaterally in CdN, Put and SN (∼ 5.2 × 106 cells per site) of
cynomolgus monkeys (Ren et al., 2013). MPTP intoxication was performed 2
weeks after grafts (0.1 mg kg-1 IV) until animals displayed stable
scores (moderate to severe, 10–14 on the PPRS) and bilateral upper limb
function was assessed through a food retrieval task. DAT levels were also
measured before and 6 weeks after MPTP intoxication. The GDNF+-MSCs
provided neuroprotection against MPTP for motor function (better performance
on the limb contralateral to grafted side), and, accordingly, DAT levels as
well as DA and DA metabolites levels were significantly increased in the
grafted side compared to the non-grafted side. There were no neuroprotective
effects seen in the MSCs-only graft group. Luquin and collaborators (Luquin et
al., 2011) performed unilateral and bilateral carotid body cell aggregates
(CBCA) in the rostral and caudal Put of cynomolgus monkeys 3 months after
stable expression of severe to moderate parkinsonism following weekly
intoxication with MPTP (0.05–6 mg kg-1). FDOPA uptake was controlled
1 week before surgery and at 6 and 12 months post-surgery. The maximum motor
recovery was observed at 6 months post-grafts and stabilized (no report about
degree of recovery). After grafts, FDOPA uptake showed a tendency to decrease
in sham-operated animals, whereas the grafted group showed a tendency to
increase. The FDOPA uptake at 12 months was significantly higher in grafted
compared to sham-operated animals. The authors reported a significant
increase of TH+GDNF+ cells in the SN of the grafted group, suggesting trophic
factors release from putaminal CBCA grafts.
Remaining studies all used iPSCs mainly in cynomolgus monkeys. Emborg and
collaborators (2013) implanted iPSCs in the anterior and posterior parts of
CdN; in the anterior, mid- and posterior parts of Put; and in SN
(2.5–5 × 105 cells per site) of hemiparkinsonian rhesus
monkeys 12 to 18 months following MPTP intoxication by intracarotid infusion
(Emborg et al., 2013b). There was no obvious behavioral recovery and no PET
change (data not shown) following transplantation. Hallet and collaborators
(Hallett et al., 2015) transplanted unilaterally iPSC-derived DA neurons
2–4 years after induction of stable parkinsonism in Put (4 sites,
1–4 × 106 cells per site) of cynomolgus monkeys treated with
intravenous injections of MPTP (0.15–0.3 mg kg-1, 1–2 times a week
for more than 10 weeks). Recovery in motor score (and notably hypokinesia)
and daytime activity was observed in only one of the three grafted cases for
which DAT levels were estimated with a PET scan and showed an increase in the
grafted side compared to the non-grafted side. Sundberg and collaborators
transplanted iPSC-derived DA neurons (Sundberg et al., 2013) in one
cynomolgus monkey treated with intravenous injections of MPTP
(0.3 mg kg-1, once a week for 5 weeks until expression of mild stable
parkinsonism). Neither motor score nor daytime activity recovery was observed
following transplantation. Wang and collaborators injected iPSCs derived from
one SFV-infected monkey (simian foamy virus, SFV, has been shown to interfere
with iPSCs production) rendered hemiparkinsonian through unilateral
intracarotid infusion of 3 mg of MPTP (Wang et al., 2015). Behavioral
recovery was observed at two time points following transplantation – i.e.,
clinical score significantly differed compared to non-grafted cases at weeks
6–8 and again after week 22 post-graft. TH+ cells were detected in grafted
Put and CdN, but not in grafted SN. Finally, Peng and collaborators (2016)
transplanted unilaterally human retinal pigment epithelial cells into the
CdN–Put (5 tracks 2 mm apart along the rostrocaudal extent of the caudal
CdN–Put, 6 to 10 × 104 cells per site) of mild to moderately
severe parkinsonian rhesus monkeys (MPTP intravenous, over several months)
and followed them behaviorally and evaluated changes in the
parkinsonism-related pattern (PRP) of glucose metabolic activity measured
with PET imaging (Peng et al., 2016). Clinical improvement was seen after 6
months in all grafted animals and stable over a 2 to 4-year period of
follow-up, whereas no improvement in the clinical rating scale could be seen
for sham-grafted animals. The PRP network activity was increased after MPTP
and significantly reduced following graft while still remaining above the
values of age-matched healthy controls.
NHP models of PD are all reproducing motor symptoms characteristic of the
disease, degeneration of nigrostriatal DA neurons and linked perturbation of
functional markers, e.g., reduction in FDOPA uptake and/or DAT binding.
However, only some models can reproduce the early onset of cognitive and
circadian disturbances also present in PD and display a slowly progressing
nigrostriatal lesion, e.g., repeated low-dose MPTP. Therefore, both the model
and the palette of reproduced parkinsonian symptoms are of importance for
appropriate translation to the clinic. Multiparametric longitudinal
monitoring of functional and behavioral consequences of cell-replacement therapy
is thus crucial for efficient translation to the clinic. More than a third of
the reviewed literature (see Table 2) did not report any in vivo
functional,
e.g., with PET-scan, nor behavioral outcome of the grafts (6 studies used
asymptomatic MPTP monkeys and one non-MPTP-treated monkeys), focusing
exclusively on postmortem evaluation of host–graft integration (Sladek Jr. et
al., 1993b, 1998, 2008; Collier et al., 1997; Leranth et al., 1998; Sortwell
et al., 1998; Sanchez-Pernaute et al., 2005; Bjugstad et al., 2008; Redmond
Jr. et al., 2009; Kriks et al., 2011; Daadi et al., 2012; Morizane et al., 2013;
Wakeman et al., 2014; Gonzalez et al., 2015; Wolff et al., 2015). In these
conditions it is impossible to infer the degree of integration required for
any behavioral or functional recovery. However, even if those studies are
necessary for testing different types of transplant before investigation in
a larger number of animals, reporting clinical motor score has been very well
documented for many parkinsonian models and should be an imperative standard,
considering that those investigations require sacrifice of NHPs. From the
remaining studies, about half of them reported in vivo functional outcome
following graft in addition to behavioral outcome assessing clinical motor
symptoms; however, some studies just reported qualitatively those functional
changes (Xu et al., 2010; Emborg et al., 2013a; Sundberg et al., 2013; Zhou et
al., 2013). Surprisingly, and even so non-motor symptoms are recognized as
having a great impact on quality of life in PD patients (Simuni and Sethi,
2008), no graft study using the NHP MPTP model to date has reported effects
on non-motor symptoms. We found one study in the 6-OHDA marmoset model
reporting effects of fVM grafts on a version of the detour task used to
assess integrity of DA innervation to the frontal cortex (Annett et al., 1994).
Assessing non-motor symptoms has just lately being explored in a rodent model
of PD (Lelos et al., 2016) and will hopefully pave the way for systematic
follow-up of non-motor symptoms in cell-repair research for PD.
Perspectives
Grafting in NHPs will enable the development of techniques for more detailed
in vivo and postmortem follow-up of the fate of the cells that can be
translated to humans. Because NHP and human cells share the same
characteristics and cell signalling regulations, NHPs are potentially the most
appropriate for in vivo screening.
However, the burdens from working with NHPs are significant in terms of time and
cost investments needed to pursue preclinical investigations and/or provide
significant contribution to scientific knowledge about the underlying
mechanisms of PD. Limitations are often required by ethic committees which
follow a country's directives; for example, recently the European Commission asked the
Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) to
update the opinion on the use of nonhuman primates in
research
https://ec.europa.eu/health/scientific_committees/consultations/public_consultations/scheer_consultation_03_en
SCHEER provides recommendations, after public consultation, on how to advance
training, improvement of techniques and protocols, sharing of knowledge,
removal of barriers and research needs for NHP use.
. Progress was made, but
it was not enough to justify a reduction in the use of NHPs in neurodegenerative
disease research. Rather, both advances in recent promising techniques and the
need for more preclinical design studies in NHPs call for a controlled
increase in the use of NHPs in neurodegenerative research. In return, rigorous
individual follow-up with pertinent functional imaging evaluations during the
different intoxication and transplantations phases (pre/post) should be
standard practice for preclinical observations.
We have seen that site of transplantation is critical for behavioral
recovery. Studies originally placed transplants into the striatum, the target
of DA neurons for practical reasons, and showed that placement into Put lead
to better motor recovery compared to caudate transplants (Annett et al.,
1995; Redmond Jr. et al., 2008). Multiple small transplants (e.g., Peng et al.,
2016) are also an efficient solution to implant more cells, but not in one
single location, which has been showed to be detrimental (Bloch et al., 2014;
Gonzalez et al., 2016). Combination of multiple target areas might promote
reconstruction of the nigrostriatal pathway but still needs further refinement in
NHPs. No clear evidence of nigrostriatal reconstruction has been shown so
far, neither with combined grafts in striatum and SN (Redmond Jr. et al., 2007;
Bjugstad et al., 2008) nor in SN grafts with trophic factors in the striatum
(Wakeman et al., 2014). However, interhemispheric cell migration is possible
(Redmond Jr. et al., 2007; Bjugstad et al., 2008), and transplanted cells favor
the natural nigrostriatal connectivity patterns for selective neuritic
outgrowth (Wakeman et al., 2014). Indeed, basal ganglia circuitry and
especially nigrostriatal and striato-cortical connectivity patterns are well
described in NHPs (Williams and Goldman-Rakic, 1998; Haber, 2003; Raghanti et
al., 2008). According to these schemes, it is more than likely that grafts
placed at given striatal sub-compartments would influence the specific
system they support – e.g., graft placed in the caudal CdN might be more
efficient in affecting cognitive troubles, whereas putaminal grafts might
correlate better with motor recovery. With increased understanding of growth
and guidance molecules affecting DA neurons, it may be feasible to place
transplants in the damaged SN and direct the growth of axons into target
regions for reconstruction of midbrain DA circuitry. Our established and
ongoing understandings of the molecular cues which support directed growth
of DA neurons form an important basis for the refinement and optimization of
grafting procedures. Adding supporting factors for survival and axonal
outgrowth of grafted cells (GDNF, NXHP3) and combining different cell types
(multipotent NSCs, GDNF-producing cells) will be the next step in the
refinement of the technique.
The latest developments in the field of neural tissue engineering could not be
implemented here, but shall certainly be taken into account in future
transplantation strategies in PD NHPs. Various biocompatible and biodegradable
biomaterials are currently being developed and may enhance survival and
integration of the grafted cells (Lins et al., 2016; reviewed in Sensharma
et al., 2017).
While the DA system is not the only neurotransmitter system altered, DA
remains central in PD. DA plays an essential role in (i) multiple cerebral
functions of the frontal lobe, e.g., in performance monitoring or in
motivational aspects of behavior; (ii) motor
function via the extrapyramidal
system; and (iii) circadian regulation of behavior through interactions with
lateral habenula and locus coeruleus. This multidimensional aspect of DA
should trigger a multiparametric follow-up of the NHP model of PD. Longitudinal
and simultaneous multiparametric follow-ups (cognitive and behavioral tasks,
motor score, rest–activity cycles, in vivo imaging) should be carried out as
much as possible given the NHP PD model chosen in future experiments. Indeed,
non-motor symptoms have only been reproduced through repeated low-dose MPTP
regimen (Schneider and Kovelowski, 1990; Taylor et al., 1990; Almirall et
al., 1999, 2001; Barcia et al., 2003; Decamp and Schneider, 2004; Vezoli et
al., 2011; Fifel et al., 2014). Overall, very few studies follow up
transplanted monkeys for more than a year (Elsworth et al., 1996; Hallett et
al., 2015; Aron Badin et al., 2016; Peng et al., 2016). However, a longer
outcome period should be considered (2–4 years post-implantation) in order
to assess potential long-term side effects, graft rejection or changes in
functional in vivo measures, especially in cases that present good motor
recovery. All these criteria will enable full validation of the safety and
efficiency of cell grafting before clinical translation.
Finally, it should be noticed that recently emerging NHP models of PD, e.g.,
overexpression of α-synuclein (Marmion and Kordower, 2017), might be able
to reproduce the slowly progressive DA lesion observed in PD without the need
to repeat MPTP injections; however, they require further characterization
before being used to evaluate cell-replacement therapy.
The authors declare that they have no conflict of
interest.
This article is part of the special issue “Stem cells in non-human primates”.
It is a result of the 2016 EPV Seminar, Toulouse, France, 22–23 September 2016.
Acknowledgements
This work was supported by the LabEx CORTEX (ANR-11-LABX-0042) of
Université de Lyon (ANR-11-IDEX-0007) operated by the French National
Research Agency (ANR) and ANR-10-IBHU-0003 (IHU CESAME).Edited by:
Rüdiger Behr Jean-Francois Brunet and one anonymous referee
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