Parkinson disease (PD), was described in details in 1817 by the English physician James Parkinson in “An Essay on the Shaking Palsy.” It is a neurodegenerative disease caused by a progressive and extensive loss of dopaminergic neurons of the nigrostriatal pathway and loss of neurons in the substantia nigra pars compacta.1 This results in motor signs and symptoms such as postural instability, stiffness (increased muscle tone), bradykinesia, and resting tremor.2,3 In addition to motor symptoms, PD manifests itself in a variety of nonmotor symptoms: neuropsychiatric disorders (like insomnia, anxiety and depression)4,5; autonomic (involving heart rate, blood pressure, urinary bladder, and bowel control)6 and sensory such as olfaction and visual disorders.7,8 Signs and symptoms of PD usually appear around 55 years old2 and when about 80% of the nigrostriatal dopaminergic system is degenerated.9,10
With regards to its epidemiology, PD is one of the most common neurodegenerative diseases,11 affecting about 10 million people globally. This number tends to be increased once the world’s population is aging.12 Because of the growing incidence of the disease, as well as the disadvantages of current treatments, several research groups are striving to develop better treatment options.
The main therapies currently used for PD are deep brain stimulation,13 the use of enzyme inhibitors and levodopa. Such treatments provide symptomatic relief, but they do not reverse the disease progression14 or act efficiently on nonmotor symptoms. Levodopa replacement, currently the main treatment for PD,15 is associated with undesirable side effects like dyskinesia15,16 and impulsive-compulsive behaviors.17 Therefore, increasing efforts are needed for curative and/or more effective treatments.18
In the search for new treatments, many animal experimental models were used, trying to reproduce the symptomatic characteristics of PD and in the attempt to develop new treatments. Mice, rats, and nonhuman primates have commonly been used and exposed to different neurotoxins.1 Among these neurotoxins, the main ones are 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone and 6-hydroxy-dopamine (6-OHDA). The animal models exposed to MPTP allowed to better understand the pathophysiological mechanisms of PD and to develop some of the current treatments against PD.19 MPTP mimics the motor and a wide variety of nonmotor symptoms.20 However, MPTP is not the most reliable model, since the injury caused by this neurotoxin is partial and rodents are less sensitive to its effects.21 In contrast, rotenone can reproduce PD for a longer time by continuous intravenous infusion in the animal.22 However, the frequency in the expression of nonmotor symptoms is low, the sensitivity to rotenone varies according to the animal model and there is a variable sensitivity within the species itself—which makes the use of rotenone a poorly reproducible model.23 Currently, the 6-OHDA-injured rat is the most used PD model as it reproduces the progressive evolution of the disease with adequate motor and nonmotor symptoms (cognitive, behavioral, and gastrointestinal disorders).22,24 At the administration site (usually in the substantia nigra or in the striatum), 6-OHDA accumulates in the cytoplasm of the cells, leading to the generation of reactive oxygen species, cytotoxicity by oxidative stress, and neuroinflammation25—elements observed in the histopathogenesis of PD.26 Many ongoing experimental therapies use animal models in studies with anti-inflammatory drugs,27,28 neurotrophic factors29,30 and alpha-synuclein neutralizers.31,32 In case of cell therapy, neuroregeneration is accompanied by symptomatic relief and few collateral effects.33–35 There is particular attention to the mesenchymal stem cells (MSC) due to their multipotentiality and immunomodulatory properties in cell therapy.36
MSC, also known as mesenchymal stromal cells, were first identified and described by Friedenstein et al.37 These cells are CD73+, CD90+, and CD105+ at their surface—but they do not express CD11b, CD14, CD19, CD79a, CD34, and HLA-DR.36 There are 2 properties that explain MSC’s neuroregenerative potential: their multipotentiality and secretome. Despite controversial existences, many studies describe MSC differentiation in tissue-specific cell type, for example neurons and glial cells.38 Because of their multipotentiality, MSC would be capable of communicating to nearby neurons by new synapses.33 Otherwise, in the context of cell therapy in PD, immunomodulatory and proregenerative paracrine effects of MSC’ secretome are more important than their multipotentiality. In the same way, growing evidences suggest that neuroinflammation would be the main cause of PD pathogenesis.39
Secretome is a group of paracrine factors formed by a large repertory of immunomodulatory cytokines—for example interleukin-6 (IL-6), growth factor beta (TGF-β) and prostaglandin E2 (PGE2)—and trophic factors classified as neurogenics (eg, glial cell derived neurotrophic factor, GDNF), angiogenics, neuroprotectors (eg, brain derived neurotrophic factor, BDNF), and synaptogenics (eg, nerve growing factor, NGF).40–44 These cytokines regulate the intensity of immune response due to the inhibition of cytotoxic T lymphocyte proliferation and stimulation of regulatory T lymphocyte proliferation.45 In contrast, trophic factors can have not only anti-apoptotic and neuroregenerative effects, but they also decrease oxidative stress and stimulate the tissues regeneration.33,36,46–48 For this reason, secretome can limit the neuroinflammatory process and revert its damage at PD.
Another advantage of MSC beyond its therapeutic potential is the diversity of tissues from which they can be extracted: adipose tissue (adMSC), umbilical cord (ucMSC), bone marrow (bmMSC), among others.49,50 Once isolated from their source and cultivated, MSC can be transplanted in differentiated or undifferentiated form.51 However, studies in animal models demonstrated that therapies with previously differentiated MSC are more efficient under certain aspects.33
Another therapeutically important property of MSC is the ability to migrate to sites of injured tissue and inflammation due to signs generated by factors released at these sites.52–54 This migratory competence allows the administration of MSC through many routes in animal models with PD, for example intracerebral, intravenous, and intranasal.48,55–57
FIRST WORKS USING CELL THERAPY WITH MSC IN PD MODELS
In 2001, the work of Li and colleagues was one of the pioneers in the study the therapeutic potential of MSC in PD models. In this work, adult male mice were treated for a week with MPTP hydrochloride (intraperitoneally administered). At the end of this week, undifferentiated bmMSCs were administered into the striatum (intrastriatal) of the mice by stereotaxic surgery. About 1 month after transplantation, the animal’s motor behavior was evaluated using a rotarod test and their brains were extracted for immunohistochemical analysis. In comparison to control mice and untreated parkinsonian mice, the parkinsonian mice treated with bmMSCs presented behavioral recovery and the transplanted cells survived for about a week expressing tyrosine hydroxylase (TH) enzyme immunoreactivity—TH catalyzes catecholamines in a limiting step, so this staining can indicate a dopaminergic cell.58
Dezawa and colleagues (2004) was seeking for a cell therapy that could reduce the progression or even cure PD when they differentiated bmMSC in functional dopaminergic neurons through gene transfection and treatment with trophic factors in rats and humans. These neurons were administered through intrastriatal route and improved motor behavior in parkinsonian rats. Future investigations based on such observations tried to achieve more efficiency with differentiation developing methodologies that did not use gene transfection.59,60 Years later, in 2006, the work of Pacary and colleagues was one of those that demonstrated the viability of the in vitro previous differentiation without using gene transfection. MSC extracted from mice’s bone marrow were treated with cobalt chloride (CoCl2) and Y-27632—which together substantially raised the expression of the EPO and VEGF genes, partially responsible for neurogenesis. Consequently, bmMSC differentiate into neuron-like dopaminergic cells61—the same differentiating effect of CoCl2/Y-27632 treatment was recently demonstrated in rat’s bmMSCs, reproducing, in morphology and cytochemistry, the results of Pacary and colleagues by our group (M.F.D. et al, unpublished data).
Hellmann and colleagues demonstrated that naive MSC and predifferentiated MSC in neuron-like cells can home and regenerate neurodegenerative sites partially. In this study, both naive bmMSC and neuron-like cells were transplanted in parkinsonian rats with lesions at contralateral hemisphere when 6-OHDA was used. Grafted cells migrated through corpus callosum and were distributed to basal nuclei of the opposite hemisphere.62,63
Little was known about the therapeutic mechanisms of MSC action in these parkinsonian models so far. In 2008, Jin et al64 took into account the ability of MSC to produce cytokines—for example NGF and BDNF64,65—and they investigated the effect of these cytokines over other cells in co-culture with rat bmMSC. These cells were co-cultured with ventral mesencephalic cells of rat embryos which are precursors of dopaminergic neurons being suitable for studying dopaminergic neurodegenerative disorders.63,66 As a result, ventral mesencephalic cells increased the expression of tyrosine hydroxylase and expression of dopamine when compared with control group. With that, one beneficial effect of MSC secretome over dopaminergic cells was demonstrated.
Many studies evidenced the therapeutic potential of these paracrine factors and immunomodulatory cytokines, as observed by Kim and colleagues. In vitro and in vivo experiments were performed with the hypothesis that neuroinflammation would be the main cause of nigrostriatal degeneration—and so, the therapeutic effect of MSC would be due to anti-inflammatory cytokines of secretome. In vitro tests, mesencephalic dopaminergic neurons and rat microglia activated by lipopolysaccharide (LPS) were co-cultured with human bmMSC, significantly decreasing the microglial activation, the death rate of neurons, as well as the proinflammatory cytokines in the medium. Likewise, LPS were intranigrally administered in rats and animals transplanted with bmMSC demonstrated less microglial activation and more dopaminergic neurons compared with the control group.67 These results evidenced that the therapeutic potential of MSC in PD are based both on its transdifferentiative capacity and (or maybe even more) on its immunomodulatory competence.
Even secretome having a large contribution to the contention of inflammatory process and neuronal survival, the neuroregeneration of missing nigrostriatal pathway is an indispensable piece for an effective cure of PD. MSC can directly or indirectly promote neuroregeneration (being differentiated in missing neurons). Levy and colleagues studied an example of direct interaction with neuroregeneration using human bmMSC previously differentiated in dopaminergic neuron-like cells intrastriatally administered in the treatment of a parkinsonian rat model (6-OHDA). Besides motor improvement, results of immunocytochemical and immunohistochemical analysis show neuro-like cells with various dopaminergic neuronal markers, integrated into the parenchyma of the striatum in place of degenerate neurons.68
Bahat-Stroomza and colleagues observed the indirect interaction of MSC. They differentiated in vitro human MSC in astrocyte-like cells, being able to produce and release neurotrophic factors—for example BDNF, NGF, and GDNF, which stimulates genesis and neuronal survival. Intrastriatal administration of astrocyte-like cells in rats injured by 6-OHDA improved the motor function. Histologic analysis showed regeneration of dopaminergic pathways. Therefore, MSC differentiated in astrocyte-like cells indirectly promoted neuroregeneration (with neurotrophic factors secreted by them).69
EVOLUTION OF THE RESEARCH
In 2010, Blandini and colleagues transplanted human MSC in animal model with PD. Undifferentiated MSC were injected after 5 days, when 6-OHDA was administered in striatum in rats. After this transplant, MSC survived, integrated in the lesion region and with acquired phenotypic characteristics for neuroglial maturation. In addition, the damage caused by 6-OHDA administration was reduced in animals treated with stem cells. The exact mechanisms involved in such improvement still need to be elucidated in details, but paracrine factors released by MSC, for example GDNF, could represent a way through which such cells exert their therapeutic effect.55,70
Still in 2010, Shi et al71 genetically manipulated MSC in order to express TH or GDNF, which are important for the synthesis and uptake of dopamine in the midbrain, respectively. 6-OHDA was administered in Sprague-Dawley rats through nigrostriatal route and, after the injury was confirmed, genetically modified MSC were transplanted in striatum. Dopamine and GDNF levels were increased in treated animals and an improved PD, as evaluated in behavioral tests, was observed, still more significant for the group that received both types of modified MSC.
In the same context of genetic manipulation, ucMSC were manipulated for expressing VEGF that protects the dopaminergic system.72,73 These cells were transplanted in rats into a rotenone-induced hemiparkinsonian model and differentiated in neuron-like dopaminergic cells, causing therapeutic benefits in animals, such as reduction in apomorphine-induced rotations and emergence of immunoreactivity of TH in the lesion of striatum or substantia nigra.72
Over the following years, several studies were carried out and new knowledge was generated in the area of cell therapy and PD. Among these studies, Cova and colleagues demonstrated that human MSC can cause a protective effect in mouse neural stem cells when in co-culture and exposed to 6-OHDA neurotoxin. This protective effect is possibly originated from the release of cytokines by the MSC, which act in order to avoid neurodegeneration in culture.74
MSC can increase autophagic process of alpha-synuclein degradation, protein which accumulation in neuronal cells is involved in PD.75 When MSC were co-culture with neuronal cells treated with MPP+ (active metabolite of the MPTP toxin), the expression of alpha-synuclein protein decreased and the number of autophagosomes LC3-II+ increased. MSC transplanted in mouse induced by MPTP through caudal vein increased the formation of autophagolysosomes and decreased the expression of alpha-synuclein, indicating that stem cells can contribute for the survival of dopaminergic neurons. In 2014, Capitelli and colleagues used rat model with PD induced by MPTP. They introduced mononuclear cells and bone narrow MSC into the jugular vein as a cell therapy. While mononuclear cells did not cause any benefit, but accelerated the degeneration process of dopaminergic neurons, bmMSC prevented it. This emphasizes the important role of MSC in the prevention of PD.76
Other approaches of MSC in PD include the qualitatively or quantitatively modification of secretome, and their use as carrier of therapeutic substances or even as vector for the transfer of gene fragments to dopaminergic neurons of the basal nuclei.77–79 On the basis of the beneficial effect of the BDNF neurotrophic factor on dopaminergic neurons,80–82 the production of BDNF was increased by bmMSC using genetic engineering. BmMSC were injected on striatum 1 day after the intranigral administration of LPS on rats. In immunohistochemical analysis, it was observed that such MSCs superproducing BNDF protected and regenerated dopaminergic pathways of striatum in situ. However, the nigrostriatal pathway was not fully protected or regenerated.82,83 Mei and Niu used similar methodology, but different results were obtained. They transformed bmMSC into cDNA vectors of conserved dopamine neurotrophic factor (CDNF), which therapeutic effects on dopaminergic neurons have already been described.84 One week after, intrastriatal injection of bmMSC-CDNF, 6-OHDA was infused on rats. The animals treated with these modified MSC (bmMSC-CDNF) had behavioral improvement and more TH+ neurons in nigrostriatal pathway than the control group, which just received undifferentiated bmMSC.83
Schwerk and colleagues used adMSC and got superior results than Hoban82, Mei and Niu.83 AdMSC have late senescence and higher basal rate of neurotrophin secretion than bmMSC, possibly being more efficient in the treatment of neurodegenerative diseases.30,78,85 Schwerk and collaborators injected human adMSC into the substantia nigra of 6-OHDA-injured rats 7 days before. The effects of this cell therapy were assessed 6 months after transplantation. AdMSC promoted cognitive improvements in treated animals, increased the number of dopaminergic neurons in the substantia nigra, interrupted the neuroinflammation, and stimulated subventricular and hippocampal neurogenesis. However, there was no improvement in the motor behavior.78 This suggests that adMSC may be therapeutically more efficient in nonmotor PD symptoms, while bmMSC may be more efficient in motor PD symptoms.
In the same year, Riecke et al86 published a meta-analysis assessing the role of MSCs therapy on behavioral outcomes in animal models of PD. In this work, a systematic search in the literature was performed and 25 studies were included for analysis. PD models were performed on mice or rats by 6-OHDA, MPTP, MG-132, or rotenone induction. In addition, the routes of cell administration were intravenous, intranasal or intrastriatal and the doses of MSCs ranged for each study. After analyzing the data, significant improvement in the behavioral outcomes of animal models of PD was observed. Through the use of meta-regression, it was also possible to conclude that higher doses of MSCs and intravenous administration had greater beneficial effect when considering the limb function tests. The results of this study reaffirm the therapeutic potential of MSCs for PD. In addition, they suggest that the intravenous route is effective, and the intracranial administration more invasive, may not be necessary for cell therapy involving MSCs and PD.
In a different study, Jinfeng et al87 used ucMSC. These MSC were administered over PC12 cells usually used as cellular model for PD. Human ucMSC were previously activated by curcumin—pigment extracted from Curcuma longa, which has anti-inflammatory and anti-apoptotic activity.28,88 PC12 cells were previously incubated with MPP+ for 24 hours. After the administration of ucMSC, the supernatant of PC12 cells had a lower amount of proinflammatory cytokines and NO, but more differentiated dopaminergic neurons, compared with control group—more DAT (dopamine transporter) protein expression, MAP-2, and TH were observed. These results suggest that curcumin-activated ucMSC have neuroprotective effect and induce neuronal differentiation in PC12 and possibly over dopaminergic neurons of basal nuclei of parkinsonian individuals.
Yao et al89 analyzed the therapeutic potential of MSC from another perspective: being enhancers of the regenerative power of neural stem cells (NSCs).90 NSCs can be found in several brain regions and offer a promise for future cell therapies in neurodegenerative conditions and central nervous system damage due to their potential for differentiation.89,91,92 In order to assess the enhancing effect, NSCs from rats were co-cultured in medium containing compounds of MSC secretome from rats, called conditioned medium. Neural stem cells in conditioned medium (NSCs-CM) were transplanted to injured areas, in rats, 28 days after receiving 6-OHDA injection in the medial forebrain and ventral tegmental area. NSCs-CM-treated rats had substantial improvement in motor behavior and spatial learning ability eight weeks post-transplantation, compared to control group. Nevertheless, immunocytochemical and immunohistochemical markings revealed that NSC-CMs survived and differentiated much more in dopaminergic neurons. In addition, these neurons spread throughout the injured regions between medial forebrain and ventral tegmental area and were integrated to them—it explains the motor and cognitive improvements of NSCs-CM treated rats.89
In human beings, the standard treatment to PD is dopamine replacement therapy (L-DOPA or levodopa), which has undesirable effects and the limitation of not delaying the progression of dopaminergic neuronal loss in the substantia nigra. In search for the regeneration of dopaminergic neurons, the encouraging results obtained from the treatment of experimental PD models using mesenchymal stem cells opened the possibility of using this approach in humans.93 Indeed, some clinical trials involving the use of MSCs for the treatment of PD have been developed, but none have shown results so far (Table 1).
In a pioneering study conducted in 2010, MSC were transplanted in human patients with PD in a study of Venkataramana and colleagues. The individuals received 1 million of autologous bone marrow stem cells per kilogram of body weight in the sub-lateral ventricular area through stereotaxic surgery. They were followed up for a period of 10 to 36 months and clinical improvement of PD was observed in 3 of 7 individuals, evaluated through classification scale of this disease and quality of life assessment scores [Unified Parkinson Disease Rating Scale—UPDRS, Hoehn and Yahr (H&Y) score, and Schwab and England (S&E) score]. No serious adverse events have been demonstrated. This study was important to encourage the possible therapeutic use of MSC in PD, boosting new researches in this area.94
Two years later, the same author designed a pilot clinical study to determine the safety, feasibility and efficacy of allogenic adult bmMSCs in PD patients. MSCs were obtained from healthy donors, expanded in culture and transplanted at a dose of 2 million cells/kg body weight, into the subventricular zone of patients, who were followed up for 12 months. The results showed improvements in the UPDRS scores of PD patients with no increase in medications during the follow-up period. Besides, they observed that patients in the early stage of PD showed more improvement and no further disease progression than the later stages. It reinforces the idea that bmMSCs transplantation in the early stages of PD has the potential to prevent further progress of the disease. The author pointed out that bmMSCs may be used as therapeutic strategy in the treatment of PD, although more studies must be conducted in order to clarify the long-term safety and sustainability of this treatment, as well the mechanisms of action of these cells in PD patients.94
The establishment of MSC therapy in clinical applications for PD must overcome important challenges before becomes a therapeutic reality, such as issues concerning cell culture conditions, number of cells for transplantation and the better source of MSCs to be clinically used. The success of MSC therapy for PD also involves the standardization of the better route of administration of the cells, patient identification likely to respond to cellular therapy, parameters for cell preparation and delivery to guarantee optimal graft survival, and mechanisms for limiting the immunologic responses to transplanted cells. In conclusion, additional basic and clinical studies will provide further information concerning these issues, contributing to the success of a future MSC therapy for PD.93
Despite the promising results observed over the years of research, there are still challenges to be overcome for the therapeutic use of MSC, such as finding the most adequate source from which good numbers of cells can be obtained and establishing the best in vitro conditions for the preservation and improvement of all therapeutic properties of these cells.95,96 In any case, studies involving MSC and PD lead to the conclusion that these cells may become usual treatment in the near future. The differentiation competence into various types of neurons demonstrates that MSC can replace dead cells not only in basal nuclei and nigrostriatal pathway, but also in other regions of the parenchyma which degeneration leads to the cognitive and psychiatric symptoms of PD. In contrast, the low immunogenicity and tumorigenicity of MSC reduce possible side effects. As for the secretome, immunomodulatory cytokines and neurotrophic factors reduce neuroinflammation and provide an environment conducive to the survival of the remaining dopaminergic neurons, as well as transdifferentiation of MSC in new neurons. In addition, the migratory capacity of MSC (homing) allows them to be administrated by noninvasive routes or even used as delivery vehicle for molecules of interest. MSC may also have a supporting role in a gene or cell therapy model for PD, enhancing the survival and benefits of other transplanted cells. Consequently, it is reasonable to believe that once the positive results of years of animal experimentation have been widely replicated in humans, MSC may fairly replace (or supplement) current treatments for PD.
The authors thank FAPEMIG (Fundação de Apoio a Pesquisa do Estado de Minas Gerais) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), agencies of the Minas Gerais State and Brazilian government, for granting MsC fellowships to D.M.F. to P.d.C.R., and D.R.M.d.P., for granting PhD fellowship to T.S.F.d.A., postdoctoral (PNPD/CAPES) fellowship to V.C., and for a financial support grant (PNPD/CAPES-2011-2016) to V.J.D.d.S. The authors also thank CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) for financial support grants (no. 309521/2013-0 and no. 467129/2014-2) to V.J.D.d.S. and to Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa (INCT-REGENERA, Grant no. 465656/2014-5). The authors would also like to thank Rafael Destro Rosa Tiveron for helping in English language translation.
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