|Cancer||Cell death||Cell cycle||Cytoskeleton||Exo/endocytosis||Differentiation||Division||Organelles||Signalling||Stem cells||Trafficking|
Can mesenchymal stem cells reduce vulnerability of dopaminergic neurons in the substantia nigra to oxidative insult in individuals at risk to Parkinson's disease?
Indrani Datta1 and Ramesh Bhonde
Manipal Institute of Regenerative Medicine, Constituent Institute of Manipal University, Bangalore, Karnataka, India
PD (Parkinson's disease) is characterized by the selective loss of DA (dopaminergic) neurons in the substantia nigra of the midbrain region, but not in the ventral tegmental area and other catecholaminergic cell group areas. The aetiology of PD is attributed both to environmental and genetic causes, and certain population of individuals may be classified as at risk of developing PD later in life. However, there are as yet no therapy regimens that can help to delay or prevent the onset of the disease to realize long-term benefits from this early diagnosis. In PD, a vicious cycle gets initiated in the substantia nigra, because of which susceptible neurons continue to degenerate whereas damaged neurons do not get enough support for regeneration. This happens primarily because of the local environment of oxidative damage brought about by the dual presence of dopamine and high levels of iron, decline in cellular detoxification systems and low density of glial cells surrounding the DA neurons in the mesencephalic region. To enhance the defence mechanism of the substantia nigra in this situation, it is necessary to combat the oxidative insult while providing trophic factors for the survival and regeneration of the damaged neurons. In light of in vitro and in vivo studies, MSCs (mesenchymal stem cells) as candidates for cell-based therapies in PD have greater scope than as mere replacement of cell type, since they can be used as a cellular system for the detoxification of ROS (reactive oxygen species) as well as a supplier of neurotrophic factors to modulate the local environment. Building on progress in unravelling the multipronged effect of MSCs, we therefore hypothesize that MSCs could be used as a prophylactic strategy to delay or prevent the onset of PD in at-risk individuals, and to slow down the progression of the disease.
Key words: at risk to Parkinson's disease, cellular system for detoxification, mesenchymal stem cells, neurotrophic factors, oxidative insult, prophylactic basis
Abbreviations: BDNF, brain-derived neurotrophic factor, bFGF, basic fibroblast growth factor, DA, dopaminergic, GPx, glutathione peroxidase, MAPK, mitogen-activated protein kinase, MSC, mesenchymal stem cell, NGF, nerve growth factor, PD, Parkinson's disease, RNS, reactive nitrogen species, ROS, reactive oxygen species, SOD, superoxide dismutase, VEGF, vascular endothelial growth factor
1To whom correspondence should be addressed (email email@example.com).
PD (Parkinson's disease) is a debilitating neurodegenerative disorder characterized by selective loss of DA (dopaminergic) neurons in the substantia nigra of the midbrain region and not in the ventral tegmental area and other catecholaminergic cell group areas. Although the aetiology of PD remains elusive, pre-disposing factors for this disease can be both genetic and environmental. Toxic gases (carbon monoxide), certain diuretics (e.g. reserpine), the antimalarial drug mefloquine, antipsychotics (e.g. chlorpromazine), calcium channel blockers (e.g. verapamil), industrial herbicides and pesticides and neurotoxins [e.g. MTPT (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine)] have all been implicated in causing or aggravating PD symptoms (Langston and Ballard, 1984; Jaeckle and Nasrallah, 1985; Pedrell et al., 1995; Hellenbrand et al., 1996; Ritz and Yuc, 2000; Dow et al., 2006; Fernandes et al., 2008; Weiden, 2008). Several studies have also indicated that transition metals such as iron, manganese, cadmium, copper and mercury can significantly increase the risk of developing PD (Youdim et al., 1993; Shukla et al., 1996; Gorell et al., 1999; Jomova et al., 2010; Rivera-Mancía et al., 2011). Besides these, external stressors such as head trauma may also contribute to development of the disease (Morano et al., 1994; Tsai et al., 2002; Bower et al., 2003). These findings suggest that certain individuals, such as defence personnel and others who are exposed to toxic chemical insults and war-like conditions, might be at a higher risk of developing PD (Schlldte et al., 1996; Nevin et al., 2008; Schwingenschuh et al., 2010).
The cellular dysfunctions that play key roles in the pathogenesis of PD are: oxidative stress, mitochondrial respiration defect and abnormal protein aggregation (Dauer and Przedborski, 2003; Nakamura et al., 2011). ROS (reactive oxygen species; H2O2, superoxide, hydroxyl radical or singlet oxygen) responsible for oxidative stress can neither be directly measured in living patients nor in post-mortem tissues because of its short half-life, but several indirect indices of ROS activity in Parkinsonian post-mortem brain are available to support the role of oxidative stress in this disease condition, such as increased membrane peroxidation as indicated by elevated levels of TBA (thiobarbituric acid)-reactive substance, and ROS-mediated DNA damage as observed by increased levels of 8-hydroxy-2 deoxyguanosine levels in the substantia nigra (Sanchez-Ramos et al., 1994; Foley and Riederer, 2000). In DA cells, ROS generation occurs by deamination of dopamine by MAO (monoamine oxidase), resulting in significant yields of H2O2 which can further interact with the reduced forms of transition metal ions such as iron, and decompose to the highly reactive hydroxyl radical (•OH). Post-mortem analysis has reported significantly higher concentration of iron selectively in the substantia nigra region in the brain of PD patients in comparison with control (Dexter et al., 1989; Gerlach et al., 1994; Griffiths et al., 1999). The DA neurons in the substantia nigra are thus particularly vulnerable to oxidative damage as compared with other neuronal cells because of the dual presence of dopamine and high levels of iron.
To further compound the problem, the counter-balancing cellular detoxification system in this region does not get automatically enhanced to cater to the increased production of ROS. PD usually affects older individuals in whom the activity of cellular detoxification enzymes such as SOD (superoxide dismutase) and GPx (glutathione peroxidase) has started naturally declining with age (Venkateshappa et al., 2012). A decrease in glutathione (the reduced form of GPx) levels is reported in the substantia nigra region, thereby indicating a relative reduction in activity of GPx in this region (Perry et al., 1982; Sian et al., 1994). This depletion of glutathione levels can not only result in decreased activity of mitochondrial complex 1 leading to mitochondrial respiration defect (Cleeter et al., 1992; Heales et al., 1995; Seaton et al., 1996) but also in increased formation of hydroxyl radicals by preventing the inactivation of H2O2 (Jenner et al., 1992). Reports also suggest that the levels of the other detoxifying enzyme catalase in substantia nigra is unaltered or slightly decreased (Ambani et al., 1975; Venkateshappa et al., 2012). Taken together, these reports suggest that the activity of cellular defences in the substantia nigra against oxidative stress is insufficient in PD.
The selective degeneration of DA neurons in the midbrain region can also be attributed to the lack of pro-survival/trophic factors in this region. It is known that astrocytes in the brain play a neuroprotective role by secreting diffusible factors [such as BDNF (brain-derived neurotrophic factor), GDNF (glial cell-derived neurotrophic factor), bFGF (basic fibroblast growth factor) and GPx], thereby attenuating the neurotoxicity for DA neurons in PD (Pascual et al., 2008; Peterson and Nutt, 2008). This protective effect again differs within the mesencephalon region because the glial cells are heterogeneously distributed in this area, with the density of astrocytes being lowest in the region of the brain where DA neurons degenerate in PD namely, substantia nigra pars compacta, and highest in the brain regions where DA neurons are preserved namely, ventral tegmental area and the catecholaminergic cell group areas (Damier et al., 1993). It has also been reported that the levels of BDNF and bFGF are decreased in the substantia nigra in PD (Igarashi et al., 1993; Mogi et al., 1999). All this suggests that DA neurons in the substantia nigra region are surrounded by a low density of glial cells, making them preferentially prone to degeneration in PD (Figures 1 and 2).
Figure 1 is a schematic representation of neurons and astrocytes present in substantia nigra region (Figure 1A) and ventral tegmentum and the catecholaminergic cell group areas (Figure 1B). Intrinsic factors such as the presence of dopamine and high iron content make the DA neurons (red) more vulnerable to oxidative stress than other neurons (blue). In addition, DA neurons in the substantia nigra region (Figure 1A) are surrounded by a low density of glial cells (green) unlike in the ventral tegmentum area and the catecholaminergic cell group areas (Figure 1B). Figure 2(A) illustrates the situation of oxidative damage, and shows that exposure to extrinsic toxic chemicals and gases can lead to an increase in oxidative insult (red circles) in brain. In such a scenario, due to their intrinsic features and the lack of pro-survival factors and detoxification agents, the DA neurons (red) of the substantia nigra preferentially fall prey to oxidative insult unlike the other neurons (blue), leading to cell death.
2. MSCs (mesenchymal stem cells) in neurodegenerative disease and other conditions
MSCs are a population of multipotent stromal cells residing in various tissue sources. They have been preferred to other stem cells for therapeutic applications because of their self-renewal ability, multiple differentiation potential and immunomodulatory properties (Pittenger et al., 1999; Le Blanc, 2003; Tse et al., 2003; Keyser et al., 2007). In addition, their adhesion properties, migrating capabilty and homoeostasis under physiological conditions further augment the fundamental pathways and play an important role in regenerative therapies (Docheva et al., 2007; Meirelles et al., 2008; Chamberlain et al., 2007). Several pre-clinical and clinical studies have also shown that the delivery of MSCs is safe and does not initiate any immunogenic effects (Pal et al., 2009; Lee et al., 2010; Venkataramana et al., 2010; Xiong et al., 2010; Prasad et al., 2011). MSCs are already in clinical trials for the treatment of stroke, limb ischaemia, graft-versus-host disease, meniscus injury and autoimmune disorders in the USA under FDA approval. There are also several reports suggesting the use of BM-MSCs for various other debilitating diseases such as post-infarcted myocardium, chronic heart failure, bone defects, Crohn's disease and diabetes (Siddappa et al., 2007; Schafer and Northoff, 2008; Grauss et al., 2008; Lanzoni et al., 2008; Urban et al., 2008). A study reported secretion of angiogenic cytokines in MSC conditioned medium which in turn stimulated endothelial cell proliferation and migration in vitro (Kinnaird et al., 2004). Similarly a regeneration of blood flow was observed in murine hindlimb ischaemia model and cardiac infarction model after infusion of MSC-conditioned media (Kinnaird et al., 2004; Gnecchi et al. 2006). In neurodegenerative conditions, the partial beneficial effect of MSCs has been reported from animal-model studies, though the underlying mechanism of these therapeutic effects is still unclear (Park et al., 2008; Blandini et al., 2010). The usual way by which MSCs are known to possess neurogenic potential is by replacement of specific cell types (Nagai et al., 2007; Shetty et al., 2009; Li et al., 2011); however, certain recent in vitro and in vivo studies indicate that the MSCs can synthesize active biomolecules and neurotrophic factors that can combat oxidative stress, support neural cell survival, induce endogenous cell proliferation and promote axonal repair (Chen et al., 2006; Crigler et al., 2006; Lanza et al., 2009; Wilkins et al., 2009; Cova et al., 2010; Kemp et al., 2010). In fact the functional recovery reported in neurodegenerative disease models after MSC transplantation is supported by studies showing beneficial effects at the cellular level with respect to endogenous neuronal growth, decrease in apoptosis and inflammation (Dasari et al., 2007; Kassis et al., 2008; Vercelli et al., 2008). Endogenous proliferative effect of BM-MSC transplantation has been reported on neural stem cells in the hippocampus of immunodeficient mice (Munoz et al., 2005). Furthermore, a study in an experimental allergic encephalomyelitis rodent model of multiple sclerosis has shown that nearly twice the number of axons survived in post intraventricular transplantation of MSCs than in the control group (Kassis et al., 2008). MSCs thus have the capacity to modify the damaged tissue microenvironment to provide neuroprotection and regeneration, which further widens the potential scope of their usage in therapeutics, both in curative and prophylactic modes, by helping to attenuate the disease progression and lessening the pre-disposition to the disease.
3. MSCs and oxidative stress
Chen et al. (2006) have showed that MSCs are resistant to ionizing radiation, indicating that they possess a better antioxidant ROS-scavenging capacity and active double-strand break repair. Recent in vitro work by Valle-Prieto and Conget (2010) has depicted that MSCs indeed have the ability to scavenge ROS and RNS (reactive nitrogen species) and efficiently manage oxidative stress. Additional studies both in vivo and in vitro (Kim et al., 2008; Iyer et al., 2010; Chen et al., 2011; Zhuo et al., 2011) indicate that MSCs exert neuroprotective effects against ROS by secreting antioxidant molecules. This feature of MSCs could be harnessed as an important contribution of MSC therapy to prevent and/or slow the progression of PD. Lanza et al. (2009) have demonstrated that the levels of cellular antioxidant molecules (metallothionines, SOD and catalase) increased in the neural cells after an oxidative insult (H2O2) and that it was successfully reversed by MSCs. A report on endotoxin-induced inflammation in a murine model, has shown improved plasma cysteine and GSH (glutathione) redox indices upon infusion of bone marrow MSCs (Iyer et al., 2010). Kemp et al. (2010) have clearly shown that MSCs secrete the antioxidant molecule SOD3, which in turn is capable of scavenging superoxide in the extracellular space (Estévez et al., 1998) thus limiting the formation of hydroxyl radicals and peroxynitrite. In neurodegenerative conditions, oxidative stress can also be initiated by increased levels of NO that would in turn lead to apoptosis of neuronal cells (Wang et al., 2003; Nozik-Grayck et al., 2005). In vitro models have shown that these effects are primarily mediated by p38 MAPK (mitogen-activated protein kinase) pathway (Wilkins and Compston, 2005). As reported by Kemp et al. (2010), MSCs can render a neuroprotective role here too by acting as an antioxidant by modulating the PI3K (phosphoinositide 3-kinase)/Akt (also known as protein kinase B) and MAPK pathways.
4. Paracrine effects of MSCs
Besides this antioxidant effect, MSCs are known to secrete several growth factors and cytokines including VEGF (vascular endothelial growth factor), bFGF, BDNF, NGF (nerve growth factor), HGF (hepatocyte growth factor), SDF (stromal cell-derived factor) and PDGF (platelet-derived growth factor), all of which can act as pro-survival factors for cells undergoing neurotoxicity (Hamano et al., 2000; Chen et al., 2002; Kurozumi et al., 2005; Crigler et al., 2006; Lanza et al., 2009; Wilkins et al., 2009). Wang et al. (2010) have reported that intravenous administration of MSCs exerts therapeutic effects on Parkinsonian rats, focusing on neuroprotective effects of stromal-derived factor-1α. A very recent in vitro study by Whone et al. (2012) has shown that human BM-MSCs bring about neuroprotection of catecholaminergic and serotonergic neuronal cells against oxidative stress by secretion of glial-derived neurotrophic factor. A report from an in vivo mouse model of PD too shows improvement of motor function along with the expression of growth factors such as NGF, VEGF, IL-6 (interleukin-6) and neuronal markers such as nestin and tyrosine hydroxylase at the site of MSC transplantation (Kang et al., 2011). We thus conclude that MSCs possess the capacity not only to combat ROS but also to provide pro-survival factors to the damaged neurons, thus gearing the shift of a neurotoxic environment in this region to a neuroprotective one.
5. The hypothesis
It is widely known that the aetiology of PD is attributed both to environmental and genetic causes, and based on these factors, certain individuals may be classified as at risk of developing PD later in life (Bras and Singleton, 2009; Koller, 1992; Di Paola and Uitti, 1996; Giladi et al., 2011). However, the long-term benefit of this early diagnosis can only be realized through a prophylactic therapy regimen that can help to delay or prevent the onset of the disease. Currently, in the absence of disease-modifying avenues of therapy, the only course available is to wait for symptoms of full-blown PD to develop (often years later) and then treat the condition with increasing doses of dopamine. There are yet no strategies that can delay, postpone or prevent the occurrence of the disease. Once the onset of the disease occurs, a vicious cycle gets initiated because of which the specialized DA neurons in the substantia nigra continue to degenerate whereas damaged neurons do not get enough support for regeneration. Pharmacological replenishment of dopamine does not help in halting the disease progression, and in fact compounds the situation because increasing dopamine dosage leads to enhanced generation of ROS by the autoxidation of dopamine, thus perpetuating and worsening the vicious cycle.
From the above, it appears that it should be at least theoretically possible to prevent or delay the onset of PD if an effective preventive regimen that can combat the hostile environment and aid the specialized neurons with pro-survival factors is instituted at the appropriate juncture. The alternative approach of treatment for these diseases is through cell-based therapies that are conventionally viewed solely from the point of cell replacement. Again, this strategy does not modify the neurotoxic environment to disrupt the vicious cycle initiated by ROS and heal the damaged neurons – in fact, the replacement cells themselves land in a toxic environment. The disease progression may be modified only if a prophylactic regimen is initiated for combating the oxidative stress and providing nutrient supply in at-risk individuals before the full-blown onset of the disease occurs. MSCs as candidates for cell-based therapies have a greater scope in this regard than as mere replacement of cell type, because they can modulate the environment through their secretory trophic factors and antioxidants. We therefore hypothesize that MSCs can be used as a cellular system for the detoxification of ROS and supplier of neurotrophic factors in at-risk individuals to PD on a prophylactic basis. The presence of MSCs in the environment may reduce the vulnerability of the DA neurons of the substantia nigra by cleaning up the toxic environment and providing nutrients for repair and regeneration of damaged cells without causing any immune reaction, which is schematically represented in Figure 2(B).
6. Testing of the hypothesis
Although the major individual elements of the hypothesis – the oxidative insult scenario in PD, the antioxidant properties and the neuroprotective effects of MSCs – have been individually validated by several studies, the combined efficacy of the clinical approach described still needs further authentication. The use and efficacy of stem cells in prophylaxis remains largely untested, and a detailed risk-benefit assessment of the prophylactic procedure suggested here needs to be carried out, first in animal models and subsequently, after exhaustive preclinical studies, in human patients at different stages of PD. Although the administration of MSCs is known to be relatively low-risk owing to their hypoimmunogenic profile, it still calls for invasive surgical procedures. Delivery protocols may also need to be critically examined and modified if needed to ensure the optimal delivery of MSCs to the critical brain areas of interest.
A more difficult part involves the assessment and identification of patient populations at risk to PD. The aetiology of PD can be attributed both to genetic and environmental causes. Several gene mutations have been identified for the familial cases of PD, such as PARK 1–10 (reviewed by Fahn and Sulzer, 2004). Similarly, several studies suggest that exposure to certain toxic chemicals, external stressors such as head trauma, transition metals and drugs can aggravate the condition of PD (Langston and Ballard, 1984; Youdim et al., 1993; Morano et al., 1994; Pedrell et al., 1995; Shukla et al., 1996; Ritz and Yuc, 2000; Dow et al., 2006; Weiden, 2008). This leads us to conclude that there are certain population groups across the world who are pre-disposed to PD and that there could be room for a preventive approach to this disease. Although various genetic and environmental risk factors have been identified, an accurate quantification of the risk of developing PD is needed to evaluate the risk-benefit of the regimen proposed. This will require a far deeper understanding of the disease progression than is available currently, along with much better-defined, more effective biomarkers and electrophysiological monitoring procedures to aid in the early diagnosis and tracking of the disease. Understanding the exact nature and extent of toxic exposures and the sequence of neurological events afterwards leading to the incidence of disease is essential if we are to develop an effective prophylactic regimen that can be implemented in at-risk populations.
PD is the second most common neurodegenerative disease after Alzheimer's disease and studies from the USA and India have indicated that the prevalence of this disease is growing (Lilienfeld and Perl, 1993; De Rijk et al., 1997; Gourie Devi, 2008). For neurodegenerative diseases, the major challenge is not only to halt the process of degeneration but also to delay or prevent the onset of such diseases. In the case of PD both familial and sporadic, the major cause for the degeneration of the specialized neurons is known to be oxidative stress or ROS. Pharmacological agents available can only replenish dopamine or lessen the degradation of dopamine but fail to address this root cause. Cell-based therapies, too, have been mainly focused on the replacement of specialized neurons. Partial beneficial effects are reported for transplantation of foetal mesencephalic tissues, but it has several side effects such as graft-versus-host disease, graft-induced dyskinesias, emergence of Lewy bodies in the grafted cells and immune response against the graft (Kordower et al., 2008; Li et al., 2008). Embryonic stem cells and IPS (induced pluripotent stem) cells have been known to form teratomas and are likely to elicit immune rejection in transplantation (Swijnenburg et al., 2008a, 2008b; Preynat-Seauve et al., 2009), besides invoking ethical dilemmas. MSCs are known to be the best candidates for cell transplantation for their unique characteristics and certain recent in vitro and in vivo studies indicate that the MSCs can provide neuroprotection as agents to combat oxidative stress and provide trophic factors. Thus, their therapeutic potential will be best harnessed if they are used as both curative and prophylactic agents by helping to attenuate the disease process and lessening the pre-disposition to the disease. The protection of at-risk individuals from developing full-blown PD is definitely an important milestone in combating neurodegenerative diseases, and this in turn would help in sustaining and enhancing the health and performance of such individuals. This hypothesis may provide new support for the banking of autologous MSCs and their use in the future, in successful efficient solutions for PD.
MSC therapy is suggested as being likely to reduce the risk of PD in individuals at higher risk of developing PD. The basis for this hypothesis lies in the fact that MSCs can act as a cellular system of detoxification of ROS and as provider of neurotrophic factors. Investigating this approach of treatment will widen the scientific scope of stem cell therapy in PD.
Current evidence suggests that it may soon be possible to define populations at increased risk to develop PD and thus to target the ‘pre-clinical’ phase of PD for neuroprotection. Functional imaging studies have already detected sub-clinical nigral DA dysfunction in individuals at risk of developing PD. More detailed future trials will test the proposed intervention for its ability to prevent or retard the development of clinically overt PD in at-risk individuals.
The initial hypothesis was conceived by Indrani Datta. There were subsequent discussions with Ramesh Bhonde for further refinement of the hypothesis. The paper and Figures were drafted by Indrani Datta with additional input from Ramesh Bhonde. Both of the authors read and approved the final paper.
We gratefully acknowledge the Vice-Chancellor and Registrar of MU for their support. We are also grateful to Mr A Datta for his valuable comments and suggestions.
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Received 15 November 2011/2 February 2012; accepted 14 March 2012
Published as Cell Biology International Immediate Publication 14 March 2012, doi:10.1042/CBI20110602
© The Author(s) Journal compilation © 2012 International Federation for Cell Biology
ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
Published by Portland Press Limited on behalf of the International Federation for Cell Biology (IFCB)
Figure 1 Represents neurons and astrocytes present in substantia nigra region (A) and ventral tegmentum and the catecholaminergic cell group areas (B)