Modulation of stem cells or dopaminergic (DA) cells with combined cellular transplantation in PD (adopted from “Potential of Neural Stem Cell-Based Therapy for Parkinson’s Disease” ).
Neural stem cell (NSC)-based therapies, such as cell transplantation, are an emerging strategy for restoring neuronal function in Parkinson’s disease (PD), which is characterized by a profound and selective loss of nigrostriatal dopaminergic (DA) neurons. Advanced researches on the microenvironment of grafted cells will promote clinical applications of NSCs for neurological disorders. A novel cell culture model of the neurovascular network was therefore devised to investigate autocrine, paracrine, and juxtacrine signaling in the neurovascular unit generated by NSCs and vascular endothelial cells. Preclinical studies using cutting-edge technologies, including cellular reprogramming, advancement in scaffolds for brain tissue engineering, image-guided injection, and noninvasive monitoring of tissue regeneration will pave the way for successful clinical trials of NSC-based therapies for PD. Once the implanted or regenerated DA neurons are integrated into the existing nigrostriatal DA pathway, the symptoms of PD can potentially be alleviated by reversing characteristic neurodegeneration.
- neural stem cell
- Parkinson’s disease
- endothelial cell
- neurovascular unit
- regenerative medicine
- tissue engineering
- cell transplantation
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and its prevalence reaches 0.3% of the entire population in industrialized countries . PD prevalence is increasing with age, affecting 1% of the population above 60 years and 4% in those aged over 80 . Since the clinical trial of neural stem cell (NSC) transplantation therapy has shown promising results for stroke patients , the NSC-based therapy could be a potential treatment for restoring neuronal function for PD patients. A better understanding of pathophysiology of PD, establishment of valid and effective NSC lines, and successful clinical trials will point to a novel neuroregeneration strategy to complement current medical treatment and deep brain stimulation.
Advances in the pathophysiology of PD have expanded our traditional knowledge that it is characterized by a profound and selective loss of nigrostriatal dopaminergic (DA) neurons. PD could be considered a developmental disorder with evidence beyond neurodegeneration, regarding relationships among deregulated neurogenesis, disease onset, and its progression. The numbers of proliferating NSCs, for instance, have been found decreased in the PD-affected postmortem brain [4, 5], but evidence of a link between altered proliferation of NSCs, functional DA neurons, and neurological deficits remains insufficient. Besides typical motor symptoms, including asymmetrical bradykinesia, rigidity, postural instability, and resting tremors, patients may have nonmotor symptoms, such as dementia, sleep disturbance, and autonomic dysfunction. Hence, public health education and routine physical examinations are substantial for early diagnosis and intervention.
NSCs preserve the ability to self-renew and differentiate into all neural lineage cells, and they are regarded as a potential graft for cellular transplantation. Reducing the possibility of tumorigenesis has to be considered during immortalization of NSC lines which provide a consistency of cell grafting. Furthermore, preclinical studies, such as transcranial injection of NSCs into animal brains with adequate follow-ups, will prove the validity of its clinical application.
Independent ethical and regulatory approval, full financial support from the foundation, and long-term follow-up of systematically collected rigorous measures are the requirements for conducting clinical trials for NSC-based therapies in PD. Appropriately transparent processing with governmental approval could encourage patient cooperation according to experience from cell transplantation therapy in other diseases. In this chapter, we will provide a comprehensive literature review as well as the perspectives on NSC applications in PD.
2. Neuronal loss in Parkinson’s disease
The pathological diagnosis of PD has been possibly made since Frederic Lewy described microscopic particles in affected brains as early as 1912, later named “Lewy bodies” . The characteristic pathophysiology of PD includes death of DA neurons in the substantia nigra pars compacta (SNpc), degeneration of DA neurotransmission, and the presence of alpha-synuclein and protein inclusions in neuronal cells that are known as Lewy bodies . In general, more than 50% of DA neurons have been lost before typical symptoms of PD develop . It has been found that a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls . Additionally, nigral neuronal loss could be observed before the appearance of alpha-synuclein aggregates . A negative correlation between neuronal density and local alpha-synuclein burden in the substantia nigra was therefore evident in PD patients. Most importantly, stage-dependent nigral neuronal loss and local burden of alpha-synuclein pathological conditions are closely coupled during disease progression of PD.
The diagnosis of PD can be made through the detection of mutations in specific genes responsible for familial PD in the era of molecular biology. But only about 10% of diagnosed patients are found carrying identifiable pathological mutations, and the majority of PD cases are sporadic . Several of the PD-associated genes are related to mitochondrial dysfunction although most are of unknown or poorly understood function. Three of the genes associated with a recessive, early-onset form of the disease (
The strongest risk factor in PD is age, beyond the other three best-documented pan-cellular factors, including genetic mutations, environmental toxins, and inflammation [2, 15]. It is widely speculated that declining mitochondrial function is a key factor why age is such a strong risk factor [10, 16]. However, the pattern of neuronal pathology and cell loss in PD is difficult to explain without cell-specific factors. It has been proposed that the opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of SNc DA neurons and accordingly the increase in mitochondrial oxidant stress and susceptibility to toxins . This cell-specific stress could increase the negative consequences of pan-cellular factors. Therefore, antagonists for L-type calcium channels have been proposed to complement current attempts to boost mitochondrial function in the early stages of PD , but there is still lack of strong evidence in its therapeutic effects.
3. Neural stem cells and adult neurogenesis
In the adult mammalian brain, NSCs are largely restricted to two regions: the subependymal zone (SEZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampal formation [18, 19]. The NSC niche can be regarded as a specialized neurovascular unit (NVU) because the vasculature plays an indispensable role for maintaining the stem cell niche . The NSC niche in the adult SEZ contains an extensive planar vascular plexus with specialized properties. Within such a unique NVU, endothelial cells (ECs) exert their influence over NSCs to regulate fate specification, differentiation, quiescence, and proliferation, through direct contact and paracrine signaling . For example, a U-shaped gradient of the soluble factor, stromal cell-derived factor 1 (SDF-1), established by both ependymal and endothelial cells, helps guide SEZ quiescent NSCs moving from the ependymal niche to the endothelial niche, where they are activated . Endothelial factors, including SDF-1, therefore have differential effects on neural progenitor populations. The vessels also produce a laminin-rich extravascular basal lamina, which is organized into branched structures known as fractones, regulating NSC behaviors via direct contact . Interestingly, vascular pericytes in the central nervous system (CNS) have been found to possess the ability of differentiating into vascular and neural lineage cells , in addition to the originally defined functions of pericytes, such as controlling cerebral blood flow and limiting blood flow by constricting capillaries [24, 25].
At the interface of neural and vascular compartments in the CNS is the blood brain barrier (BBB), which is the first barrier leading to transport limitations for both cellular and acellular elements. Paul Ehrlich demonstrated the integrity of this barrier first in 1885 when he injected vital dyes into the circulatory system and observed that all organs except the brain and the spinal cord were stained . The integrity of this barrier was attributed to ECs and could be examined with an electron microscope demonstrating the tight junctions . The barrier function of endothelium is considered a hallmark feature when validating models of the BBB. It is also important to assess the barrier function while culturing ECs with other types of cells comprising the NVU in order to investigate adult neurogenesis .
The CNS endothelium is not only the inner lining of the blood vessel, but also an active participant in many signaling pathways. Brain-derived neurotrophic factor (BDNF), for instance, is one of the endothelium-secreted factors affecting the behaviors of NSCs [29, 30]. Blood capillaries may regulate NSCs through interactions via collagen IV and laminin in the basal lamina . Blood vessels also provide an access to circulate systemic factors, including glucocorticoids, sex hormones, and prolactins. The barrier properties of the BBB allow only certain molecules to cross the endothelium. The BBB is maintained when endothelium has a prevalence of tight junctions and specific transport proteins. The BBB is characterized by an organ-specific high transendothelial electrical resistance (TEER, up to 5000 ohm·cm
In the neurogenic niche of the mouse brain, the basal processes of NSCs contact the vasculature, and at these sites of contact, a modified BBB exists that lacks astrocytic endfeet and pericytic coverage . Direct physical contact between the brain capillary ECs and the NSCs reflects their intimate relationships. Juxtacrine signaling is therefore essential for devising a NVU model using ECs and NSCs. A NVU with direct contact between NSCs and ECs provides a neurovascular network, where the concentration of soluble factors recently released from nearby cells can remain high locally, and this cannot be observed using the transwell co-culture system. Furthermore, extracellular matrix (ECM) molecules produced by ECs and NSCs, which mediate cell differentiation and tissue morphogenesis, are involved in contact-dependent signaling between NSCs and ECs. The firm adhesion of cells to an ECM is indispensable to a cell culture model of three-dimensional cytoarchitecture for investigating NSCs and adult neurogenesis within a specific NVU.
4. Paracrine and juxtacrine signaling in the neurovascular unit
To devise an advanced NVU model and to promote NSC-based therapies may benefit from studies on the neurovascular development. Accumulating evidence shows that shared molecules and coordinated cellular mechanisms regulate the development of vascular and neuronal systems [35, 36]. Neurogenesis and angiogenesis are also found co-regulated in both embryonic and adult brains, as well as damaged brains. To date, most of this evidence has been obtained from
4.1. Paracrine signaling
Paracrine signaling is a form of cell-to-cell communication in which the target cell is close to the signaling cell and the secreted and diffusible signal molecule affects only nearby target cells. During CNS development, common signaling molecules guide vascular and axonal outgrowth via paracrine mechanisms, and these factors may have to be considered in NSC-based therapies in PD. For example, growth cones of axons project numerous filopodia that actively extend and retract in response to four families of extracellular guidance cues: ephrins, semaphorins, netrins, and slits . Guidance cues can be divided into attractive or repulsive signals. These cues are cell-membrane-bound acting on nearby axons or secreted forming gradients that influence the trajectories of extending axons .
4.1.1. NSC paracrine signaling to EC
The brain vascular system develops from the cephalic mesenchyme through the sprouting of capillaries into the brain parenchyma. This process is regarded primarily as angiogenesis which refers to the
VEGF is strongly expressed by NSCs in the ventricular zone. VEGF is a key signal orchestrating vascularization of the neuroectoderm . At the tips of vascular sprouts, the leading endothelial tip cells extend filopodia toward hypoxic regions where higher VEGF is produced . Tip cells react to VEGF via VEGF receptor 2 (VEGFR2) expressed on filopodia. Tip cells produce high levels of the Notch ligand delta-like 4 (Dll4) that activates Notch signaling on adjacent ECs. These ECs then differentiate into stalk cells, which form the stalk of the sprouting vessel with a lumen that allows for blood flow and tissue oxygenation . Stalk cells down-regulate expression of VEGFR2 and VEGFR3 and increase levels of the decoy receptor VEGFR1, thus becoming less sensitive to VEGF . These studies suggest that VEGF/VEGFR2 is one of the signaling pathways involved in angiogenesis and is also important for neurogenesis during CNS development.
4.1.2. EC paracrine signaling to NSC
Vascular-derived neurotrophic factors, such as BDNF, are key factors in the co-ordination of vascular and neural development . In a co-culture experiment using transwell inserts, mouse ECs released soluble factors that stimulated the self-renewal of mouse NSCs and inhibited their differentiation . Depending on the culture condition, mouse ECs may favor maintenance of the progenitor phenotype of mouse NSCs through the production of soluble factors or to promote neuronal differentiation through direct contact .
4.2. Autocrine signaling
Autocrine signaling is a form of cell signaling in which a cell secretes a substance that binds to its own surface receptors, leading to changes within the cell. Initially discovered for their role in axon guidance during vessel formation, VEGFs and their high-affinity tyrosine kinase VEGF receptors are now implicated in the development of the CNS . In embryonic mouse forebrain and embryonic cortical neurons grown
4.3. Juxtacrine signaling
Juxtacrine is a type of cell-to-cell or cell-to-ECM signaling that requires close contact. This stands in contrast to autocrine or paracrine signaling, where a signaling molecule is released and diffused into extracellular space . Cell-to-cell communication between blood vessels and glia cells in the NVU occurs primarily via intervening vascular basement membranes that contain a variety of growth factors and ECM proteins .
Juxtacrine signaling is indispensable for neuroblasts migrating along blood vessels as neuroblasts primarily interact with the ECM surrounding astrocyte endfeet in a vasophilic migration model in the mouse brain . In the SEZ neurogenic niche, NSCs differentiate into neural progenitors (NPCs) which have a limited proliferative ability and does not exhibit self-renewal. The relatively quiescent NPCs give rise to rapidly dividing transit-amplifying cells which further differentiate into neuroblasts. These neuroblasts sense microenvironmental cues and migrate tangentially from the SEZ to the olfactory bulb along rostral migratory stream (RMS).
5. Restoration of the disrupted neurovascular microenvironment by tissue and cell transplantation
Tissue regeneration or cell replacement for loss of DA neurons is a potential approach for PD. Since the late 1980s, over 300–400 PD patients worldwide have received transplants of human fetal ventral mesencephalic (VM) tissue, which is rich in postmitotic DA neurons . Two double-blind, placebo-controlled trials of VM transplants for PD patients, however, showed variable efficacy and occurrence of side effects, such as “off-medication” and “graft-induced dyskinesias” (GIDs) [59, 60]. It was observed that the PD pathologic process might propagate from host to grafted cells, and the presence of Lewy bodies in grafted neurons suggests host-to-graft disease propagation . Implanted neurons could be affected by the disease process and did not function normally. Parkinson’s pathogenesis or GIDs therefore could propagate from host to grafted cells although recipients had experienced long-term symptomatic relief with the majority of grafted cells functioning unimpaired. On the other hand, CNS involvement of graft versus host disease (GvHD) has been found as a cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT) which is administered systemically . Although transplantation of fetal tissue or stem cells was conducted transcranially instead for PD patients, the rare heterogeneous chronic CNS GvHD symptoms might happen with cerebrovascular manifestations, demyelinating disease, or immune-mediated encephalitis. GvHD could be prevented or treated with immunosuppressant such as corticosteroids, but CNS-related GvHD after allo-HSCT is associated with a poor prognosis.
GIDs could be serious side effects after transplantation of fetal VM tissue for PD patients. Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in PD have been investigated . On-medication dyskinesias are typically generalized and choreiform. In contrast, off-medication dyskinesias are usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off-medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias which are associated with partial or incomplete dopaminergic reinnervation of the striatum . The pathophysiological mechanism underlying GIDs can be partially attributed to excessive serotonergic innervation in the grafted striatum of patients who developed off-medication dyskinesias later following the initial improvement of motor symptoms after transplantation. It has been realized that the dyskinesias can be markedly attenuated by systemic administration of a serotonin [5-hydroxytryptamine (5-HT)] receptor (5-HT1A) agonist . A recent study demonstrated a mechanistic link between serotonin 5-HT6 receptor or a cyclic adenosine monophosphate (cAMP)-linked designer receptors exclusively activated by designer drugs (DREADD), intracellular cAMP, and GIDs since exclusive activation of serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs . GIDs resulting from cell therapies for PD with fetal tissue or stem cells are therefore possibly avoided and treated with serotonin receptor agonists.
The TRNSEURO (NCT01898390), a multicenter European initiative on PD transplantation using fetal VM tissue, has been conducted since 2012, in an attempt to overcome obstacles such as inconsistent methods between the previous trials . The issues on administration of immunosuppressant and anticonvulsant, the method of graft preparation, and the precise site of graft placement will be further resolved. However, heterogeneous compositions of the graft, difficulties in standardization of cellular material, and ethical concerns are limitations in these trials using fetal VM tissue. In addition, complications associated with procedures of transplantation, such as subdural hematoma, have to be prevented .
NSCs preserve the ability to self-renew and differentiate into all neural lineage cells, including neurons, astrocytes, and oligodendrocytes, and they are therefore a source of potential graft for cellular transplantation in neurological disorders. Together with ECs and pericytes, NSC can constitute the functional NVU for tissue restoration in PD. Since neurons are integrated into the neurovascular network with other cellular and acellular compositions in the NVU, combined transplantation of NSCs with other types of cells or biomaterials may be more efficacious for tissue replacement. Local factors within the microenvironment of transplanted NSCs affect the fate of the cells, as measured by survival, proliferation, differentiation, and neurogenesis . Several groups have studied modulation of stem cells or DA cells with combined cellular transplantation in animal models of PD (Table 1) . Besides the attempt to replace damaged tissues, it was shown that grafted cells may promote endogenous vasculogenesis and neurogenesis in the neighboring tissues .
|Type of transplanted cells||Animal model||Significance||Ref.|
|Mouse fetal DA neurons||Mouse mesencephalic NSCs overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs)||6-OHDA rat||Apomorphine-induced rotation was reduced by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress GDNF, which supports differentiation into DA cells and their survival.|||
|Human embryonic NSC||Macaque autologous Schwann cells (SCs)||6-OHDA macaque||Gomez-Mancilla dyskinesia score in the group of co-transplantation with SCs and NSCs was significantly lower than the control group. SCs harvested from the autologous peripheral nerves can avoid rejection.|||
|Human umbilical cord-derived MSCs||Human dermal fibroblasts||MPTP rat||Fibroblasts may be common cell contaminants affecting purity of MSC preparations and clinical outcome in stem cell therapy protocols.|||
|Rat embryonic DA neurons||Rat Schwann cells (SCs) overexpressing basic fibroblast growth factor (FGF-2)||6-OHDA rat||Co-transplantation of DA neurons and FGF-2 overexpressing SCs differentially affects survival and reinnervation. Behavioral recovery underlines the necessity of direct contact between FGF-2 and DA neurons.|||
To administer cell transplantation therapies, NSCs can be delivered transcranially through the needle into deep targets, such as putamen for PD. This approach minimizes the problem that BBB could be a barrier preventing intravascularly transplanted cells from crossing the vessel wall into brain tissue . It has been proposed that 100,000 surviving DA neurons per putamen is the minimum required for a successful outcome following intracranial transplantation . Bilateral injection targeting putamen is favored more than unilateral transplantation although there seems to be no consensus yet.
It is reasonable to optimize the microenvironment surrounding the transplanted NSCs or DA neurons in order to support differentiation into DA cells and their survival
6. Application of stem cells in Parkinson’s disease
Technically DA neurons could be derived from embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), umbilical cord blood hematopoietic stem cells (HSCs), and induced-pluripotent stem cells (iPSCs) generated from adult somatic cells, as well as directly from NSCs . Several factors including the long-term survival and phenotype stability of stem cell-derived neurons or glial cells in the graft following transplantation, the purity of populations of cells derived from NSCs, and safety issues related to the risk of tumorigenesis have to be evaluated in greater depth . An appropriate cell culture model for investigating, paracrine, autocrine, and juxtacrine signaling pathways within the neurovascular environment can provide a platform for characterizing cells with various origins and for selecting the optimal cells for transplantation .
NSCs derived from the whole ganglionic eminence and the ventral mesencephalon region of human fetuses have been immortalized using the technique of c-mycER transduction, and these NSC lines have been induced and differentiated to neurons potentially producing tyrosine hydroxylase (TH), a critical enzyme involved in dopamine synthesis [77, 78]. A recently devised cell culture model combined human adult brain ECs with fetal-derived NSCs which retain the ability of differentiating and further integrate together with ECs into the neurovascular tissue . In this system, a distinctive neurovascular cytoarchitecture comprised of NSCs and ECs was observed. It simulates several features of the neurovascular niche, such as diffusible proteins, an extensive matrix, and expression of receptors, and genes unique to each cell type . Moreover, complex multi-stage angiogenic processes can be studied by modulating the contact and soluble factor-mediated signaling pathways . Studies using this NVU model will promote the best regimen for NSC-based therapies in PD .
Appropriate cell-to-matrix interactions are required for neurovascular tissue regeneration by NSCs and ECs. It is therefore important to investigate contact-dependent factors, including ECM components which are involved in NSC-mediated endothelial morphogenesis and vasculature shaping. ECM molecules are differentially expressed within the NVU  and they may have inhibitory and excitatory bioactivities. Astrocyte-derived thrombospondins, for example, have been shown to induce presynaptic differentiation in the CNS , but conversely, thrombospondin-1 functions as a negative regulator of angiogenesis . The functions of these ECM molecules are associated with expression of their respective receptors, such as integrins. Most integrins recognize several ECM molecules, and most matrix molecules bind to more than one integrin. Consequently, various ECM molecules compete to bind specific integrins . When studying neurovascular regeneration for NSC-based therapies in PD, an ideal
7. Perspectives on the neural stem cell-based therapy for Parkinson’s disease
Researches on pathophysiology of PD and establishment of valid and effective NSC lines will benefit from development of advanced cell culture models of the NVU. Patients with PD will have the opportunity to be treated with the cells if DA neuronal differentiation can be guided appropriately. Preclinical studies on image-guided injection and noninvasive monitoring of tissue regeneration in animal models of PD will provide the optimal therapeutic window, cell dose, and delivery route for cell transplantation . Finally, appropriate patient selection and clinical follow-ups are required as a precondition for successful clinical translation of NSC-based therapies.
Recently, a preclinical study using a primate model suggests that human iPSC-derived DA progenitors are clinically applicable for the treatment of patients with PD. It was demonstrated that human iPSC-derived DA progenitor cells survived and functioned as midbrain DA neurons in a primate model of PD (
Alternatively, using parthenogenetic stem cells as a source of donor tissue have raised hopes for PD patients . The parthenogenetic cells are derived from unfertilized oocytes through suppression of the second meiotic division, leading to a pluripotent diploid cell line containing exclusively maternal chromosomes . They are therefore different from other pluripotent cell sources such as ESCs or iPSCs and may overcome obstacles such as the possibility of tumorigenesis. However, their lack of paternal imprinting may be associated with unique challenges in their adoption clinically as this could affect their cell cycle and differentiation capacity . Notably, preparation of these cells and the transplantation procedure has to be produced under Good Manufacturing Practice (GMP) conditions, the established guidelines and safety regulations .
In conclusion, combined with cutting-edge technologies, including cellular reprogramming, advancement in scaffolds for brain tissue engineering, image-guided injection, and noninvasive monitoring of tissue regeneration, NSC-based therapies will alleviate symptoms of PD patients in upcoming clinical trials of cell replacement therapy once the implanted or regenerated DA neurons are integrated into the existing nigrostriatal DA pathway.
Preparation of this article was supported by the Ministry of Science and Technology Taiwan, the Republic of China (104-2314-B-016-017-MY3) and Tri-Service General Hospital, National Defense Medical Center (TSGH-C105-085, TSGH-C107-007-007-S05, MAB-106-041, MAB-106-042, and MAB-106-044). The funder had no role in the decision to publish or in manuscript preparation.
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