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Abstract

Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical and therapeutic applications. Stem cells are providing hope for many diseases that currently lack effective therapeutic methods, including stroke, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Embryonic stem (ES) cells were originally targeted for differentiation into functional dopamine neurons for cell therapy. Today, induced pluripotent stem (iPS) cells are being tested for such purposes as generating functional dopamine neurons and treating a rat model of Parkinson's disease. In addition, neural stem cell and mesenchymal stem cells are also being used in neurodegenerative disorder therapies for stroke and Parkinson's disease. Although stem cell therapy is still in its infancy, it will likely become a powerful tool for many diseases that currently do not have effective therapeutic approaches. In this article, we discuss current research on the potential application of neural stem cells, mesenchymal stem cells, ES cells, and iPS cells to neurodegenerative disorders.

Keywords

Stem cell therapy Neurodegenerative disorders Regenerative medicine

Introduction

Many novel therapeutic approaches have been developed over the past 50 years, yet treatments for many neurodegenerative disorders such as stroke, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease are still limited to conventional approaches that primarily address symptoms. Stem cells, which are capable of self-renewal and differentiation into a wide range of cell types, have potential to become parts of powerful clinical techniques. One example of a current stem cell application is the use of hematopoietic stem cells (HSCs) from bone marrow transplants to treat leukemia, hemophilia, and anemia. Mesenchymal stem cells (MSCs) are being studied in terms of their response to ischemia and other injuries, as well as their role in revascularization and tissue repair (29). However, the science of stem cell transplantation is still in its infancy, and most research is still based on animal models.

In this article, we will give a brief overview of research involving four stem cell types that have potential for neurodegenerative disorder therapy applications (Fig. 1):

Figure 1.

The potential application of neural stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells to neurodegenerative disorders.

MSCs, which are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and stroma cells. MSCs are currently being used for many cell replacement therapy applications (1,14). Researchers are looking at ways that MSCs can support hematopoiesis isolated from bone marrow, synovial fluid, umbilical cord blood, amniotic fluid, deciduous teeth, and placental, adipose, and dermal tissues (23,48). Other researchers are studying the ability of MSCs to differentiate into several connective tissue cell types (3,4,7).

Neural stem cells (NSCs) are capable of differentiating into neuronal and glial lineages (42). Using flow cytometry, NSCs can be isolated based on physical properties such as granularity (36,40), size (forward scattering), and surface antigens [e.g., cluster of differentiation 34 (CD34), CD133] (18,53). NSCs are being studied as candidates for neural transplantation in response to neurological disorders (52).

Embryonic stem cells (ESCs)—pluripotent cells derived from the inner cell masses of mammalian blastocysts—are capable of differentiating into three embryonic germ layers (endoderm, mesoderm, and ectoderm) (2). ESCs have significant potential for use in clinical cell therapies due to their ability to self-renew and differentiate into a wide range of specialized cell types (33). ESCs that differentiate into functional dopamine neurons are being tested for various cell therapies (20).

Induced pluripotent stem (iPS) cells, which were originally generated using fibroblasts transfected with the transcriptional factors octamer-binding transcription factor 4 (Oct4), sex-determining region Y Box 2 (Sox2), v-myc myelocytomatosis viral oncogene homolog (c-Myc), and Krüppel-like factor 4 (Klf4) (50). Human iPS cells are similar, but not identical to human ESCs in terms of proliferation, morphology, gene expression, surface antigens, epigenetic status of pluripotent cell-specific genes, and telomerase activity (49). iPS cells may help researchers overcome hurdles associated with ESCs due to their generation from mature somatic cells. They may support efforts to obtain pluripotent stem cells, which are viewed as having significant cell therapy potential.

Cerebrovascular Accidents (CVAS)—Strokes

Cerebral ischemia, a major causal factor in strokes, triggers a cascade of multiple physiological and biochemical events (54) that are mediated, at least in part, by alterations in molecular transcriptional and translational activities (31). There is great variability in the effectiveness of current pharmacological treatments for stroke; stem cell transplantation is viewed as having considerable promise for CVA therapies (27).

Perhaps the most important characteristic of NSCs is their ability to home in on injured areas via stromal derived factor 1/CXC chemokine receptor type 4 (SDF1/ CXCR4) ligand and receptor binding (15,19). A number of researchers have transplanted NSCs into the injured areas of cerebral ischemia animal models as a form of cell therapy (25,30). Studies of NSCs and continuous neurogenesis in adult mammalian brains are at the center of a conceptual revolution in neuroscience and are increasing optimism for the development of clinical techniques for nervous tissue repair (39). In a previous study, we determined that a combination of the cytokines erythropoietin and granulocyte colony-stimulating factor (G-CSF) produced increased angiogenesis and tissue plasticity in ischemic animal models, resulting in greater functional recovery than that achieved using either agent individually (30). However, NSC transplantation efficiency decreases as patient age increases. In an effort to overcome this age hurdle, Jin et al. (17) delayed human neural precursor cell transplantation and reported improved outcomes for focal cerebral ischemia in aged rats. NSCs are considered challenging because of the difficulties of isolating them from brain tissue. For this reason, MSCs are considered more convenient for developing cell therapies.

Regarding MSC research associated with CVAs, we previously reported that the implantation of nonsenescent heat shock protein 27 (Hsp27)-upregulated MSCs promoted neuroplasticity in a mouse stroke model (28). We also observed that human umbilical cord mesenchymal stem cells (hUCMSCs) that exhibit senescence are detrimental to cell engraftment and differentiation via activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway in animal models. Human stem cells incubated in human umbilical cord serum (hUCS) might reduce senescence by upregulating Hsp27, thus increasing implantation efficiency (28). According to Lin et al. (27), the therapeutic benefits of hUCMSC transplantation for ischemic stroke is likely due to the ability of those cells to produce growth-promoting factors.

ESCs have also been used in cell therapies for stroke patients, but they require differentiation into neural stem (progenitor) cells or MSCs. In 2006, Hayashi et al. (13) transplanted neuronal progenitor cells derived from monkey ES cells into ischemic mouse brains, and confirmed their survival and differentiation. The following year, Ma et al. (32) described a treatment for hypoxic–ischemic encephalopathy in mice involving the transplantation of ES-derived cells expressing Nestin and microtubule associated protein 2 (MAP-2). Pignataro et al. (45) have described neuroprotection induced by stem cell-derived brain implants into ischemic mouse brains. ES cell proliferation capability means that large numbers of cells can be obtained in vitro; however, we failed to obtain pure ES cell-derived neuronal progenitor cells. This is an important challenge to overcome—the contamination of ES cell-derived neuronal progenitor cells by undifferentiated ES cells can trigger in vivo teratomas.

The most important aspect of iPS cells is their higher resistance to immune rejection compared to ES cells. In their study of iPS cell transplantation therapy for ischemic strokes, Jiang et al. (16) observed transplanted iPS cell migration to injured brain areas and subsequent differentiation into neuron-like cells. In their study, iPS cells could be directly transplanted into an animal model without differentiation, suggesting that iPS cells may serve as the basis for powerful cell level stroke therapies.

Amyotrophic Lateral Sclerosis (ALS)

ALS is a neurodegenerative disease marked by the loss of motor neurons in the spinal cord, brain stem, and motor cortex (41). Of all diagnosed cases, approximately 10% are familial, with the other 90% considered sporadic. A genetic link to point mutations in the gene encoding the enzyme Cu/Zn superoxide dismutase 1 (SOD1) has been identified in 20% of familial ALS patients (47). In addition to loss of SOD1 function, these mutations are also associated with toxicity in motor neurons; therefore, cell therapy approaches must take into consideration the difficult task of eliminating mutation SOD1 activity. Stem cells are being tested as a potential ALS treatment approach. iPSCs from ALS patients may support autologous cell transplantation, drug discovery, and increased understanding of ALS pathobiology (43).

In 2005, Gao et al. (10) transplanted human neural stem cell-derived cholinergic neurons into motoneuron-deficient adult rats and reported that axons moved through the ventral root and sciatic nerve to form neuromuscular junctions with peripheral muscle targets. That same year, Klein et al. (22) reported the overexpression of glial cell-derived neurotrophic factor (GDNF) in neural progenitor cells. The cells were capable of survival, integration, and GDNF release in the spinal cords of superoxide dismutase 1 (SOD1) (G93A) rats. In 2010, Mitrecic et al. (37) described the distribution, differentiation, and survival of NSCs injected intravenously into ALS rats. They used NSCs marked with GFP for transplantation into the central nervous system (CNS) of an ALS model via intravenous tail vein injection (37). Cell delivery efficiency to the CNS was highest in symptomatic ALS rats (up to 13%), moderate in presymptomatic ALS rats (up to 6%), and lowest in wild-type animals (up to 0.3%) (37). Mitrecic et al.'s data indicated that NSCs could be delivered to the CNS. Their results may help facilitate bench-to-bedside translational projects.

MSCs are also being tested for ALS cell therapies. Garbuzova-Davis et al. (11) studied the distribution, migration, and differentiation of human umbilical cord blood cells administered intravenously into an ALS mouse model and concluded that cord blood has therapeutic potential for replacing damaged neurons (11). According to Zhao et al. (59), following intravenous injection into a SOD1-G93A ALS mice model, hMSCs showed neuroglia differentiation in a mouse model and migrated to the brain and spinal cord; observed cells survived more than 20 weeks. In addition, hMSC-transplanted mice showed a significant delay in disease onset (14 days), increased lifespan (18 days), and delayed disease progression compared to untreated mice (59). According to these data, MSCs can ameliorate the phenotype of SOD1-G93A ALS mice via differentiation into neuroglia. Results from Phase I clinical trials (35) have confirmed the safety of MSC transplantation into the spinal cords of ALS patients, suggesting that MSCs may have clinical utility.

As described above for strokes, ES cells must differentiate into NSCs before being used for cell therapy. Lee et al. (24) transplanted human ESC-derived motoneurons into adult rat spinal cords and observed neural grafts consisting of large numbers of human motoneurons with outgrowths of choline acetyltransferase-positive fibers. Their evidence supports the in vivo survival of hESC-derived motoneurons, a key requirement in the development of hESC-based cell therapies for motoneuron diseases.

A significant challenge in ALS research is the inability to collect destroyed motor neural cells for purposes of determining ALS mechanisms. iPS cells offer a means for overcoming this hurdle, since they are capable of differentiating into any cell type, including motor neural cells. Patient-specific iPS cells can be used for disease modeling, drug discovery, and perhaps autologous cell replacement therapies. Note that one iPS cell line has been generated from an 82-year-old female ALS patient (8). iPS cells can also differentiate into motor neurons for drug screening or studying ALS cell mechanisms. Their ability to overcome immune rejection adds to their therapeutic potential.

Alzheimer's Disease

Alzheimer's disease is characterized by the degeneration of neuronal synapses in the brain (60). Currently, there are no effective treatments for Alzheimer's disease, although some have been shown to temporarily slow the progress of dementia symptoms. This disease is currently the focus of one of the world's largest biomedical research efforts, with some strategies involving stem cell therapy, primarily NSCs. In 2007, Marutle et al. (34) reported phenserine-modulated human neural stem cell (hNSC) differentiation in an Alzheimer's transgenic mouse model. The combined use of transplantation and treatment with (+)-phenserinet or other drugs may help researchers identify mechanisms that regulate stem cell migration and differentiation under neurodegenerative conditions (34). According to data presented by Wu et al. (56), treatment with NSCs can improve learning and memory in rats with Alzheimer's disease. They injected okadaic acid into rat lateral ventricles to establish a chronic Alzheimer's rat model and grafted NSCs that were stably transduced with neural growth factor onto the cerebral cortexes of research animals. The transplanted NSCs survived, were integrated into the host brain, and subsequently enhanced cognitive performance (56).

In terms of potential treatments involving MSCs, Habisch et al. (12) have described the efficient processing of Alzheimer's-related amyloid-β peptides by neuroectodermally converted MSCs. According to their in vitro results, MSCs may serve as useful vehicles for anti-Aβ activity, representing a potential causal stem cell-based therapeutic approach for treating Alzheimer's disease.

ES cell-derived NSCs may also hold clues for effective Alzheimer's treatment. Wang et al. (55) transplanted ES cell-derived NSCs into the cortexes of Alzheimer's mice and observed dramatic reductions in cholinergic deficits and short-term memory disruption. Moghadam et al. (38) transplanted mouse embryonic stem cell-derived neural precursor cells into the cortexes of Alzheimer's rats, and reported improvement in cognitive function.

Parkinson's Disease

Degenerative Parkinson's disease entails the loss of dopamine neurons in the substantia nigra. Current symptom treatments include levodopa administration, neural lesion surgery, and deep brain stimulation. Cell replacement therapies in the form of dopamine neuron or neural stem cell transplants are being studied as alternative treatment strategies (6).

The use of human neural stem cells in the treatment of Parkinson's disease has been studied since 1999 (9). A team from Cedars-Sinai Medical Center in Los Angeles completed Phase I clinical trials involving the injection of stem cells harvested from Parkinson's patients into their own brains. Results indicate that 30% of the transplanted dopaminergic cells survived the first two months (9). In 2003, Li et al. (26) measured transplanted neural stem cell survival and differentiation in mice with MPTP-induced Parkinson's and reported low efficiency levels. A genetically modified NSC approach was developed over the next several years, with Zou et al. (61) transplanting tyrosine hydroxylase gene-modified neural stem cells into a Parkinson's rat model and reporting enhanced treatment efficacy. Xu et al. (57) used the same model and approach with hemiparkinsonian rhesus monkeys and observed modified NSC survival in transplantation sites. The cells assumed normal dopaminergic neuronal properties leading to functional restoration.

In 2011, Thomas et al. (51) experimented with bone marrow stromal cells for Parkinson's therapies, based on their characteristics of being ethically acceptable, easily procured, and readily expanded. They reported that the cells differentiated into mesenchymal origin cells, but without a functional neuronal phenotype. A major issue with this method is feeder cell contamination. According to Pereira et al. (44), MSC contamination with fibroblasts accelerated neurodegeneration in an experimental rat Parkinson's model. They also reported that the cotransplantation of MSC and fibroblasts reversed the damaging effects of neurodegeneration and motor deficits in MPTP-exposed rats.

In 2002, Kim et al. (21) used an animal model to show that ES stem cell-generated dopamine neurons exhibit electrophysiological and behavioral properties typical of midbrain neurons, a finding that might support the development of Parkinson's treatment therapies. In 2010, Yang et al. (58) used porcine (p) ES cells to direct differentiation into neural lineages to study therapeutic potential in a rat Parkinson's model. They used medium containing retinoic acid (RA), sonic hedgehog (SHH), and fibroblast growth factor (FGF) without going through embryoid body formation to direct pES differentiation into neural lineages. These cells were transplanted into Parkinson's rats, which exhibited stably decreasing asymmetric rotations (58). Combined, these results suggest that ES cells that differentiate into neural lineages may help the development of therapies involving stem cell transplantation.

Regarding iPS cell research and Parkinson's, Rhee et al. (46) reported that human iPS cells were capable of generating functional dopamine neurons, which were used to treat a Parkinson's rat model. In their study, protein-based human iPS cells differentiated into neural progenitor cells that were highly expandable without senescence. Significant improvement in motor deficits was observed in Parkinson's rats into which these neural progenitor cells were transplanted (46). In a separate study, Cai et al. (5) measured the survival and integration of similar dopaminergic neurons transplanted into the brains of 6-OHDA-lesioned rats and reported that survival was sufficient for development into bona fide mature DA neurons.

Conclusion and Research Directions

The potential for stem cell-based therapies is providing hope for many diseases that currently lack effective therapeutic methods, including stroke, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. There are many hurdles that must be overcome before clinical applications can be tested with humans. While iPS cell technology may provide answers to some current challenges, the technology is still in its infancy. The most important characteristics of iPS cells are cell generation safety and efficiency, the safety of in vivo iPS-derived cells transplanted into the body, and the ability to rescue injured areas in vivo. These characteristics will be at the center of research conducted in this decade.

Footnotes

Acknowledgments

The authors wish to thank the Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004), China Medical University Hospital (DMR-98-120), and China Medical University (CMU99-N1-05) for their financial support and Jon Lindemann for his editing assistance. The authors declare no conflict of interest.

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Stem Cell Applications in Regenerative Medicine for Neurological Disorders

Abstract

Keywords

Introduction

Cerebrovascular Accidents (CVAS)—Strokes

Amyotrophic Lateral Sclerosis (ALS)

Alzheimer's Disease

Parkinson's Disease

Conclusion and Research Directions

Footnotes

Acknowledgments

References