==== Front Neural Regen ResNeural Regen ResNRRNeural Regeneration Research1673-53741876-7958Medknow Publications & Media Pvt Ltd India 30028342NRR-13-129410.4103/1673-5374.235085ReviewStem cells: a promising candidate to treat neurological disorders Song Chang-Geng 1Zhang Yi-Zhe 1Wu Hai-Ning 1Cao Xiu-Li 1Guo Chen-Jun 1Li Yong-Qiang 1Zheng Min-Hua Ph.D.1http://orcid.org/0000-0002-5279-9366*Han Hua Ph.D.12http://orcid.org/0000-0002-1872-9700*1 Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China2 Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi Province, China* Correspondence to: Hua Han or Min-Hua Zheng, huahan@fmmu.edu.cn or zhengmh@fmmu.edu.cn. Author contributions: CGS wrote the original draft. YZZ, HNW, XLC, CJG, and YQL carried out the paper revision. MHZ and HH participated in original writing and finalized the paper. All authors approved the final version of the paper. 7 2018 13 7 1294 1304 20 5 2018 Copyright: © Neural Regeneration Research2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Neurologic impairments are usually irreversible as a result of limited regeneration in the central nervous system. Therefore, based on the regenerative capacity of stem cells, transplantation therapies of various stem cells have been tested in basic research and preclinical trials, and some have shown great prospects. This manuscript overviews the cellular and molecular characteristics of embryonic stem cells, induced pluripotent stem cells, neural stem cells, retinal stem/progenitor cells, mesenchymal stem/stromal cells, and their derivatives in vivo and in vitro as sources for regenerative therapy. These cells have all been considered as candidates to treat several major neurological disorders and diseases, owing to their self-renewal capacity, multi-directional differentiation, neurotrophic properties, and immune modulation effects. We also review representative basic research and recent clinical trials using stem cells for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and age-related macular degeneration, as well as traumatic brain injury and glioblastoma. In spite of a few unsuccessful cases, risks of tumorigenicity, and ethical concerns, most results of animal experiments and clinical trials demonstrate efficacious therapeutic effects of stem cells in the treatment of nervous system disease. In summary, these emerging findings in regenerative medicine are likely to contribute to breakthroughs in the treatment of neurological disorders. Thus, stem cells are a promising candidate for the treatment of nervous system diseases. nerve regenerationstem cellstransplantationstem cell therapynervous systemneurodegenerative diseaseneurological disordersanimal experimentclinical trialregenerative medicineneural regeneration ==== Body Introduction The central nervous system is considered to be the most sophisticated and less understood system in the human body. Disorders or diseases of the central nervous system, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), usually lead to deterioration and irreversible impairment of the structures and functions of nervous tissue, which is often accompanied by serious cognitive or physical loss in affected patients. Apart from the limited potential of endogenous regeneration in the central nervous system, therapies for such disorders are largely symptomatic and pharmaceutical, thus possessing inherent disadvantages of temporary efficacy or overwhelming cost (Lindvall and Kokaia, 2006). Therefore, it is urgent to find effective ways to cope with damage associated with central nervous system disorders or diseases. Stem cell therapy is a promising candidate to treat neurological disorders, and the rationale and feasibility of stem-cell-based therapies have been verified during recent years. Neural stem cells (NSCs) are the origin of various types of neurons, astrocytes, and oligodendrocytes during embryonic development of the central nervous system and subsequently exist primarily in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus in the adult mammalian brain (Lim and Alvarez-Buylla, 2014). Their capacity for self-renewal and the ability to generate various neural cell types make NSC transplantation therapy a promising method to cure disorders and diseases of the central nervous system. In addition to NSCs, other types of stem cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem/stromal cells (MSCs) are considered options for transplantation. However, it is worth noting that although numerous animal experiments have been implemented and results reflecting a certain amount of success have been achieved, in vivo progress for human subjects in clinical and preclinical trials is still limited. In this review, different types of stem cells used for transplantation therapy of neurological disorders and diseases will be described and an overview presented of advances in stem cell transplantation therapy. Stem Cells as a Therapeutic Platform NSCs In the postnatal mammalian brain, NSC populations are detected mainly in two regions, the SVZ and the SGZ of the hippocampal dentate gyrus (Yang et al., 2017). These cells can be identified by their expression of NSC markers such as Nestin, Musashi-1, CD133, and glial fibrillary acidic protein (GFAP) (Lendahl et al., 1990; Sakakibara et al., 1996; Doetsch et al., 1999; Uchida et al., 2000). The SVZ, a thin layer of dividing cells persisting along the lateral wall of the lateral ventricle, is composed of four cell types: neurogenic astrocytes (type B cells), immature precursors (type C cells), migrating neuroblasts (type A cells), and ependymal cells. SVZ astrocytes (type B cells) remain labeled with the NSC marker SOX2 throughout their long survival in the adult brain, where they divide to give rise to type C cells and then type A cells, suggesting that SVZ astrocytes act as adult NSCs in both normal and regenerating brain (Doetsch et al., 1999). Ependymal cells, which separate the SVZ from the lateral ventricles, play a significant role in maintenance of the neurogenic niche by inducing neurogenesis and suppressing gliogenesis through secretion of neural regulatory factors, such as the bone morphogenetic protein inhibitor Noggin (Chmielnicki et al., 2004). In the SGZ of the hippocampal dentate gyrus, NSCs continue to proliferate and differentiate into granule cells that migrate into the granule cell layer of the dentate gyrus throughout life (Gould, 2007). The proliferation rate of NSCs in the SGZ is associated with the age of the animal. In C57BL/6J mice, the rate of neurogenesis in the dentate gyrus is highest during the first month of life, and subsequently declines by 80% when mice are 4 months of age (Ben Abdallah et al., 2010). Evidence has suggested that a few genes important for NSC proliferation, such as Stat3, manifest increased expression in the aging dentate gyrus, while genes modulating neuronal differentiation, such as Heyl, exhibit decreased expression (Shetty et al., 2013). Self-renewing NSCs isolated from the SVZ and SGZ of adult human brain can generate neurons, astrocytes, and oligodendrocytes in vitro (Johansson et al., 1999). Moreover, derived neurons can be supported for prolonged culture with epidermal growth factor (Ayuso-Sacido et al., 2010), fibroblast growth factor-2, and brain-derived neurotrophic factor (Pincus et al., 1998). In summary, in vitro-cultured NSCs maintain the capacity for self-renewal, while they can differentiate into various kinds of neurons and glia. These properties provide the foundation of NSC-based therapies. In the spinal cord, which is typically considered a part of the central nervous system, cells surrounding the central canal in adults acquire stem cell properties in response to injury. Ependymal cells are ciliated cells that line the central canal of the spinal cord. Several NSC markers, such as Sox2, CD133, and GFAP (Hamilton et al., 2009; Fiorelli et al., 2013), have been detected in ependymal cells. After injury, increases in nestin-positive ependymal cells indicate the multipotent properties of ependymal cells (Mothe and Tator, 2005). In response to injury, ependymal cells proliferate and migrate from the periventricular region into the injured area where they differentiate primarily into astrocytes (Mothe and Tator, 2005). Those ependymal-cell-derived astrocytes localize to the center of glia scars, which are considered to have protective effects against neuronal degeneration and the expansion of damage (Kawano et al., 2012). ESCs Human ESCs, undifferentiated pluripotent cells isolated from the inner cell mass of a blastocyst, are characterized by a group of surface markers including stage-specific embryonic antigen (SSEA)-3, SSEA-4, TRA-1-60, TRA-1-81, and alkaline phosphatase (Thomson et al., 1998). ESCs have the potential to differentiate into cell types of all three germ layers. In addition, a number of transcription factors including OCT3/4, NANOG and SOX2 have been identified in human ESCs (Niwa et al., 2000; Chambers et al., 2003; Chew et al., 2005). These transcription factors have since been used to induce pluripotent cells from fibroblasts and other somatic cells in vitro. The pluripotency of ESCs, which allows them to differentiate into cell types of all three germ layers, has aroused tremendous research interest in the field of neurological disease treatment. The foundations of ESCs as cell source for therapies for neurological disorders are as follows. First, ESCs can differentiate into neurons and glia after transplantation (Arnhold et al., 2000), and exhibit long-term stability that allows them to integrate into local structure (Nasonkin et al., 2009). Second, neural derivatives of ESCs have the ability to secrete neurotrophic factors that provide trophic support in the injured region (Zhang et al., 2006). Third, ESC-derived neurons of appropriate cortical identity can contribute to the reconstruction of damaged cortical circuitry of the same areal identity (Michelsen et al., 2015). Medial ganglionic eminence-like progenitor cells and retinal progenitor cells differentiated from ESCs have been verified to manifest regenerative significance in AD and retinal degenerative disease, respectively (Liu et al., 2013; Qu et al., 2015). iPSCs Successful induction of somatic cells into iPSCs represents a milestone in the field of stem cell and regeneration research. Takahashi and Yamanaka (2006) successfully achieved the induction of pluripotent stem cells from mouse embryonic and adult fibroblasts by introducing four factors (Oct3/4, Sox2, c-Myc, and Klf4) under ESC culture conditions. Almost simultaneously, Yu et al. (2007) established another induction method for iPSCs using a combination of Oct4, Sox2, Nanog, and Lin28. iPSCs obtained from both methods are very similar to ESCs with regard to morphology, proliferation, expression of cell-surface markers, and gene expression profiles. ESC marker genes Esg1, Nanog, Gdf3, and Cripto can be detected in these iPSCs (Takahashi and Yamanaka, 2006). Moreover, Takahashi et al. (2007) successfully induced iPSCs from human dermal fibroblasts with the same four factors in Yamanaka’s protocol. These iPSCs are able to form tissues of all three germ layers in vitro and in teratomas (Takahashi et al., 2007), suggesting prospects for iPSCs in disease modeling and transplantation therapy. Other cell types from developmentally diverse origins such as hepatocytes, circulating T lymphocytes, and keratinocytes (Chun et al., 2010), have also been successfully reprogrammed into iPSCs with varying efficiencies. Potential utilization of iPSCs covers a broad range of applications, from constructing disease models to patient-specific therapeutic transplantations (Peng et al., 2016). Indeed, availability of iPSCs from patients suffering from a particular neurological disease is already contributing to the development of better disease models. For example, an iPSC-based model of AD, a neurodegenerative disease, has been established (Israel et al., 2012). iPSC derivatives have also been used to investigate the pathogenesis of retinal degenerative diseases (Gamm et al., 2013). In addition, iPSC derivatives have an intriguing role in experimental therapies for neurological disease. Transplantation of human iPSC derivatives has achieved positive effects in some neurological disease models. For example, in spinal cord injury (Tropepe et al., 2000), intracerebral hemorrhage (Qin et al., 2013), and retina-related diseases like macular degeneration (Du et al., 2011), iPSCs and their derivatives have achieved valid structural and/or functional recovery. Retinal stem/progenitor cells The retina, which is considered part of the central nervous system, was first recognized to possess regenerative characteristics in the middle of the 20th century by researchers investigating salamander eyes (Stone, 1950). In adult vertebrates, numerous investigations have been conducted to identify endogenous stem cells in retina. This research revealed at least three types of cells possessing stem-cell-like properties in the retina, including retinal pigment epithelial (RPE) cells, Müller glial cells, and ciliary pigment epithelial cells. Human RPE cells remain dormant and quiescent after maturation of the retina, but they can be activated in disease states or by culturing endogenous RPE cells in vitro. In certain pathogeneses, such as proliferative vitreoretinopathy (Kim and Arroyo, 2002), RPE cells can transform into a proliferative state after local injury. Moreover, retinal pigment epithelial stem cells, a subpopulation of adult human RPE cells, can be activated in vitro into self-renewing, proliferative cells that can differentiate into neural or mesenchymal progenies (Salero et al., 2012). Stem cell multipotency is also detected in Müller glial cells, which can differentiate into photoreceptors after artificially induced degeneration of the retina (Lawrence et al., 2007). Located in the ciliary marginal zone, ciliary pigment epithelial cells are found to proliferate clonally in vitro to form spheres before differentiating into retinal-specific cells, such as rod photoreceptors and bipolar neurons (Tropepe et al., 2000), although the efficiency of this process is still unsatisfactory in some research (Gualdoni et al., 2010). Retinal progenitor cells can also be derived from fetal retinas, which comprise a population of progenitors capable of giving rise to all types of retinal cells (Reh, 2006). Investigations have been conducted to verify the therapeutic efficacy of retinal progenitor cell transplantation. Research in rat models has shown that cultured human retinal progenitor cells integrate into the degenerating retina, whereby they preserve the structure of the outer nuclear layer and elicit improved visual acuity (Luo et al., 2014). Prior to grafting, immunocytochemical analysis showed that cultured human retinal progenitor cells widely expressed NSC markers including nestin, Sox2, and vimentin (Klassen et al., 2007). However, other research demonstrated that rod photoreceptors successfully integrated (formed synaptic connections) and improved visual function, only when rod precursors were transplanted and not proliferating retinal progenitor cells (MacLaren et al., 2006). Thus, these findings suggest different applicable ontogenetic stages of donor cells for successful rod photoreceptor transplantation. Mesenchymal stem cells (MSCs) MSCs, also known as mesenchymal stromal cells, are a type of pluripotent stem cell extensively located in various tissues of the human body, especially connective tissues. MSCs were first discovered in human bone marrow (Friedenstein et al., 1968), but can also be isolated from peripheral blood, adipose tissue, muscle, skin, placenta, and amniotic fluid (Yen et al., 2005; Choi et al., 2010; Kim et al., 2013). With increasing understanding of MSCs, researchers discovered their capability to differentiate into cell types of all three germ layers (Safford et al., 2002; Seo et al., 2004; Choi et al., 2010). This attracted a wide range of attention to utilize MSCs as a replacement therapeutic source for various diseases. The neurogenic property and immune modulatory effects of MSCs provide a foundation upon which MSCs can be used to treat neurological disorders (Safford et al., 2002; Bernardo and Fibbe, 2013). In fact, autologous bone marrow-derived MSC treatments of neurodegenerative diseases, including PD and AD, have manifested tremendous therapeutic efficacy in both disease models and clinical trials (Venkataramana et al., 2010; Bae et al., 2013). Stem Cell Therapies for Neurodegenerative Diseases PD The pathological hallmark of PD is a gradual loss of nigrostriatal dopaminergic neurons, which often leads to rigidity, slow physical movements (bradykinesia), tremor and postural instability that severely affects patient quality of life. Current treatments for PD primarily include pharmacological therapies, such as orally administered L-3,4-dihydroxyphenylalanine and dopamine receptor agonists, and deep brain stimulation in which electrodes are surgically implanted into the subthalamic nucleus and globus pallidus. These treatments are effective for amelioration of symptoms, but are inefficient for ceasing disease progression (Lane et al., 2008). The inspiration for regenerative therapy of PD dates back to transplantation trials of human embryonic mesencephalic tissues two decades ago, whereby histopathological and functional improvements were reported in several experiments and open-label trials (Kordower et al., 1995, 1998; Piccini et al., 1999). However, difficulties in standardizing the cell types present in grafted tissues led to a high variability in the degree of symptomatic relief. In addition, it has been reported that PD pathology might propagate from the host to the graft (Li et al., 2008). Furthermore, ethical concerns prevented further transplantation trials using human embryonic tissues. Therefore, stem cells might be an ideal source for regenerative therapies and have been tested through different strategies. Cellular sources for tested stem cell therapies of PD include ESCs, MSCs, NSCs, and iPSCs. Dopaminergic cells derived from various stem cell sources have been shown to survive in the host and induce behavioral improvement and motor recovery in mammalian models from rodent to monkey (Takagi et al., 2005; Rodriguez-Gomez et al., 2007). Transplanted cells promote functional recovery primarily through two mechanisms. First, transplanted cells have the ability to survive, express tyrosine hydroxylase, and release and reuptake dopamine, therefore potentially replacing the function of lost or damaged neurons. Second, apart from cell replacement and dopamine release, transplanted stem cells might lead to symptomatic relief through neurotrophic and protective effects. A recent report showed that transplanted NSCs can express brain-derived neurotrophic factor, which can restore depleted dopamine levels and modulate dopaminergic and glutamatergic systems (Goldberg et al., 2015). In addition, NSC transplantation can also exert neuroprotection through regulation of the host niche, for example, by facilitating local astrocytes undergoing de-differentiation and promoting expression of host-derived growth factors (Zuo et al., 2015). However, before stem cell therapies can be put into clinical utilization, several critical issues must be taken into consideration: (1) suitable inclusion criteria of patients; (2) the source of stem cells and their eligible accreditation; and (3) the risk of stem-cell-associated tumorigenesis. These issues must be appropriately addressed and several clinical trials have rendered rational references. Although there are no established inclusion criteria for patient selection, several trials have introduced criteria to include patients in their procedures. One study included patients with intact higher mental functions, at least two symptomatic features of PD, and good response to L-3,4-dihydroxyphenylalanine (Venkataramana et al., 2010). Another trial selected patients with motor complications despite adequate oral anti-PD therapy (Venkataramana et al., 2012). To address the problem of cellular source, a whole system was recently established to attain completely xeno-free clinical-grade human ESCs in China (Gu et al., 2017), and a clinical trial of ESC-derived neural progenitor transplantation was subsequently initiated in PD patients. Although the therapeutic effects are still indefinable, their work provides valuable criteria for human ESC production and certification, which contribute to international standards for stem cell therapy. Moreover, utilization of iPSCs has made it possible to obtain cells from the patient’s own somatic cells, which alleviates the problem of immune rejection (Wernig et al., 2008). Several studies have demonstrated that no tumor formation occurs during the 10–36 months of their trials (Venkataramana et al., 2010, 2012; Yin et al., 2012) and a long-follow up study reported no sign of tumorigenesis up to 18 years after transplantation (Kefalopoulou et al., 2014). However, it should be mentioned that the life expectancy of PD patients is almost normal. Therefore, even a slight risk of tumorigenesis is unfavorable and current available data do not guarantee the absolute avoidance of tumor formation over prolonged periods of time. After receiving transplantation of stem cells and their derivatives, improvements are detected in PD patients during both “on” and “off” periods of the Unified Parkinson’s Disease Rating Scale (Venkataramana et al., 2010, 2012; Yin et al., 2012). These patients were reported to manifest symptomatic improvements, such as a reduction in tremors, rigidity, and freezing attacks (Venkataramana et al., 2012; Bernardo and Fibbe, 2013). Positron emission tomography showed increased dopamine release, while magnetic resonance spectroscopy revealed improvement in N-acetylaspartate/creatine ratio (Brazzini et al., 2010; Yin et al., 2012). These may explain the mechanisms underlying symptomatic improvements. Altogether, current results of clinical trials provide an encouraging perspective for clinical use of stem cell therapies for PD. AD AD, which is subclassified into familial AD and sporadic AD, is a progressive neurodegenerative disorder with a prevalence of 46.8 million affected individuals worldwide (Prince, 2015). Pathologically symbolized by β-amyloid (Aβ) senile plaques and phosphorylated TAU protein neurofibrillary tangles, AD can elicit memory, cognition and coordination dysfunction in patients. Current treatments for AD mainly focus on pharmaceutical regulation to deplete accumulated Aβ, such as Aβ-degrading enzymes cathepsin B and neprilysin. However, these drugs are dose-dependent and have no effect on disease progression. Stem cell sources for treating AD in both animal models and clinical trials range from iPSCs and ESCs to NSCs and their derivatives. Large numbers of animal studies have thoroughly illustrated the characteristics of transplanted stem cells and their derivatives in the brain of AD models, thus paving the theoretical way for clinical trials in AD patients. Animal experiments have demonstrated the following. (1) Transplanted stem cells can migrate into the nervous system and integrate into local neural circuits to enhance synaptogenesis and improve synaptic transmission (Bae et al., 2013; Zhang et al., 2014b). (2) Improved neuropathological features can be detected after transplantation, including reduced deposition and upregulated Aβ clearance (Bae et al., 2013; Shin et al., 2014). (3) Stem cell transplantation decreases neuroinflammation via suppressed expression of proinflammatory mediators, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (Zhang et al., 2015), and provides long-term protective immunomodulatory effects (Kim et al., 2013). (4) Transplanted stem cells are capable of secreting nerve growth factor and exerting neurotrophic influence (Marei et al., 2015), such that tested animals showed apparent or moderate cognitive and memory improvements (Kim et al., 2013; Zhang et al., 2014b, 2015; Marei et al., 2015). Collectively, this evidence provides a solid foundation for advancing stem cell transplantation therapy into clinical trials. In addition to therapeutic strategies, stem cells provide novel approaches to model AD. Traditional transgenic mouse models can mimic familial AD symptoms, but the pathological feature of neurofibrillary tangles is not reflected (Elder et al., 2010). Since the successful introduction of human iPSCs, they have been used to successfully model AD (Israel et al., 2012), thus ameliorating problems caused by species-specific differences and allowing for the stratification of drug responses in an era of personalized medicine. The first iPSC model for AD was established by Israel et al. (2012), who collected iPSCs from two familial AD patients, two sporadic AD patients, and two non-demented age-matched control subjects. The results demonstrated that iPSC-derived neurons from familial AD and sporadic AD groups exhibited significantly higher levels of Aβ, phospho-Tau, and active glycogen synthase kinase-3β compared with controls. Neurons from familial AD and sporadic AD patients also accumulated in large Rab5-positive early endosomes compared with controls (Israel et al., 2012). In recent studies, iPSC-based AD models have proved to be an effective tool for understanding the underlying genetic basis of AD, in addition to offering a novel platform for drug screening and toxicology studies (Hossini et al., 2015). Clinical trials of stem-cell-based therapies have been performed or are underway for AD; at present, all are based on allogeneic approaches. In a phase I clinical trial of nine patients conducted by Kim et al. (2015), human umbilical cord blood-derived MSCs were stereotactically injected into bilateral hippocampus and the right precuneus. Importantly, no patients showed serious adverse events during the follow-up period. Thus, this trial provides proof that stereotactic administration of MSCs is feasible and well tolerated, and it paves the way for further efficacy and clinical benefit studies (Kim et al., 2015). In addition, autologous therapeutic approaches for AD might be established based on iPSC techniques. Patient-specific iPSCs could be genetically modified to provide therapeutic benefits after placing them back into patients (Hunsberger et al., 2015). Age-related macular degeneration (AMD) Subclassified into non-neovascular AMD (dry form) and neovascular AMD (wet form), AMD is a neurodegenerative disease that affects the RPE and photoreceptor cells. Affected individuals in both non-neovascular AMD and neovascular AMD suffer from progressive dysfunction and death of RPE cells and photoreceptors. However, neovascular AMD can be more sudden and severe because of fluid leakage or bleeding from highly-permeable vascular networks. Currently, there is no curative treatment for patients affected by AMD. Although, vitamin C and E supplementation is recommended for a small proportion of patients (Sin et al., 2013). For neovascular AMD, administration of anti-vascular endothelial growth factor proved to be applicable; however, this therapy is laborious because of tedious monthly injections and the inability to prevent AMD progression (Young et al., 2014). Macular translocation and RPE transplantation surgeries resulted in decreased visual loss and improvement of vision in some patients (Stanga et al., 2002). These results verified that normal RPE can facilitate the survival and function of photoreceptors, which supports the feasibility of using stem cells and their RPE derivatives as transplantation sources to treat AMD. Numerous studies have investigated the feasibility and efficacy of stem cells and RPE transplantation to treat AMD, and most studies have shown encouraging results. Tsai et al. (2015) found that transplantation of iPSC-derived neural progenitor cells limited disease progression and reduced retinal pathology resulting from the accumulation of undigested photoreceptor outer segments in rat models. Another study confirmed that ESC-derived neural progenitor cells survived in host retinas and protected retinal structure and function in the early stage following transplantation (Qu et al., 2015). Additionally, subretinal transplantation of bone marrow-derived MSCs significantly rescued dystrophic photoreceptors and yielded a thicker outer nuclear layer in the treated group (Tzameret et al., 2014). Apart from direct stem cell transplantation, the transplantation of RPE cells derived from pluripotent stem cells has also demonstrated efficacy in animal models. RPE cells derived from iPSCs reportedly have the protective capacity to significantly attenuate photoreceptor degeneration on postoperative days 14 and 21, and could survive up to at least 12 weeks after transplantation (Sun et al., 2015). Interestingly, ESC-derived RPE in a polarized monolayer seems to have higher efficacy than ESC-derived RPE cells in suspension. Hsiung et al. (2015) found that polarized human ESC-derived RPE monolayers exhibited resistance to oxidative stress-induced cell death and expressed higher levels of anti-apoptotic signaling factors such as p-Akt and Bcl-2. The safety of pluripotent stem-cell-derived RPE transplantation has also been investigated. In a tumorigenicity study, no tumors were observed with grafting of iPSC-derived RPE sheets during 6–12 months of monitoring, suggesting negligible tumorigenic potential of iPSC-derived RPE (Kanemura et al., 2014). Further, long-term data (spanning the life of animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal ESC-RPE transplantation (Lu et al., 2009). These results suggest iPSCs and ESCs could serve as potentially safe sources of RPE for efficacious treatment of AMD. The first report providing a description of human ESC-derived RPE transplanted into human patients was published in 2012. After transplantation surgery, human ESC-derived RPE showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection, and the vision of AMD patients was slightly improved (Schwartz et al., 2012). The safety of human ESC-derived RPE transplantation was further confirmed by a study in four Asian AMD patients, whereby there was no occurrence of adverse proliferation, tumorigenicity, ectopic tissue formation, or other serious safety issues during the 1-year follow-up (Song et al., 2015b). In another open-label phase I/II study using human ESC-derived RPE, increasing subretinal pigmentation patches, improved visual acuity, and ameliorated vision deficits were observed (Schwartz et al., 2015). However, in a pilot clinical trial of autologous bone marrow-derived CD34+ stem cell transplantation, mild progression of geographic atrophy was noted in both the transplanted eye and contralateral eye during 6-month follow-up, indicating that CD34+ stem cells may not be an ideal candidate to treat AMD (Park et al., 2015). Other recent clinical trials involving stem cell transplantation for AMD are shown in Table 1. Table 1 Selected stem cell trials in AMD Stem Cell Therapy for Traumatic Brain Injury (TBI) Damage to the brain caused by external mechanical force such as rapid acceleration, blast wave, or penetration wound is defined as TBI, which often leads to impairment of cognition, physical, and psychological functions. TBI involves a complex disease process composed of the primary injury, including contusion and hemorrhage resulting from instant external mechanical disruption, and the triggered secondary injury caused by a cascade of metabolic, cellular, and molecular events such as the imbalance of glutamate and gamma-aminobutyric acid, active oxygen and free radical formation, and impairment of the blood-brain barrier (Xiong et al., 2013). As primary injury occurs immediately after exposure to the external trauma, it can only be preventable. However, the prolonged characteristics of second injury provide a window of opportunity for treatment. Endogenous neurogenesis has been detected and reported during TBI (Zheng et al., 2013; Thomsen et al., 2014; Goodus et al., 2015). In TBI brain specimens, NSC/neural progenitor cell markers, including DCX, Sox2 and NeuroD, were increased in the perilesional cortex (Zheng et al., 2013). In addition, NSCs along the SVZ reportedly undergo robust proliferation with increased regenerative capacity (Thomsen et al., 2014; Goodus et al., 2015). However, this endogenous regenerative neurogenesis is not enough to prevent and restore the damage. In addition, the heterogeneity of TBI pathophysiology makes it difficult to find a sufficiently effective therapy. In consideration of these facts, stem cell transplantations have been tested in both animal models and clinical trials of TBI, and have exhibited promising therapeutic benefits. A number of pre-clinical studies have verified the significant ameliorative effects of motor, memory, and cognitive impairment elicited by stem cell transplantation in TBI animal models (Bedi et al., 2013; Wang et al., 2013a; Tajiri et al., 2014b). This research provides insight into potential underlying mechanisms. First, transplanted cells exert anti-inflammatory and immunomodulatory properties against the adverse immune response after TBI (Zhang et al., 2013). Indeed, MSC transplantation after TBI was associated with a lower density of activated microglia/macrophages and peripheral infiltrating leukocytes at the injury site (Bedi et al., 2013; Zhang et al., 2013), which led to improved spatial learning. Second, stem cell transplantation contributes to the reduction of neuron/tissue loss and is capable of increasing white matter integrity (Wang et al., 2013a). Upon engraftment of iPSC-derived NSCs into adult rats after spinal cord injury, these cells differentiated and extended axons into the injured spinal cord, frequently penetrating gray matter and forming synapses with other neurons, which functionally restored neural cells and tissues (Cawsey et al., 2015). Third, transplanted MSCs can inhibit vascular permeability and stabilize the structure and function of the blood-brain barrier by modulating vascular endothelial cadherin/beta-catenin signaling (Pati et al., 2011). In addition, Torrente et al. (2014) reported that paracrine factors of human MSCs promoted wound healing and reduced reactive oxygen species production in TBI models, which was beneficial for harnessing disease progression and damage recovery. As mentioned above, endogenous neurogenesis is not enough to repair the tissue impairment caused by TBI. However, Tajiri et al. (2013) reported that transplanted human MSCs have the ability to recruit host cells and facilitate endogenous neurogenesis and restoration through a stem-cell-paved “biobridge”. After transplantation, a biobridge was established between the neurogenic SVZ and injured cortex. While initially composed of transplanted stem cells, it eventually became overgrown by newly formed host cells. The transplanted cells manifested themselves as pathways for trafficking the migration of host neurogenic cells, but once this biobridge was formed between the neurogenic site and the injured brain site, the grafted cells disappeared and relinquished their task to host neurogenic cells (Tajiri et al., 2013, 2014a). This novel observation linked transplanted human MSCs with endogenous neurogenesis and partially revealed the mechanisms of stem-cell-based therapeutic effects for TBI. The first clinical trial of 97 TBI patients in whom MSCs were transplanted into the subarachnoid was published in 2013. The results suggested that bone marrow-derived MSCs were safe and effective in TBI patients. Twenty-seven of the 73 patients with motor disorder showed motor function improvements (Tian et al., 2013). In another trial where visual function of patients was impaired as a result of severe cortical injury, the treatment group received intracerebroventricular transplantation of human NSC/neural progenitor cells and exhibited visual function improvement (Luan et al., 2013). In another completed clinical trial, improvement of neurological functions was detected in the group who underwent four umbilical cord-derived MSC transplantations via lumbar puncture, including enhanced upper and lower extremity motor functions, sensation, balance, self-care, and social cognition (Wang et al., 2013b). However, there are also clinical trials in which patients suffered from severe adverse effects. For example, a case of acute promyelocytic leukemia in a 36-year-old patient who accepted MSC transplantation treatment for TBI was reported (Song et al., 2015a). Stem Cell Therapy for Glioblastoma With a median survival expectation of approximately 12–16 months, glioblastoma is a common form of primary brain tumors that is highly malignant and fatal. Importantly, as glioblastoma has an aggressive nature involving infiltration and invasion, surgical resection is frequently unable to remove all of the glioblastoma foci. This is supported by the fact that most patients die within a year from a reoccurring secondary tumor foci near the resected area (Hochberg and Pruitt, 1980). Further complicating matters, the deep location of tumors and existence of the blood-brain barrier make it sophisticated and difficult for chemical agents to achieve satisfactory therapeutic effects (Sweet et al., 2012). Since Aboody et al. (2000) first reported the tumor tropism characteristics of NSCs, utilizing NSCs engineered with cytotoxic agents to “home” to glioblastoma has been studied as a potential therapy. Various NSC lines have been investigated for their tumor-tropic migration, including human HB1.F3 NSCs (Zhao et al., 2008), iPSC-derived NSCs (Yamazoe et al., 2015), bone-marrow-derived MSCs (Hu et al., 2012), and adipose tissue-derived MSCs (Liu et al., 2014). Although numerous studies have been conducted to examine the mechanism underlying the tumor tropism of stem cells, it remains incompletely understood. It seems that hypoxia present within the glioblastoma contributes to tumor tropism. During hypoxia, glioblastoma cells upregulate the expression of several chemoattractants and pro-angiogenic factors, such as hypoxia-inducible factor-1 alpha and its downstream targets stromal-cell-derived factor-1 and vascular endothelial growth factor, that attract stem cells to migrate towards the tumor foci (Zhao et al., 2008; Zhang et al., 2012). One study demonstrated that glioma stem cells, a small neural stem-like population of tumor cells, exhibited enhanced chemotaxis for NSC tropism compared with other more differentiated cells. Chemokines expressed by glioma stem cells, such as vascular endothelial growth factor, epidermal growth factor, and basic fibroblast growth factor, contributed to the hypoxia-enhanced NSC-tropic migration (Zhang et al., 2014a). This study suggested a crucial role of glioma stem cells in the migration of NSCs. A variety of anti-glioblastoma substances have been integrated into NSCs as cargos to kill tumor cells, including cytokines, enzyme/pro-drugs, and oncolytic viruses. Cytokines of the interleukin families, including IL-4, IL-7, and IL-23, manifested antitumor efficacy that could be explained by interleukin-mediated increased infiltration of anti-tumor immune cells and an enhanced immune response (Benedetti et al., 2000; Yuan et al., 2006; Gunnarsson et al., 2010). Tumor necrosis factor-related apoptosis-inducing ligand, a cytokine that can activate caspase-8-dependent apoptosis, dramatically inhibited tumor growth (Kauer et al., 2012). In addition, stem cells carrying enzymes capable of transferring inactive pro-drugs into active and toxic substances is another strategy to treat glioblastoma. For example, herpes simplex virus type 1 thymidine kinase (HSV-tk) phosphorylates ganciclovir (GCV), such that the latter incorporates into DNA to disturb DNA synthesis in glioblastoma cells. The HSV-tk/GCV system has been tested in preclinical studies and the results showed increased tumor cell death and repressed tumor growth (de Melo et al., 2015). Another pro-drug activating enzyme is cytosine deaminase, which transfers 5-fluorocytosine to toxic 5-fluorouracil to cause glioblastoma cell death. Indeed, significant tumor volume reduction was detected in model animals who received transplantation of cytosine deaminase-expressing NSCs and MSCs (Jung et al., 2015). The oncolytic virus strategy involves viruses with the ability to infect, replicate within, and then lyse glioblastoma cells. NSCs loaded with replicating oncolytic adenovirus distribute prominently around tumor margins (Morshed et al., 2015) and can infect glioblastoma cells. Moreover, studies using stem cells loaded with myxoma virus and herpes simplex virus have demonstrated efficacy for repressing tumor growth (Josiah et al., 2010; Duebgen et al., 2014). Although a large amount of intriguing and exciting research has explored the feasibility of stem cell therapy for glioblastoma, only a few clinical trials are completed or in progress. In a completed pilot study, genetically modified NSCs were injected at the tumor site after surgical resection of the tumor foci (NCT02039778). Thus, further studies are needed to determine immunogenicity, efficacy, and optimum route of NSC transplantation. In vivo Tracing of Transplanted Stem Cells in the Brain The development of techniques to monitor the functional consequences of stem cell grafts after transplantation treatments is highly important. Tracing the fate of stem cells in the brain can be performed by direct labeling or the introduction of reporter genes. Direct labeling is based on imaging agents, such as radiotracers for nuclear imaging, or superparamagnetic iron oxide nanoparticles (Steinbeck and Studer, 2015). Alternatively, stem cells can be genetically modified to express reporter genes. The most commonly used reporter genes are luciferases for bioluminescence imaging and the transferring performed for MRI images (Duffy et al., 2014). Use of tracing techniques will lead to important discoveries about stem cell survival, migration, retention, and therapy monitoring. Conclusion and Perspective Over the decades, both basic scientists and clinicians have put tremendous efforts into the translation of stem cell therapies for treatment of neurological disorders. Preclinical research using disease models has yielded a large amount of evidence supporting the feasibility and efficacy of stem cell therapies. Clinical trials are also completed or underway for several neurological diseases, such as PD, AD, and AMD. However, in spite of these impressive and inspiring breakthroughs, major obstacles continue to hinder translation from basic research to real clinical application. These obstacles cannot be overlooked before stem cell therapies enter practical utilization. Generating the right types of cells and understanding underlying therapeutic mechanisms are both important aims to be considered. For example, substantial improvement in PD requires specific types of dopaminergic substantia nigra neurons. However, the situations in AD and TBI are more complex, as is often the case for neurological diseases, as various categories of cells are involved including neurons, glial cells, and vascular endothelial cells. Thus, transplanted cells may have to differentiate into several cell types to exert therapeutic effects. Cell replacement, whereby stem cells and their derivatives replace impaired or lost cell types to restore function, is considered to be the major mechanism underlying efficacy of stem cell transplantation. However, other mechanisms, such as the secretion of neurotrophic factors, immune modulation, and stimulation of endogenous neurogenesis also reportedly contribute to observed therapeutic effects. Thus, it is inadequate and irresponsible to administer stem cell therapies in patients without thoroughly understanding the underlying mechanisms. Current models of neurological disorders cannot completely reflect all aspects of a disease, which makes it risky, at least to some degree, to put basic research outcomes into clinical use. First, rodent models are unable to duplicate the exact physiological status of humans. Many models of AD use young, otherwise healthy mice, while the clinical situation for AD patients includes advanced age frequently with other chronic medication. Second, animal models are sometimes insufficient for demonstrating substantial improvement of clinically relevant functional deficits. For example, in PD rodent models, stem cell therapy was reported to attenuate rotational asymmetry. However, this deficit does not reflect any symptom observed in PD patients. Third, some adverse effects of stem cell therapy cannot be fully discovered by animal model studies. When dyskinesia was detected in patients who received human embryonic dopamine-neuron transplantation, it came as a surprise, because no preclinical studies had observed such adverse effects (Freed et al., 2001). Another obstacle is about tumorigenicity and adverse effects. Patients of some types of neurological disorders, PD patients for example, have a virtually normal life expectancy. In that case, even a minor possibility of tumor formation associated with stem cell therapy would be intolerable. Thus, more efforts should be made to thoroughly understand the mechanism of tumorigenicity of stem cells and their derivatives. In some clinical trials, devastatingly severe adverse events are detected, either related to the surgery or effects triggered by the stem cells. In a patient with TBI, acute promyelocytic leukemia occurred after autologous bone marrow-derived MSC transplantation, and the patient later died of disseminated intravascular coagulation. Basic researchers and clinicians are supposed to work together to minimize the possibility of such serious events and related damage to patients. To enter clinical application, a stem cell therapy needs to hold sufficient competitiveness compared with other conventional therapies, both in availability and therapeutic effectiveness. Currently, the sources of stem cell therapy, including ESCs and NSCs from human embryos or iPSCs from patients, are limited and associated with several problems, which may greatly increase the financial cost of stem cell therapy. ESC therapy is associated with ethical concerns and graft rejection. Meanwhile, the induction rate of iPSCs from patient somatic cells is relatively low, and may increase the cost of personalized treatment (Gamm et al., 2013). In the future, technical and protocol improvements are in great need to maximize the therapeutic effects and minimize the financial costs of stem cell therapies; only then will they finally be clinically competitive and useful. Additional file: Open peer review reports 1 and 2. Click here for additional data file. Conflicts of interest: None of the authors of this review has a financial interest related to this manuscript, and authors claim no conflicts of interest related to this work. Financial support: This paper was supported by the National Natural Science Foundation of China, No. 31471044; and a grant from the Ministry of Science and Technology of China, No. 2015AA020918. The funders did not participant in the study design, in the collection, analysis and interpretation of data, in the writing of the paper, and in the decision to submit the paper for publication. Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication. Plagiarism check: Checked twice by iThenticate. Peer review: Externally peer reviewed. Open peer reviewer: Yuan Wang, Sichuan University, State Key Laboratory of Biotherapy, China; Elham H A Ali, Ain Shams University, Egypt. Funding: This paper was supported by the National Natural Science Foundation of China, No. 31471044; and a grant from the Ministry of Science and Technology of China, No. 2015AA020918. ==== Refs 1 Aboody KS Brown A Rainov NG Bower KA Liu S Yang W Small JE Herrlinger U Ourednik V Black PM Breakefield XO Snyder EY Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas Proc Natl Acad Sci U S A 2000 97 12846 12851 11070094 2 Arnhold S Lenartz D Kruttwig K Klinz FJ Kolossov E Hescheler J Sturm V Andressen C Addicks K Differentiation of green fluorescent protein-labeled embryonic stem cell-derived neural precursor cells into Thy-1-positive neurons and glia after transplantation into adult rat striatum J Neurosurg 2000 93 1026 1032 11117845 3 Ayuso-Sacido A Moliterno JA Kratovac S Kapoor GS O’Rourke DM Holland EC Garcia-Verdugo JM Roy NS Boockvar JA Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells J Neurooncol 2010 97 323 337 19855928 4 Bae JS Jin HK Lee JK Richardson JC Carter JE Bone marrow-derived mesenchymal stem cells contribute to the reduction of amyloid-beta deposits and the improvement of synaptic transmission in a mouse model of pre-dementia Alzheimer’s disease Curr Alzheimer Res 2013 10 524 531 23036020 5 Bedi SS Hetz R Thomas C Smith P Olsen AB Williams S Xue H Aroom K Uray K Hamilton J Mays RW Cox CS Jr Intravenous multipotent adult progenitor cell therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury Stem Cells Transl Med 2013 2 953 960 24191266 6 Ben Abdallah NM Slomianka L Vyssotski AL Lipp HP Early age-related changes in adult hippocampal neurogenesis in C57 mice Neurobiol Aging 2010 31 151 161 18455269 7 Benedetti S Pirola B Pollo B Magrassi L Bruzzone MG Rigamonti D Galli R Selleri S Di Meco F De Fraja C Vescovi A Cattaneo E Finocchiaro G Gene therapy of experimental brain tumors using neural progenitor cells Nat Med 2000 6 447 450 10742153 8 Bernardo ME Fibbe WE Mesenchymal stromal cells: sensors and switchers of inflammation Cell Stem Cell 2013 13 392 402 24094322 9 Brazzini A Cantella R De la Cruz A Yupanqui J Leon C Jorquiera T Brazzini M Ortega M Saenz LN Intraarterial autologous implantation of adult stem cells for patients with Parkinson disease J Vasc Interv Radiol 2010 21 443 451 20346882 10 Cawsey T Duflou J Weickert CS Gorrie CA Nestin-positive ependymal cells are increased in the human spinal cord after traumatic central nervous system injury J Neurotrauma 2015 32 1393 1402 25599268 11 Chambers I Colby D Robertson M Nichols J Lee S Tweedie S Smith A Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells Cell 2003 113 643 655 12787505 12 Chew JL Loh YH Zhang W Chen X Tam WL Yeap LS Li P Ang YS Lim B Robson P Ng HH Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells Mol Cell Biol 2005 25 6031 6046 15988017 13 Chmielnicki E Benraiss A Economides AN Goldman SA Adenovirally expressed noggin and brain-derived neurotrophic factor cooperate to induce new medium spiny neurons from resident progenitor cells in the adult striatal ventricular zone J Neurosci 2004 24 2133 2142 14999064 14 Choi YS Dusting GJ Stubbs S Arunothayaraj S Han XL Collas P Morrison WA Dilley RJ Differentiation of human adipose-derived stem cells into beating cardiomyocytes J Cell Mol med 2010 14 878 889 20070436 15 Chun YS Chaudhari P Jang YY Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease Int J Biol Sci 2010 6 796 805 21179587 16 de Melo SM Bittencourt S Ferrazoli EG da Silva CS da Cunha FF da Silva FH Stilhano RS Denapoli PM Zanetti BF Martin PK Silva LM dos Santos AA Baptista LS Longo BM Han SW The anti-tumor effects of adipose tissue mesenchymal stem cell transduced with hsv-tk gene on u-87-driven brain tumor PLoS One 2015 10 e0128922 26067671 17 Doetsch F Caille I Lim DA Garcia-Verdugo JM Alvarez-Buylla A Subventricular zone astrocytes are neural stem cells in the adult mammalian brain Cell 1999 97 703 716 10380923 18 Du H Lim SL Grob S Zhang K Induced pluripotent stem cell therapies for geographic atrophy of age-related macular degeneration Semin Ophthalmol 2011 26 216 224 21609235 19 Duebgen M Martinez-Quintanilla J Tamura K Hingtgen S Redjal N Wakimoto H Shah K Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy J Natl Cancer Inst 2014 106 dju090 24838834 20 Duffy BA Weitz AJ Lee JH In vivo imaging of transplanted stem cells in the central nervous system Curr Opin Genet Dev 2014 28 83 88 25461455 21 Elder GA Gama Sosa MA De Gasperi R Transgenic mouse models of Alzheimer’s disease Mt Sinai J Med 2010 77 69 81 20101721 22 Fiorelli R Cebrian-Silla A Garcia-Verdugo JM Raineteau O The adult spinal cord harbors a population of GFAP-positive progenitors with limited self-renewal potential Glia 2013 61 2100 2113 24123239 23 Freed CR Greene PE Breeze RE Tsai WY DuMouchel W Kao R Dillon S Winfield H Culver S Trojanowski JQ Eidelberg D Fahn S Transplantation of embryonic dopamine neurons for severe Parkinson’s disease New Engl J Med 2001 344 710 719 11236774 24 Friedenstein AJ Petrakova KV Kurolesova AI Frolova GP Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues Transplantation 1968 6 230 247 5654088 25 Gamm DM Phillips MJ Singh R Modeling retinal degenerative diseases with human iPS-derived cells: current status and future implications Exp Rev Ophthalmol 2013 8 213 216 26 Goldberg NR Caesar J Park A Sedgh S Finogenov G Masliah E Davis J Blurton-Jones M Neural stem cells rescue cognitive and motor dysfunction in a transgenic model of dementia with lewy bodies through a BDNF-dependent mechanism Stem Cell Rep 2015 5 791 804 27 Goodus MT Guzman AM Calderon F Jiang Y Levison SW Neural stem cells in the immature, but not the mature, subventricular zone respond robustly to traumatic brain injury Dev Neurosci 2015 37 29 42 25377490 28 Gould E How widespread is adult neurogenesis in mammals? Nat Rev Neurosci 2007 8 481 488 17514200 29 Gu Q Wang J Wang L Liu ZX Zhu WW Tan YQ Han WF Wu J Feng CJ Fang JH Liu L Wang L Li W Zhao XY Hu BY Hao J Zhou Q Accreditation of biosafe clinical-grade human embryonic stem cells according to chinese regulations Stem Cell Rep 2017 9 366 380 30 Gualdoni S Baron M Lakowski J Decembrini S Smith AJ Pearson RA Ali RR Sowden JC Adult ciliary epithelial cells, previously identified as retinal stem cells with potential for retinal repair, fail to differentiate into new rod photoreceptors Stem Cells 2010 28 1048 1059 20506130 31 Gunnarsson S Bexell D Svensson A Siesjo P Darabi A Bengzon J Intratumoral IL-7 delivery by mesenchymal stromal cells potentiates IFNgamma-transduced tumor cell immunotherapy of experimental glioma J Neuroimmunol 2010 218 140 144 19914721 32 Hamilton LK Truong MK Bednarczyk MR Aumont A Fernandes KJ Cellular organization of the central canal ependymal zone, a niche of latent neural stem cells in the adult mammalian spinal cord Neuroscience 2009 164 1044 1056 19747531 33 Hochberg FH Pruitt A Assumptions in the radiotherapy of glioblastoma Neurology 1980 30 907 911 6252514 34 Hossini AM Megges M Prigione A Lichtner B Toliat MR Wruck W Schroter F Nuernberg P Kroll H Makrantonaki E Zouboulis CC Adjaye J Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer’s disease donor as a model for investigating AD-associated gene regulatory networks BMC Genomics 2015 16 84 25765079 35 Hsiung J Zhu D Hinton DR Polarized human embryonic stem cell-derived retinal pigment epithelial cell monolayers have higher resistance to oxidative stress-induced cell death than nonpolarized cultures Stem Cells Transl Med 2015 4 10 20 25411476 36 Hu Y Cheng P Xue YX Liu YH Glioma cells promote the expression of vascular cell adhesion molecule-1 on bone marrow-derived mesenchymal stem cells: a possible mechanism for their tropism toward gliomas J Mol Neurosci 2012 48 127 135 22562815 37 Hunsberger JG Rao M Kurtzberg J Bulte JWM Atala A LaFerla FM Greely HT Sawa A Gandy S Schneider LS Doraiswamy PM Accelerating stem cell trials for Alzheimer’s disease Lancet Neurol 2015 15 219 230 26704439 38 Israel MA Yuan SH Bardy C Reyna SM Mu Y Herrera C Hefferan MP Van Gorp S Nazor KL Boscolo FS Carson CT Laurent LC Marsala M Gage FH Remes AM Koo EH Goldstein LS Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells Nature 2012 482 216 220 22278060 39 Johansson CB Svensson M Wallstedt L Janson AM Frisen J Neural stem cells in the adult human brain ExpCell Res 1999 253 733 736 40 Josiah DT Zhu D Dreher F Olson J McFadden G Caldas H Adipose-derived stem cells as therapeutic delivery vehicles of an oncolytic virus for glioblastoma Mol Ther 2010 18 377 385 19904233 41 Jung JH Kim AA Chang DY Park YR Suh-Kim H Kim SS Three-dimensional assessment of bystander effects of mesenchymal stem cells carrying a cytosine deaminase gene on glioma cells Am J Cancer Res 2015 5 2686 2696 26609476 42 Kanemura H Go MJ Shikamura M Nishishita N Sakai N Kamao H Mandai M Morinaga C Takahashi M Kawamata S Tumorigenicity studies of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration PLoS One 2014 9 e85336 24454843 43 Kauer TM Figueiredo JL Hingtgen S Shah K Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas Nat Neurosci 2012 15 197 204 44 Kawano H Kimura-Kuroda J Komuta Y Yoshioka N Li HP Kawamura K Li Y Raisman G Role of the lesion scar in the response to damage and repair of the central nervous system Cell Tissue Res 2012 349 169 180 22362507 45 Kim HJ Seo SW Chang JW Lee JI Kim CH Chin J Choi SJ Kwon H Yun HJ Lee JM Kim ST Choe YS Lee K-H Na DL Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: A phase 1 clinical trial Alzheimer’s Dementia 2015 1 95 102 46 Kim IK Arroyo JG Mechanisms in proliferative vitreoretinopathy Ophthalmol clin North Am 2002 15 81 86 12064085 47 Kim KS Kim HS Park JM Kim HW Park MK Lee HS Lim DS Lee TH Chopp M Moon J Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model Neurobiol Aging 2013 34 2408 2420 23623603 48 Klassen H Kiilgaard JF Zahir T Ziaeian B Kirov I Scherfig E Warfvinge K Young MJ Progenitor cells from the porcine neural retina express photoreceptor markers after transplantation to the subretinal space of allorecipients Stem Cells 2007 25 1222 1230 17218397 49 Kordower JH Freeman TB Chen EY Mufson EJ Sanberg PR Hauser RA Snow B Olanow CW Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease Mov Disord 1998 13 383 393 9613726 50 Kordower JH Freeman TB Snow BJ Vingerhoets FJ Mufson EJ Sanberg PR Hauser RA Smith DA Nauert GM Perl DP Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease New Engl J Med 1995 332 1118 1124 7700284 51 Lane EL Handley OJ Rosser AE Dunnett SB Potential cellular and regenerative approaches for the treatment of Parkinson’s disease Neuropsychiatr Dis Treat 2008 4 835 845 19183776 52 Lawrence JM Singhal S Bhatia B Keegan DJ Reh TA Luthert PJ Khaw PT Limb GA MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics Stem Cells 2007 25 2033 2043 17525239 53 Lendahl U Zimmerman LB McKay RD CNS stem cells express a new class of intermediate filament protein Cell 1990 60 585 595 1689217 54 Li JY Englund E Holton JL Soulet D Hagell P Lees AJ Lashley T Quinn NP Rehncrona S Bjorklund A Widner H Revesz T Lindvall O Brundin P Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation Nat Med 2008 14 501 503 18391963 55 Lim DA Alvarez-Buylla A Adult neural stem cells stake their ground Trends Neurosci 2014 37 563 571 25223700 56 Lindvall O Kokaia Z Stem cells for the treatment of neurological disorders Nature 2006 441 1094 1096 16810245 57 Liu Y Weick JP Liu H Krencik R Zhang X Ma L Zhou GM Ayala M Zhang SC Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits Nat Biotechnol 2013 31 440 447 23604284 58 Liu Z Jiang Z Huang J Huang S Li Y Sheng F Yu S Yu S Liu X Mesenchymal stem cells show little tropism for the resting and differentiated cancer stem cell-like glioma cells Int J Oncol 2014 44 1223 1232 24481670 59 Lu B Malcuit C Wang S Girman S Francis P Lemieux L Lanza R Lund R Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration Stem Cells 2009 27 2126 2135 19521979 60 Luan Z Qu S Du K Liu W Yang Y Wang Z Cui Y Du Q Neural stem/progenitor cell transplantation for cortical visual impairment in neonatal brain injured patients Cell transplantation 22 Suppl 2013 1 S101 112 61 Luo J Baranov P Patel S Ouyang H Quach J Wu F Qiu A Luo H Hicks C Zeng J Zhu J Lu J Sfeir N Wen C Zhang M Reade V Patel S Sinden J Sun X Human retinal progenitor cell transplantation preserves vision J Biol Chem 2014 289 6362 6371 24407289 62 MacLaren RE Pearson RA MacNeil A Douglas RH Salt TE Akimoto M Swaroop A Sowden JC Ali RR Retinal repair by transplantation of photoreceptor precursors Nature 2006 444 203 207 17093405 63 Marei HE Farag A Althani A Afifi N Abd-Elmaksoud A Lashen S Rezk S Pallini R Casalbore P Cenciarelli C Human olfactory bulb neural stem cells expressing hNGF restore cognitive deficit in Alzheimer’s disease rat model J Cell Physiol 2015 230 116 130 24911171 64 Michelsen KA Acosta-Verdugo S Benoit-Marand M Espuny-Camacho I Gaspard N Saha B Gaillard A Vanderhaeghen P Area-specific reestablishment of damaged circuits in the adult cerebral cortex by cortical neurons derived from mouse embryonic stem cells Neuron 2015 85 982 997 25741724 65 Morshed RA Gutova M Juliano J Barish ME Hawkins-Daarud A Oganesyan D Vazgen K Yang T Annala A Ahmed AU Aboody KS Swanson KR Moats RA Lesniak MS Analysis of glioblastoma tumor coverage by oncolytic virus-loaded neural stem cells using MRI-based tracking and histological reconstruction Cancer Gene Ther 2015 22 55 61 25525033 66 Mothe AJ Tator CH Proliferation migration and differentiation of endogenous ependymal region stem/progenitor cells following minimal spinal cord injury in the adultrat Neuroscience 2005 131 177 187 15680701 67 Nasonkin I Mahairaki V Xu L Hatfield G Cummings BJ Eberhart C Ryugo DK Maric D Bar E Koliatsos VE Long-term, stable differentiation of human embryonic stem cell-derived neural precursors grafted into the adult mammalian neostriatum Stem Cells 2009 27 2414 2426 19609935 68 Niwa H Miyazaki J Smith AG Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells Nat Genetics 2000 24 372 376 10742100 69 Park SS Bauer G Abedi M Pontow S Panorgias A Jonnal R Zawadzki RJ Werner JS Nolta J Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings Invest Ophthalmol Vis Sci 2015 56 81 89 70 Pati S Khakoo AY Zhao J Jimenez F Gerber MH Harting M Redell JB Grill R Matsuo Y Guha S Cox CS Reitz MS Holcomb JB Dash PK Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/beta-catenin signaling Stem Cells Dev 2011 20 89 101 20446815 71 Peng YN Zhao ZQ Application of human induced pluripotent stem cells-derived dopaminergic neurons in the Parkinson’s disease models:present and future Zhongguo Zuzhi Gongcheng Yanjiu 2016 20 5458 5465 72 Piccini P Brooks DJ Bjorklund A Gunn RN Grasby PM Rimoldi O Brundin P Hagell P Rehncrona S Widner H Lindvall O Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient Nat Neurosci 1999 2 1137 1140 10570493 73 Pincus DW Keyoung HM Harrison-Restelli C Goodman RR Fraser RA Edgar M Sakakibara S Okano H Nedergaard M Goldman SA Fibroblast growth factor-2/brain-derived neurotrophic factor-associated maturation of new neurons generated from adult human subependymal cells Ann Neurol 1998 43 576 585 9585351 74 Prince M Wimo A Guerchet M Ali GC Wu YT Prina M World Alzheimer Report 2015. In: Resource document Alzheimer's Dis Int 2015 75 Qin J Song B Zhang H Wang Y Wang N Ji Y Qi J Chandra A Yang B Zhang Y Gong G Xu Y Transplantation of human neuro-epithelial-like stem cells derived from induced pluripotent stem cells improves neurological function in rats with experimental intracerebral hemorrhage Neurosci Lett 2013 548 95 100 23680458 76 Qu Z Guan Y Cui L Song J Gu J Zhao H Xu L Lu L Jin Y Xu GT Transplantation of rat embryonic stem cell-derived retinal progenitor cells preserves the retinal structure and function in rat retinal degeneration Stem Cell Res Ther 2015 6 219 26553210 77 Reh TA Neurobiology: right timing for retina repair Nature 2006 444 156 157 78 Rodriguez-Gomez JA Lu JQ Velasco I Rivera S Zoghbi SS Liow JS Musachio JL Chin FT Toyama H Seidel J Green MV Thanos PK Ichise M Pike VW Innis RB McKay RD Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease Stem Cells 2007 25 918 928 17170065 79 Safford KM Hicok KC Safford SD Halvorsen YD Wilkison WO Gimble JM Rice HE Neurogenic differentiation of murine and human adipose-derived stromal cells Biochem Biophys Res Commun 2002 294 371 379 12051722 80 Sakakibara S Imai T Hamaguchi K Okabe M Aruga J Nakajima K Yasutomi D Nagata T Kurihara Y Uesugi S Miyata T Ogawa M Mikoshiba K Okano H Mouse-Musashi-1 a neural RNA-binding protein highly enriched in the mammalian CNS stem cell Dev Biol 1996 176 230 242 8660864 81 Salero E Blenkinsop TA Corneo B Harris A Rabin D Stern JH Temple S Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives Cell Stem Cell 2012 10 88 95 22226358 82 Schwartz SD Hubschman JP Heilwell G Franco-Cardenas V Pan CK Ostrick RM Mickunas E Gay R Klimanskaya I Lanza R Embryonic stem cell trials for macular degeneration: a preliminary report Lancet 2012 379 713 720 22281388 83 Schwartz SD Regillo CD Lam BL Eliott D Rosenfeld PJ Gregori NZ Hubschman JP Davis JL Heilwell G Spirn M Maguire J Gay R Bateman J Ostrick RM Morris D Vincent M Anglade E Del Priore LV Lanza R Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies Lancet 2015 385 509 516 25458728 84 Seo BM Miura M Gronthos S Bartold PM Batouli S Brahim J Young M Robey PG Wang CY Shi S Investigation of multipotent postnatal stem cells from human periodontal ligament Lancet 2004 364 149 155 15246727 85 Shetty GA Hattiangady B Shetty AK Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus Age 2013 35 2165 2176 23322452 86 Shin JY Park HJ Kim HN Oh SH Bae JS Ha HJ Lee PH Mesenchymal stem cells enhance autophagy and increase beta-amyloid clearance in Alzheimer disease models Autophagy 2014 10 32 44 24149893 87 Sin HP Liu DT Lam DS Lifestyle modification, nutritional and vitamins supplements for age-related macular degeneration Acta Ophthalmol 2013 91 6 11 22268800 88 Song K Li W Li M Acute promyelocytic leukemia following autologous bone marrow-derived mesenchymal stem cell transplantation for traumatic brain injury: a case report Oncol Lett 2015a 10 2905 2908 26722261 89 Song WK Park KM Kim HJ Lee JH Choi J Chong SY Shim SH Del Priore LV Lanza R Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients Stem Cell Rep 2015b 4 860 872 90 Stanga PE Kychenthal A Fitzke FW Halfyard AS Chan R Bird AC Aylward GW Retinal pigment epithelium translocation after choroidal neovascular membrane removal in age-related macular degeneration Ophthalmology 2002 109 1492 1498 12153801 91 Steinbeck JA Studer L Moving stem cells to the clinic: potential and limitations for brain repair Neuron 2015 86 187 206 25856494 92 Stone LS Neural retina degeneration followed by regeneration from surviving retinal pigment cells in grafted adult salamander eyes Anat Rec 1950 106 89 109 15404757 93 Sun J Mandai M Kamao H Hashiguchi T Shikamura M Kawamata S Sugita S Takahashi M Protective effects of human iPS-derived retinal pigmented epithelial cells in comparison with human mesenchymal stromal cells and human neural stem cells on the degenerating retina in rd1 mice Stem Cells 2015 33 1543 1553 25728228 94 Sweet JA Feinberg ML Sherman JH The role of avastin in the management of recurrent glioblastoma Neurosurg Clin North Am 2012 23 331 341 95 Tajiri N Kaneko Y Shinozuka K Ishikawa H Yankee E McGrogan M Case C Borlongan CV Stem cell recruitment of newly formed host cells via a successful seduction? Filling the gap between neurogenic niche and injured brain site PLoS One 2013 8 e74857 24023965 96 Tajiri N Duncan K Antoine A Pabon M Acosta SA de la Pena I Hernadez-Ontiveros DG Shinozuka K Ishikawa H Kaneko Y Yankee E McGrogan M Case C Borlongan CV Stem cell-paved biobridge facilitates neural repair in traumatic brain injury Front Syst Neurosci 2014a 8 116 25009475 97 Tajiri N Acosta SA Shahaduzzaman M Ishikawa H Shinozuka K Pabon M Hernandez-Ontiveros D Kim DW Metcalf C Staples M Dailey T Vasconcellos J Franyuti G Gould L Patel N Cooper D Kaneko Y Borlongan CV Bickford PC Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats J Neurosci 2014b 34 313 326 24381292 98 Takagi Y Takahashi J Saiki H Morizane A Hayashi T Kishi Y Fukuda H Okamoto Y Koyanagi M Ideguchi M Hayashi H Imazato T Kawasaki H Suemori H Omachi S Iida H Itoh N Nakatsuji N Sasai Y Hashimoto N Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model J Clin Invest 2005 115 102 109 15630449 99 Takahashi K Yamanaka S Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors Cell 2006 126 663 676 16904174 100 Takahashi K Tanabe K Ohnuki M Narita M Ichisaka T Tomoda K Yamanaka S Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 2007 131 861 872 18035408 101 Thomsen GM Le Belle JE Harnisch JA Mc Donald WS Hovda DA Sofroniew MV Kornblum HI Harris NG Traumatic brain injury reveals novel cell lineage relationships within the subventricular zone Stem Cell Res 2014 13 48 60 24835668 102 Thomson JA Itskovitz-Eldor J Shapiro SS Waknitz MA Swiergiel JJ Marshall VS Jones JM Embryonic stem cell lines derived from human blastocysts Science 1998 282 1145 1147 9804556 103 Tian C Wang X Wang X Wang L Wang X Wu S Wan Z Autologous bone marrow mesenchymal stem cell therapy in the subacute stage of traumatic brain injury by lumbar puncture Exp Clin Transplantation 2013 11 176 181 104 Torrente D Avila MF Cabezas R Morales L Gonzalez J Samudio I Barreto GE Paracrine factors of human mesenchymal stem cells increase wound closure and reduce reactive oxygen species production in a traumatic brain injury in vitro model Human Exp Toxicol 2014 33 673 684 105 Tropepe V Coles BL Chiasson BJ Horsford DJ Elia AJ McInnes RR van der Kooy D Retinal stem cells in the adult mammalian eye Science 2000 287 2032 2036 10720333 106 Tsai Y Lu B Bakondi B Girman S Sahabian A Sareen D Svendsen CN Wang S Human iPSC-Derived neural progenitors preserve vision in an AMD-Like model Stem Cells 2015 33 2537 2549 25869002 107 Tzameret A Sher I Belkin M Treves AJ Meir A Nagler A Levkovitch-Verbin H Barshack I Rosner M Rotenstreich Y Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy Exp Eye Res 2014 118 135 144 24239509 108 Uchida N Buck DW He D Reitsma MJ Masek M Phan TV Tsukamoto AS Gage FH Weissman IL Direct isolation of human central nervous system stem cells Proc Natl Acad Sci U S A 2000 97 14720 14725 11121071 109 Venkataramana NK Pal R Rao SA Naik AL Jan M Nair R Sanjeev CC Kamble RB Murthy DP Chaitanya K Bilateral transplantation of allogenic adult human bone marrow-derived mesenchymal stem cells into the subventricular zone of Parkinson’s disease: a pilot clinical study Stem Cells Int 2012 2012 931902 22550521 110 Venkataramana NK Kumar SK Balaraju S Radhakrishnan RC Bansal A Dixit A Rao DK Das M Jan M Gupta PK Totey SM Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease Transl Res 2010 155 62 70 20129486 111 Wang JY Liou AK Ren ZH Zhang L Brown BN Cui XT Badylak SF Cai YN Guan YQ Leak RK Chen J Ji X Chen L Neurorestorative effect of urinary bladder matrix-mediated neural stem cell transplantation following traumatic brain injury in rats CNS Neurol Disord Drug Targets 2013a 12 413 425 23469853 112 Wang S Cheng H Dai G Wang X Hua R Liu X Wang P Chen G Yue W An Y Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury Brain Res 2013b 1532 76 84 23942181 113 Wernig M Zhao JP Pruszak J Hedlund E Fu D Soldner F Broccoli V Constantine-Paton M Isacson O Jaenisch R Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease Proc Natl Acad Sci U S A 2008 105 5856 5861 18391196 114 Xiong Y Mahmood A Chopp M Animal models of traumatic brain injury Nature reviews Neuroscience 2013 14 128 142 23329160 115 Yamazoe T Koizumi S Yamasaki T Amano S Tokuyama T Namba H Potent tumor tropism of induced pluripotent stem cells and induced pluripotent stem cell-derived neural stem cells in the mouse intracerebral glioma model Int J Oncol 2015 46 147 152 25310640 116 Yang CS He D Tan J Co-culture with vascular endothelial progenitor cells: effects on proliferation and apoptosis of neural stem cells and vascular remodeling in rats with ischemia reperfusion injury Zhongguo Zuzhi Gongcheng Yanjiu 2017 21 718 723 117 Yen BL Huang HI Chien CC Jui HY Ko BS Yao M Shun CT Yen ML Lee MC Chen YC Isolation of multipotent cells from human term placenta Stem Cells 2005 23 3 9 15625118 118 Yin F Tian ZM Liu S Zhao QJ Wang RM Shen L Wieman J Yan Y Transplantation of human retinal pigment epithelium cells in the treatment for Parkinson disease CNS Neurosci Ther 2012 18 1012 1020 23190934 119 Young M Chui L Fallah N Or C Merkur AB Kirker AW Albiani DA Forooghian F Exacerbation of choroidal and retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration Retina 2014 34 1308 1315 24451923 120 Yu J Vodyanik MA Smuga-Otto K Antosiewicz-Bourget J Frane JL Tian S Nie J Jonsdottir GA Ruotti V Stewart R Slukvin II Thomson JA Induced pluripotent stem cell lines derived from human somatic cells Science 2007 318 1917 1920 18029452 121 Yuan X Hu J Belladonna ML Black KL Yu JS Interleukin-23-expressing bone marrow-derived neural stem-like cells exhibit antitumor activity against intracranial glioma Cancer Res 2006 66 2630 2638 16510582 122 Zhang Q Wu HH Wang Y Gu GJ Zhang W Xia R Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer’s disease J Neurochem 2015 doi: 10.1111/jnc.13413 123 Zhang R Liu Y Yan K Chen L Chen XR Li P Chen FF Jiang XD Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury J Neuroinflammation 2013 10 106 23971414 124 Zhang S Luo X Wan F Lei T The roles of hypoxia-inducible factors in regulating neural stem cells migration to glioma stem cells and determinating their fates Neurochem Res 2012 37 2659 2666 22991140 125 Zhang S Xie R Zhao T Yang X Han L Ye F Lei T Wan F Neural stem cells preferentially migrate to glioma stem cells and reduce their stemness phenotypes Int J Oncol 2014a 45 1989 1996 25176161 126 Zhang W Wang GM Wang PJ Zhang Q Sha SH Effects of neural stem cells on synaptic proteins and memory in a mouse model of Alzheimer’s disease J Neurosci Res 2014b 92 185 194 24265160 127 Zhang YW Denham J Thies RS Oligodendrocyte progenitor cells derived from human embryonic stem cells express neurotrophic factors Stem Cells Dev 2006 15 943 952 17253955 128 Zhao D Najbauer J Garcia E Metz MZ Gutova M Glackin CA Kim SU Aboody KS Neural stem cell tropism to glioma: critical role of tumor hypoxia Mol Cancer Res 2008 6 1819 1829 19074827 129 Zheng W ZhuGe Q Zhong M Chen G Shao B Wang H Mao X Xie L Jin K Neurogenesis in adult human brain after traumatic brain injury J Neurotrauma 2013 30 1872 1880 21275797 130 Zuo FX Bao XJ Sun XC Wu J Bai QR Chen G Li XY Zhou QY Yang YF Shen Q Wang RZ Transplantation of human neural stem cells in a parkinsonian model exerts neuroprotection via regulation of the host microenvironment Int J Mol Sci 2015 16 26473 26492 26556344