Stem Cells in Neurological Disorders: Emerging Therapywith Stunning Hopes

Ghanshyam Upadhyay & Sharmila Shankar &

Rakesh K. Srivastava

Received: 28 June 2014 /Accepted: 27 August 2014# Springer Science+Business Media New York (outside the USA) 2014

Abstract Neurodegenerative diseases are still a challenge forresearchers and clinicians due to its complexity. Traditionalmedicines usually do not provide sufficient protection againstthese diseases due to drug resistance and relapse. The discov-ery of the therapeutic potential of stem cells offers new op-portunities for the treatment of incurable neurological dis-eases. Based on their biological properties, stem cells candifferentiate into specific tissue type and maintain the cellulartissue/organ homeostasis in physiological and pathologicalconditions. Recently, it has been demonstrated that somaticcells of patients can be reprogrammed to a pluripotent statefrom which neural lineage cells can be derived. Potentialstrategies such as cell replacement therapy and gene transferto the diseased or injured brain have opened a new line oftherapeutic approach for a broad spectrum of human neuro-logical diseases. Thus, stem cell replacement therapy forcentral and peripheral nervous system disorders aims atrepopulating the affected neural tissue with new neurons.However, the limiting factors that have hampered thedevelopment of this promising therapeutic approach arethe lack of suitable cell types for cell replacementtherapy in patients suffering from neurological disorders.

In this review, we have discussed the recent advances instem cell replacement therapy with particular emphasisto neurological disorders.

Keywords Neuron . Stem cells . Neurodegenerative diseases

AbbreviationsDA DopaminergicESCs Embryonic stem cellsiPSCs Induced pluripotent stem cellsiPS cells Induced pluripotent stem cellsADSCs Adipose-derived stromal cellsBM-MSCs Bonemarrow-derived mesenchymal stem cellsNSCs Neural stem cellsNGF Nerve growth factorBDNF Brain-derived growth factorOct4 Octamer-binding transcription factor 4Mbd3 Methyl-CpG-binding domain protein 3NuRD Nucleosome remodeling and deacetylaseAscl1 Achaete-scute complex homolog 1Brn2 Brain-2Myt1l Myelin transcription factor 1-likeNeuroD Neuronal differentiationOLIG2 Oligodendrocyte lineage transcription factor 2Zic1 Zinc finger protein of the cerebellum 1miR-9/9* Bifunctional microRNA strands 9miR-124 MicroRNA 124Lmx1a LIM homeobox transcription factor 1 alphaNurr1 Nuclear receptor related 1Pitx3 Paired-like homeodomain 3Foxa2 Forkhead box A2EN1 Engrailed homeobox 1Lhx3 LIM homeobox 3Hb9 Homeobox 9

G. UpadhyayDepartment of Biology, City College of New York, MarshakBuilding, 160 Convent Avenue, New York, NY 10031, USAe-mail: upadhyayiitr@gmail.com

S. Shankar (*) : R. K. Srivastava (*)Kansas City VA Medical Center, 4801 Linwood Boulevard, KansasCity, MO 66128, USAe-mail: sharmila.shankar@va.gove-mail: rsrivastava.lab@gmail.com

S. ShankarDepartment of Pathology, University of Missouri-Kansas City,Kansas City, MO 64108, USA

Mol NeurobiolDOI 10.1007/s12035-014-8883-6

Isl1 Islet 1 (ISL LIM homeobox 1)Ngn2 Neurogenin 2Sox2 Sex determining region Y box 2Klf4 Krüppel-like factor 4c-Myc v-Myc avian myelocytomatosis viral

oncogene homologE47/Tcf3 Transcription factor 3Aβ Amyloid-betaAPP Amyloid precursor proteinASC Adult Stem CellsBM-MSC Bone marrow mesenchymal stem cellChAT Choline-acetyltransferaseEPI-NCSC Epidermal neural crest stem cellES Embryonic stem cellNGFR Nerve growth factor receptorhNSC Human neural stem cellmNSC Murine neural stem cellUCB-MSC Umbilical cord blood mesenchymal stem cellLRRK2 Leucine-rich repeat kinase 2PINK1 PTEN-induced putative kinase 1Fbxo7 F-Box only protein 7PSEN1 Presenilin protein 1PSEN2 Presenilin protein 2TREM2 Triggering receptor expressed on myeloid

cells 2APP Amyloid precursor proteinSOD1 Superoxide dismutase 1VAPB Vesicle-associated membrane protein-

associated protein B/CTDP43 TAR DNA-binding protein 43C9ORF72 Chromosome 9 open reading frame 72FUS Fused in sarcomaABCG2 ATP-binding cassette sub-family G member 2CXCR4 C-X-C chemokine receptor type 4FGF R4 Fibroblast growth factor receptor 4Frizzled-9 Frizzled class receptor 9Glut1 Glucose transporter 1SSEA-1 Stage-specific embryonic antigen 1BLBP/FABP7

Brain lipid binding protein (also fatty acidbinding protein 7)

GLAST/SLC1A3

Glutamate aspartate transporter or solutecarrier family 1 (glial high-affinity glutamatetransporter) member 3

GFAP Glial fibrillary acidic proteinS100B S100 calcium binding protein BPAX6 Paired box protein 6TBR2 T-box brain protein 2 or eomesoderminFGF Fibroblast growth factorIslet-1 and 2 ISL LIM homeobox 1 and 2Lhx3 LIM/homeobox protein 3Olig2 Oligodendrocyte transcription factorMOG Myelin oligodendrocyte glycoproteinGalC Galactosylceramidase

NeuN Feminizing locus on X-3 Fox-3 Rbfox3, orhexaribonucleotide binding protein-3

NF-L Light neurofilamentNF-M Medium neurofilamentTH Tyrosine hydroxylaseGAD Glutamic acid decarboxylasePSD-95 Postsynaptic density protein 95VAMP Vesicle-associated membrane proteinsEMT Mesenchymal to endothelial transition

Introduction

Neurological diseases are characterized by any disorder in thecentral nervous system (CNS) or the peripheral nervous sys-tem (PNS) due to structural, biochemical, and electrophysio-logical dysfunctions of neurons or glial cells. Neurodegener-ative diseases are common types of neurological disordersresulting from progressive degeneration or functional loss ofneurons [1–3]. Parkinson’s disease (PD), Alzheimer’s disease(AD), Huntington’s disease (HD), and amyotrophic lateralsclerosis (ALS) are included in the category of neurodegener-ative diseases (Fig. 1). Regardless of the type of neurologicaldisease, all symptoms result from the significant loss of neu-rons or glial cells in the nervous system. For example, PD iscaused by the death of dopaminergic (DA) neurons in thesubstantia nigra pars compacta of the midbrain; HD resultsfrom the death of medium spiny neurons in the basal ganglia,and ALS is caused by the death of motor neurons [1–3].

Although being a most prominent elderly problem, nopromising therapy is available for the treatment of neurode-generative diseases. Various scientific attempts have beenmade in past to address this alarming issue with limited orno success. Advancement of knowledge about stem cells hasdrawn attention towards stem cell therapy as a promisingtherapeutic option for the treatment of various neurologicdisorders. Stem cells hold great promise for regenerativetherapies by virtue of their ability to regenerate tissues andcontribute to their homeostasis [4]. The stem cells have bio-logical properties of self-renewal and have capability to giverise to differentiated cell progenies that maintain tissue ho-meostasis in physiological and pathological conditions. It isnow well known that stem cells can be specifically and effi-ciently directed toward distinct cell lineages in vitro apart frompluripotency. These properties of stem cells could be translat-ed in clinics for the treatment of disease that have limitedtherapeutic hopes [5–7]. The baseline and clinical studies,harboring these properties of stem cells, are underway, andthe hopes are stunning. Advancement in the approach of stemcell therapy is not limited to neurological disorders but in-cludes a wide spectrum of diseases such as cardiovascular,gastrointestinal, pulmonary diseases, etc.

Mol Neurobiol

Currently, a number of stem cells such as embryonic stemcells (ESCs), induced pluripotent stem cells (iPSCs), adipose-derived stromal cells, bone marrow-derived mesenchymalstem cells (BM-MSCs), and neural stem cells (NSCs) arebeing investigated for their therapeutic potential using animalmodels. Studies have shown that neurons, oligodendrocytes,and astrocytes could be generated from ESCs and adult stemcells (ASCs) [8–11] (Fig. 2). Moreover, it has been also foundthat the NSCs in the sub-ventricular zone of the lateral ventri-cles and the sub-granular zone of the dentate gyrus in thehippocampus of the mammalian brain maintain the capabilityto generate new neural cells throughout the lifetime [9, 12, 13].

Although various animal studies to date have been con-ducted indicating the therapeutic potential of stem cells incombating against neurological diseases, a lot needs to bedone before clinical application on human subjects. In thisreview, we have discussed the recent advances in stem cellreplacement therapy, challenges, and future prospects withparticular emphasis to neurological disorders.

Strategies in stem cell replacement therapyfor neurological diseases

The process of stem cell replacement therapy is very stringent,particularly in case of neurological disorders. The success de-pends on precautions and fine-tuning of the development oftightly controlled isolation, expansion, and sorting processes.Maintaining the self-renewal and multi-potential properties ofstem cells is critical along with safety and efficacy of transplan-tation procedures [14, 15]. The basic strategies in stem cellreplacement therapy for neurological diseases include stem cellstransplantation within the brain or infusion by blood circulation;stem and progenitor cells mobilization by cytokines, or trophicand growth factors, into the brain in vivo; delivery of stem cells

through bone marrow transplantation; engineering of stem cellsto correct the genetic defect; reprogramming of neuronal cells;and coupling of stem cells with biomaterials (Fig. 3).

A study by Osanai et al. reported that the carotid arteryinjection of stem cells could, together with in vivo opticalimaging to track the injected cells after transplantation, poten-tially be part of a new approach for stem cell transplantation inhuman brain trauma injuries [16]. In this study, the stem cellsobtained from the rats’ bone marrow were labeled with quan-tum dots (a biocompatible, fluorescent semiconductor), con-stituted a non-invasive method of monitoring the stem cellsfor a period of 4 weeks following transplantation [16]. Theywere able to show that the injected cells entered the brainwithout entering the general circulation. They also observedthat the stem cells started migrating from the capillaries intothe injured part of the brain within 3 h.

For the proper migration and spreading of transplanted stemcells, it is important to select the best injection site, the correcttherapeutic cell number, and the monitoring of proper engraft-ment and differentiation of stem cells within the brain [8]. Somepositives came out while transplanting ESCs or ASCs into thebrain of animal models of AD, PD, HD, lysosomal storagedisorders (LSDs), demyelinating disorders, and traumatic lesionsof the brain and spinal cord [5, 17, 18]. Combination of stem celltransplantation with nerve growth factor (NGF) and brain-derived growth factor (BDNF), therapeutic molecules, or genetransfer technology was also investigated [10, 19, 20] withlimited success. Another alternative approach was the transplan-tation of more lineage restricted progenitor cells. In this context,novel technologies were used to facilitate the generation of largenumbers of committed cell populations for testing in cell replace-ment and regenerative paradigms [5, 21].

Concurrently, serious efforts of tissue engineering weremade that include the transplantation of stem cells in combi-nation with natural or synthetic biomaterials citing the studies

Fig. 1 Genetic mutationsassociated withneurodegenerative diseases:Mutations in the LRRK2, parkin,PINK1, SNCA, Fbxo7 result inPD; mutations in PSEN1, PSEN2,APP, TREM2, etc., can lead toAD; expansion CAG repeat inHuntingtin gene (HTT) is wellknown cause of HD; mutations inSOD1, VAPB, TDP43,C9ORF72, FUS led to ALS

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that have shown the enhancement of donor cell survival aftertransplantation of intact tissue [22, 23]. This success could beattributed to the presence of a three-dimensional architectureand a higher accessibility of extracellular adhesive proteinswith which donor cells can interact [23]. Remarkably, thetissue-engineering approaches have some success, and thetransplantation of encapsulated growth factor-secreting cellsand NSCs within porous poly-glycolic acid scaffolds haveshown positive results against hypoxia/ischemia [24]. Theseefforts also got momentum from the reports stating that chem-ical and biological modifications of biomaterials could direct-ly influence stem cell behavior such as alteration of substrateproperties, nano-pattern design, and scaffold degradation rate[23, 25]. Additionally, these stem cells were also used incombination with a three-dimensional biomaterial (scaffolds)for the treatment of traumatic brain injury or the regenerationof injured spinal cord [26].

However, limitation of transplantation therapy, such as hostimmune response to the cells or specific antigens and otherassociated risks, in neurogenesis and differentiation in vivo,

and ethical issues, particularly of scientific work on abortedfetuses, drove the focus on the development of more ethicalmethods (such as using ASCs) that could enable us to researchethically [15]. Reprogramming of neuronal cells is of majorfocus these days. Adult somatic cells, such as skin fibroblasts,are targeted to generate new class of pluripotent stem cells(induced pluripotent cells (iPS)) by introduction ofembryogenesis-related genes like Oct4, Sox2, Klf4, and c-Myc [11, 27–32]. The process requires initial cell proliferationfollowed by a conversion of a fraction of the cell progeny intoan embryonic stem (ES)-like state with different time latencies[27]. Since then, a number of successful attempts ofreprogramming with different compositions of these geneshave been tried (Table 1). Epigenetic regulation by a varietyof chromatin modifiers also play critical role inreprogramming. Rais et al. recently showed that depletion ofMbd3, a core member of the Mbd3/NuRD repressor complexfor nucleosome remodelling and deacetylation, together withOct4, Sox2, Klf4, and c-Myc co-transduction andreprogramming in naive pluripotency promoting conditions,

Astrocytes: CD44

FGF R3, GFAP,

Glast, S100B

Early progenitor

cells

Differentiated

cells

Neural progenitors can broadly

classified in radial glial cells

(BLBP/FABP7,

GLAST/SLC1A3, GFAP,

Nestin, S100B, Vimentin) and

basal progenitors (PAX6–

SOX2– TBR2)

Differentiated Post-Mitotic

Neuronal Cells: NeuN

Neurofilaments (e.g. NF-L,

NF-M), GAD, TH, PSD-95,

Synaptophysin, VAMP

Oligodendrocytes:

GalC, MOG, Myelination

Antigen O1, O4 and Sox10

Neural stem

cells

Neural stem cells:

ABCG2, CD133, CXCR4,

FGF R4, Frizzled-9, Glut1,

SSEA-1, Notch-1 & -2

Glial-restricted

progenitors: A2B5, FGF

Receptors, Nestin

Motor neuron progenitors:

Islet-1 & -2, Lhx3,

Neurogenin-2, Olig2

Neuron-restricted

progenitors:

Doublecortin, NCAM,

MAP2, β-III Tubulin

Motor Neurons: Islet 1 & -2,

Lhx3, Neurogenin 2, Olig2

Late progenitor

cells

Fig. 2 Differentiation of stem cells in neuronal lineages: Neural stemcells have capability of self renew itself and give rise early neuralprogenitors. These early progenitors further differentiate into committedprogenitors like glial-restricted progenitors, motor neuron progenitors,

and neural-restricted progenitors that ultimately generate mature neuralpopulation. Each neural population can be identified and purified on thebasis of certain markers/proteins they express during the course ofdifferentiation

Mol Neurobiol

result in deterministic and synchronized iPS cellreprogramming [54]. These findings have mobilized the ap-proach as iPS cells could offer the opportunity to generatepatient-specific stem cells from somatic differentiated cells ofpatients affected by several neurological disorders as com-pared with the traditional ESCs [11, 55, 56].

Applications of Stem Cells in Neurological Diseases

The stem cell research, in particular, translational stem cell-based research and stem cell-based clinical applications, hasincreased during recent years [8, 17, 57]. Stem celltransplanting approaches for neurological diseases compriseof ESCs and several types of ASCs. These include bonemarrow-derived cells (both hematopoietic stem cells and bonemarrow-derived stem cells), NSCs, human umbilical cordblood stem cells, and mesenchymal stem cells [8, 17]. More-over, patient-specific iPS cells also have influence on thedevelopment of new therapies for neurological disorders [6,27].

Generally, clinical trials based on stem cell replacementtherapy are confined to patients with PD, HD, ALS, and someLSDs [5]. Although stem cell research for these diseases to

date has limited success and variable results, the positive is theability of stem cells to integrate into host brain tissues in mostof the cases with some positive effects for the recipients. In afew cases, stem cells were able to restore the degeneratedtissue [58–63].

Neurological diseases include a variety of disorders of thebrain, the spinal cord, and the PNS and have some commonfeatures such as neural dysfunctions, progressive deteriora-tion, and extensive loss of neural cells. The pathogenic mech-anism is diverging and complex. Therefore, the effective stemcell replacement therapy demands that these cells should betailored to the specific dysfunctions.

Parkinson’s Disease

PD is a progressive neurological disorder characterized byshaking (tremors) and difficulty with walking, movement,and coordination. It is one of the most common nervoussystem disorders of the elderly and is characterized by the lossof DA neurons and glial cells [1, 64]. To date, no specifictreatment strategy has been developed for the treatment of PD;however, recent focus is stem cell therapy (Table 2). Strategiesin PD stem cell therapy basically involve the replacement of

Gene Therapy

Stem cells

Implantation

Stem cells

Implantation by

blood infusion

Stem cells and

biomaterials

(Neural-

engineering)

Foetal brain

Pre-implantation embryo

Embryonic

stem cells

Fibroblast cells

Mesenchymal

stem cells

iPS cells

Neural progenitor or

neuronal cells

Reprogramming

EMT Sox2

c-Myc

Oct4

Klf4

Stem cells

Implantation by

BMT

Fig. 3 Strategies in stem cell replacement therapy for neurologicaldiseases: The major problem with stem cell therapy is to obtain startingcell population. Embryonic stem cells that have capability to differentiatein neural progenitors can be obtained from pre-implantation embryoswhich is a major ethical consideration. Ethical consideration is associated

with neural stem cells and committed neural progenitors obtained fromfetal brain also. Other methods to obtain starting cell population could betrans-differentiation of mesenchymal cells to neural progenitors orreprogramming of adult cells (like fibroblast) to iPSCs, which can bedifferentiated into neural progenitors for the therapy

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degenerated neurons with other dopamine-producing cells[77]. The first clinical stem cell therapy of PD took place in1987 using aborted human fetal ventral midbrain tissue, andsince then, more than 400 PD patients have undergone stemcell therapy [78–80]. Initial attempts in this direction were

consisted of the transplantation of cells isolated from pieces offetal midbrain tissue containing neuronal progenitor celltypes, as donor cells [81]. In PD, where the DA neurons areprogressively lost over time, the goals of stem cell therapy wasthe replacement of those neurons and for the restoration of

Table 1 Summary of primarycells, infection method, and com-position of factors for directreprogramming to neuronal cells

Primary cells Infectionmethod

Factors References

Fibroblasts Lentiviral Ascl1, Brn2, Myt1l [33, 34]

Fibroblasts Lentiviral Ascl1, Brn2, Myt1l, NeuroD [35]

Fibroblasts Lentiviral Ascl1, Myt1l, NeuroD2, miR-9/9*,and miR-124

[36]

Fibroblasts Lentiviral Ooc4, Sox2, Nanog, and Lin28 [37]

Fibroblasts Lentiviral Oct4, Sox2, Klf4, and Myc [38]

Fibroblasts Lentiviral Ascl1, Brn2, Myt1, Lmx1a, Fox2 [39]

Fibroblasts Retroviral Ascl1, Brn2, Myt1l, NeuroD1,Lhx3, Hb9, Isl1, Ngn2

[40]

Fibroblasts: Coriell, GM11272,GM16548, GM17880, GM11270

Retroviral Sox2, Oct4, c-Myc, and Klf4 [41]

Fibroblasts: Patient biopsy andCoriell, GM17880, GM11270

Retroviral Oct4, Sox2, Klf4, and Myc [42]

Fibroblasts Lentiviral Sox2, Brn2, FoxG1 [43]

Fibroblasts Retroviral Sox2, Brn4/Pou3f4, Klf4, c-Myc, E47/Tcf3 [44]

Fibroblasts Retroviral Oct3/4, Sox2, Klf4, and c-Myc [45]

Fibroblasts Retroviral Oct4, Sox2, Klf4, and c-Myc [46]

Fibroblasts Lentiviral Brn2, Myt1l, miR-124 [47]

Fibroblasts Lentiviral Ascl1, Lmx1a, Nurr1 [48]

Fibroblasts Retroviral Sox2 [49]

hiPSCs derived from fibroblasts Lentiviral Rex1, Nanog, Crupto, Oct4, and Sox2 [50]

Fibroblasts Retroviral c-Myc, Oct3/4, Klf4, and Sox2 [51]

Fibroblasts: Coriell, GM02038,GM01792, GM01835, GM02497

Lentiviral Oct4, Sox2, Klf4, Myc, and Lin28 [52]

Fibroblasts Lentiviral Ascl1, Lmx1a, Nurr1, Pitx3, FoxA2, EN1 [53]

Table 2 Summary of stem cell research conducted in animal models of PD

Animal model Cell source Outcome Reference

6-OHDA unilateral lesion rat iPS clone O9 Ipsilateral rotation (amphetamine)—decrease [65]

iPS cells IMR90 clone 4 Decline in rotation score [66]

iPS cells excisable virus Ipsilateralrotation (amphetamine) —decrease [67]

Mesencephalic DA neurons Ipsilateralrotation (amphetamine) —complete reversal [68]

mES cells-derived dopamine neurons Ipsilateralrotation (amphetamine) —complete reversal [69]

hES cells-derived dopamine neurons Ipsilateralrotation (amphetamine) —complete reversal [70]

hES cells-derived dopamine neurons Ipsilateralrotation (amphetamine) and contralateralrotation (apomorphine)—decrease

[71]

hES cells Ipsilateralrotation (amphetamine) and contralateralrotation (apomorphine)—decrease

[72]

6-OHDA bilateral lesion rat mES cells-derived dopamine neurons Ipsilateralrotation (amphetamine) —complete reversal [73]

6-OHDA unilateral lesion mouse mES cells-derived dopamine neurons Ipsilateralrotation (amphetamine) —decrease [74]

ntES cell-derived dopamine neurons Ipsilateralrotation (amphetamine) —decrease [75]

ntES cell-derived from parkinsonian mice Ipsilateralrotation (amphetamine) —complete reversal [76]

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normal neuronal sprouting, connectivity, and functionality[82]. Many groups harbor the molecular mechanisms bywhich ESCs generate various kinds of neurons includingDA neurons. Friling et al. showed the generation of DAneurons from mouse and human ESCs due to over-expression of Lmx1a, a transcription factor acting as a deter-minant of mesencephalic dopamine neurons during embryo-genesis [83].

Several studies reported symptomatic improvement in PDpatients after transplantation of these cells [84, 85]; however,several studies showed negative results also [86, 87]. Failureof these studies could be attributed to the difficulties in surgi-cal transplantation of fetal mesencephalic cells, or from non-specific cells within the fetal tissue that could have interferedwith cell growth and differentiation [88–90]. During the lastdecade, the advancement of the knowledge aboutreprogramming of adult cells to iPS cells has given a lot ofhope. Byers et al. established iPS cells with capacity to dif-ferentiate into functional neurons from a patient with a dom-inant autosomal form of PD [91]. Later on,Wernig et al., usinga mouse model, showed that iPS cells can be efficientlydifferentiated into neural precursor cells with the potential togive rise to glial and neuronal cells including glutamatergic,GABAergic, and catecholaminergic subtypes upon transplan-tation into the fetal mouse brain. They further illustrated thatthe iPS cells induced to differentiate into dopamine neuronswere able to improve behavior in a rat model of PD upontransplantation into the adult brain [65]. Recently, Sagal et al.showed that ectopic expression of Atoh1, in combination withcell extrinsic factors, drives the hPSCs into functional DAneurons with >80 % purity. These neurons recapitulate keybiochemical and electrophysiological features of midbrain DAneurons and provide a reliable disease model for studying PDpathogenesis [92].

Alzheimer’s Disease

AD is an irreversible, progressive neurological disorder thatslowly destroys memory and thinking skills and eventuallyeven the ability to carry out the simplest tasks [93]. It is a late-onset disease, and symptoms appear mostly after the age of60 years. AD is the most common cause of dementia, charac-terized by the loss of cognitive functioning-thinking, remem-bering, and reasoning, to such an extent that it interferes with aperson’s daily life and activities [93, 94]. An early symptom ismemory lapses (amnesia). As disease progresses, memoryproblems worsen, increasing confusion and disorientation,obsessive, repetitive, or impulsive behavior, recognition prob-lem (agnosia), and delusions. In the later stages ofAlzheimer’s disease, the symptoms become increasingly se-vere with problems with speech or language (aphasia), dis-turbed sleep, changes in mood, difficulty performing spatial

tasks (apraxia), problems with eyesight, etc. Estimates vary,but experts suggest that as many as 5.2 million Americansmay have AD [95]. The cause of AD is not entirely known,but it is thought to include both genetic and environmentalfactors. A diagnosis of AD is made when certain symptomsare present, and by making sure other causes of dementia arenot present.

Stem cell-based therapy for AD is confined to theneurogenesis or repopulation of the degenerated brain. Atpresent, stem cell treatment is limited to preclinical studieson AD animal models, and preclinical findings have to beextrapolated in clinics. However, preclinical studies havesome points, and hopes are rising for the development ofnew therapeutic approach (Table 3). ESCs, as well as ofseveral ASC types, has already been shown to be effective;the recent approach combining stem cells with molecules witha neurological function is more promising. In fact, the intro-duction of additional factors is a necessary support for thetherapy of the disease [109–111]. Recently, Sugaya et al.generated neural cells in the mouse brain by using both neuraland mesenchymal stem cell transplantation and a small mo-lecular compound (phenserine, a cholinesterase inhibitordrug), leading to an improvement of cognitive function inanimal models [110]. These results are interesting, and animprovement in the mouse’s cognitive functions and otherAD pathogenesis hallmarks was observed.

Evidence from in vitro mouse ESC culture studies hasindicated that neural progenitor cells (NPCs) can be generatedfrom ESCs, expanded, and differentiated efficiently into neu-rons and glial cells by serum-free culture [112, 113]. Wanget al. showed that ESC-derived neurospheres transplanted intothe frontal cortex of animals in an nbM lesion mouse modelsurvive and produce many ChAT-positive neurons and a fewserotonin-positive neurons in and around the engrafted cellsand improve working memory [106]. Moghadam et al.transplanted primed and unprimed mESC-derived NPCs intothe unilateral nbM in a rat model of AD. The results showedsignificant learning and memory improvements and also themajority of the engrafted NPCs retain a neuronal phenotypeand approximately 40 % of these cells show a cholinergic cellphenotype [114]. Tang et al. also showed therapeutic effects ofNPCs derived from ESCs following transplantation into a ratAD model with dorsal hippocampal injury induced by Aβ.The transplantation resulted in amelioration of memory im-pairment after 16 weeks [115]. Furthermore, some studieshave also shown hESCs having the potential to treat manyneurodegenerative diseases and brain injuries including AD[116–118].

In contrast to ESC-based therapy, which is complicated byimmune rejection because of immunological incompatibilitybetween patients and donor cells, iPSCs can be generatedfrom the patient’s own somatic cells, thus avoiding the ethi-cally controversial use of human embryos and immunogenic

Mol Neurobiol

rejection [119]. Patient-derived iPSCs retain the patient’s ge-notype, therefore enabling the applicable recapitulation of ADphenotype in a dish. The high-content screening assays andthe barriers that exist to evaluate the full potential in predictiveefficacy, toxicology, and disease modeling in these cells couldenable rapid analysis of thousands of drugs for AD simulta-neously [120]. Yagi et al. generated iPSCs from fibroblasts ofearly onset familial AD (FAD) patients with mutations in PS1(A246E) and PS2 (N141I), and showed that secretion ofAβ42 from FAD-iPSC-derived neurons is increased signifi-cantly and markedly reduced by γ-secretase inhibitors andmodulators [121, 122]. Using this human iPSC-based modelof AD, Yahata et al. screened for the effectiveness of anti-Aβdrugs, such as β-secretase inhibitors, γ-secretase inhibitors(GSI), and a nonsteroidal anti-inflammatory drug (NSAID),between early and late differentiation stages. As a result, theyfound that GSI treatment results in a drastic decline of Aβproduction [123].

Huntington’s Disease

HD is a neurodegenerative genetic disorder that affects musclecoordination and leads to cognitive decline and dementia. It is

middle-age-onset disease and is the most common geneticcause of abnormal involuntary writhing movements calledchorea [124, 125]. Physical symptoms of HD may appear onearly age, but frequency is more in between 35 and 44 years ofage [126]. In some cases (∼6 %), the symptoms may appearbefore the age of 21 years with an akinetic-rigid syndrome.The prevalence of this disease ismore in the people ofWesternEuropean origin than in those from Asia or Africa. It is aninheritable disease caused by an autosomal dominantmutationon either of an individual’s two copies of a gene calledHuntingtin with a 50 % risk of inheriting the disease to thechild by the affected person [124, 125].

HD is an ideal model for the development of stem cell-based therapeutic strategies due to its unique pathogenesischaracteristics. The approach is basically centered on theprevention of neuronal dysfunction/cell death and replace-ment of lost neurons in the striatum. In fact, a phase-I clinicaltrial consisted of implantation of fetal striatal primordium intothe striatum of five HD patients [59]. Such kind of efforts islimited due to ethical, social, and logistical issues associatedwith the use of human fetal tissues for brain transplantation.Adult/autologous stem cells, therefore, could be an alternativesource, and wide preclinical research transplanting differenttypes of stem cells into HD animal models is needed in this

Table 3 Summary of stem cell research conducted in animal models of AD

Animal model Stem cells Outcomes Ref

Aged rats (30 months) Murine BM-MSC Aged rats—learn more rapidly [96]

Ibotenic acid-inducedNBM lesion rats

Murine BM-MSC Ibo-induced memory impairment group—significant reduction in latency tofind platform in Morris water maze

[96]

Acute Aβ-inducedmodel mice

Murine BM-MSC BM-MSCs promoted microglial activation; reduced Aβ deposits of acutelyinduced AD mice

[97]

AF64A cholinotoxininjection in rats

hNSC Rats receiving NSCs overexpressing ChAT showed full recovery in learning and memoryfunctions, whereas those receiving NSCs only remained memory impaired

[98]

Aged rats (22 months) hNSC SGZ increased in cell number [99]

Matured rats (6 months) hNSC Cognitive function significantly improved in matured and aged memory-impaired groups [100]

Aged rats (24 months) hNSC Morphologically functional hNSC-derived cells were found in the hippocampus and cortex [100]

DS model mice (Ts65Dn) mNSC Decreased tau-positive clusters in trisomic (28.6 %) and disomic (58.6 %) mice [101]

Triple transgenic ADmodel mice

mNSC NSC transplant rescues learning and memory deficits; no change in Aβ, tau pathologybut increased synaptic density in mice’s hippocampus

[102]

Double transgenic neuronalinjury model mice

mNSC Improved hippocampal-dependent memory and increased synaptic density and neuronalnumber

[103]

Rat fimbria–fornix transaction mNSC Improved memory and learning in Y-maze testing; increased in the number ofp75NGFR-positive neurons

[104]

Transgenic AD-model mice Human adipose-derived stem cell

Both intravenous and intracerebral adipose-derived stem cell transplantation rescued memoryimpairment and improved spatial learning; reduced amyloid plaque formation, upregulatedinterleukin-10 and neurotrophic factors in the brain of Tg2576 mice

[105]

Ibotenic acid-induced NBMlesion mice

Murine ES andES-derived NSC

NPC restored memory, ES significantly decrease working memory; ES induced massiveteratoma formation

[106]

Rat hippocampal Aβ injection EPI-NCSC Significant improvement in cognitive tasks (Y-maze and passive avoidance tests), increasedneuron number and differentiation into other cell type

[107]

APP and presenilin (PS1)double-transgenic mice

Human UCB-MSC Improved spatial learning and memory in Morris water maze tests; reduced Aβ load andtauhyperphosphorylation, inhibited proinflammatory cytokine release from microglia

[108]

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context [7, 127]. Using quinolinic acid (QA) lesion rat modelof HD, Vazey et al. showed that adult neural progenitor cellssurvive transplantation, undergo neuronal differentiation witha proportion of newly generated cells expressing markerscharacteristic of striatal neurons, and reduce functional im-pairment in the QA lesion model of HD [128]. These resultsgot further support by studies of Amin et al. who used bonemarrow mesenchymal stem cells [129]. Some other studiesexplored the benefits of combining stem cells with therapeuticdrugs [7, 127]. Juopperi et al. showed that iPSCs derived froma father with adult-onset HD and 50 CAG repeats (F-HD-iPSC) and his daughter with juvenile HD and 109 CAGrepeats (D-HD-iPSC) were capable of producing phenotypi-cally normal, functional neurons in vitro and were able tosurvive and differentiate into neurons in the adult mouse brainin vivo after transplantation. They further stated that theastrocytes derived from patient-specific iPSCs exhibit a vac-uolation phenotype, a phenomenon previously documented inprimary lymphocytes from HD patients [130]. Recently, Finket al., using 3-nitropropionic acid rat model of HD, showedthat transplantation of adenovirus-generated iPSCs preservedmotor function [131]. Transplanted iPSCs were found tosurvive and differentiate into region-specific neurons in thestriatum of 3-NP rats, at all transplantation time points, andcould provide a potential avenue for therapeutic treatment ofHD [131].

Amyotrophic Lateral Sclerosis

ALS, also known as Lou Gehrig’s disease, is a disease of thenerve cells in the brain and spinal cord that control voluntarymuscle movement [132, 133]. Pathogenesis is complex andpoorly understood, but it is observed that in about 10 % ofcases; ALS is caused by a genetic defect. It is characterized byneuronal loss and the inability to send messages to muscleseventually leading to muscle weakening, twitching, and aninability to move the arms, legs, and the body. Its prevalence ishigh, and ALS affects approximately 5 out of every 100,000people worldwide. The only known risk factor is familyhistory. This is late-onset disease, and symptoms usually donot develop until after age 50 years. Persons with ALS have aloss of muscle strength and coordination that eventually getsworse and makes it impossible to do routine tasks [132–134].Initially, breathing or swallowing muscles are affected; subse-quently, as the disease progresses, more muscle groups devel-op problems. ALS does not affect the senses (sight, smell,taste, hearing, touch). It only rarely affects bladder or bowelfunction, or a person’s ability to think or reason [132–134].

Stem cell treatment is a reality for ALS, and some clinicaltrials have been conducted in the past [135]. Ongoing preclin-ical studies have shown the efficacy of stem cell transplanta-tion in restoring neural loss as well as in treating the adverse

effects of ALS clinical implications. The hopes for ALSpatients are that stem cell transplantation will be able toreplace motor neurons that may further lead to the recoveryof neuromuscular functions. Results from a follow-up studywith 13 patients 1 year after stem cell transplantation showed asignificant improvement in nine patients as confirmed byelectro-neuromyography [60]. Some positives also came outfrom other stem cell clinical procedures, such as allogeneichematopoietic stem cell transplantation, confirming the abilityof stem cells to restore neural dysfunctions [61]. UsinghSOD1G93A mouse model, Sun et al. showed that intrave-nous administration of human amniotic mesenchymal stemcells (hAMSCs), derived from human amniotic membrane(HAM), significantly retarded disease progression, extendedsurvival, improved motor function, prevented motor neuronloss, and decreased neuro-inflammation [136]. Boido et al.showed that hMSCs, when intracisternally administered, canexert their paracrine potential, influencing the inflammatoryresponse of the host [137]. Recently, Chestkov et al. used thereprogramming technology to generate iPSCs with patientswith familial ALS. The iPS cells were obtained by bothintegration and transgene-free delivery methods ofreprogramming transcription factors and had the propertiesof pluripotent cells and were capable of direct differentiationinto motor neurons [138]. Nizzardo et al. observed that aspecific NSC population characterized by high aldehyde de-hydrogenase activity, low side scatter, and integrin VLA4positivity that could migrate and get engrafted into the CNSand could improve neuromuscular function and motor unitpathology in ALS mouse model. They linked these positiveeffects to multiple mechanisms, including production of neu-rotrophic factors and reduction of micro- and macrogliosis[139].

Miscellaneous

Neurological symptoms are the hallmarks of many otherdiseases, such as LSDs [18, 140–143]. Major causes of LSDsare mutations of genes that encode the lysosomal enzymeproteins and related cofactors. LSDs are rare and usuallymanifests in the accumulation of un-degraded products inlysosomes leading to enlargement of cells, cellular dysfunc-tion, and cell death. Most LSDs are autosomal recessive.Manifestations of neurological disease begin in infancy orchildhood with initial delay and subsequent arrest of psycho-motor development, neurological regression, blindness, andseizures. Inexorable progression leads to a vegetative state.

Current therapies for LSDs are ineffective, and results arequite poor. The stem cell replacement approach for this dis-ease generally is focused on the production of a functionalenzyme and the recovery of the damaged brain. The combi-nation of gene/cell therapy strategy could be a better approach

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in comparison to the conventional allogeneic hematopoieticstem cell transplantation [144].

Ongoing studies are exploring the efficacy of stem cell-based treatment in other neurological diseases also [55, 145].The treatment for spinal cord injury now ranges from stem celltransplantation procedures to their combination with bioactivemolecules [145]. Studies with mouse model of multiple scle-rosis have also shown promising results. The basic strategy forthese studies was to increase the number of hematopoietic,mesenchymal, and NSCs in order to provide practical vehiclesfor in situ immunomodulation, neuroprotection, and regener-ation of the damaged tissue. Besides these approaches, inves-tigations are also directed in line of gene/cell therapy strategiesto restore antigen-specific tolerance or to deliver anti-inflammatory molecules [146]. Finally, the efforts made forthe treatment of epilepsy exploring therapeutic potential ofstem cells indicated a restoration of the normal balance be-tween excitation and inhibition in epileptic patients (e.g., NSCand ESC-derived neural progenitors) [20].

A promise and demands towards the generation of newtherapies for neurological disorders

Prospective studies have made a promise that stem cells willbe a powerful part of the therapeutic armamentarium of neu-rologists in upcoming years and decades. Therapeutic ap-proaches with stem cells are appealing and have captured theattention of not only the scientists and clinicians but also ofcommon people. The expectations have some emotional touchas individuals who have suffered greatly owing to injury ordisease thinks that their suffering and disability could bereduced or eliminated by these exciting pleas. Many feel thatstem cells have the potential to treat, cure, and restore functionto patients suffering from almost any disease. The reality willbe much more sobering on several fronts. Some diseases willbe intractable to recovery or even slowing of disease by virtueof the mechanism or extent of neural injury. Assumptionscould only be translated if the demands of stem cell therapywill be fulfilled. Neurogenesis will need to be combined withprolonged rehabilitation therapies to ‘retrain’ the nervoussystem, much as the prolonged rehabilitation after an organor joint replacement or even more. But even with thosecautionary notes, there is the likelihood that we will be ableto alter the course of devastating neurologic diseases usingstem cells in the future, and we will begin to see this potentialin human patients in the next 5–10 years.

Future Perspective

Although our understanding of neural stem cell (NSCs) biol-ogy has increased, there are still enormous hurdles before

universal acceptance of its transplantation for neurologicaldisorders. Certain key issues related to cell selection forstarting point, time of rehabilitation following transplantation,programming of cells in vitro to generate predictable cell typesin vivo, and ethical concerns need to be addressed. ES cell-derived NSCs for stem cell therapy have ethical consider-ations and require neural specification and purification apartfrom its tendency to generate tumors. NSCs, on the otherhand, represent less of a risk for tumor formation followingtransplantation (as they are more lineage-restricted than EScells); however, ethical considerations, long-term mainte-nance, restricted potential, and low availability have limitedtheir uses in stem cell therapy.

In last few years, the capacity of non-NSCs, including bonemarrow, skin, and umbilical cord stem cells, to generatevarious types of neurons and glia has been widely investigated[147–151]. The recent advancement is the patient-derivediPSCs that allow scientists and clinicians to model, in vitro,the progression of neurodegenerative diseases for each indi-vidual patient and provide a real opportunity for stratifiedmedicine applications. Additionally, iPSC technology couldbe coupled with high-throughput screening that can provide amore efficacious and cost-effective platform to assess a num-ber of former and new drug candidates for treatment of neu-rodegenerative disorders simultaneously. Although promis-ing, implementation of iPSC-based therapy is far from becom-ing a reality. The complex nature of various neurologicaldisorders has made the process even more unpredictable.Methods described in mouse and human ESCs translate fairlywell into iPS cells in the specific cases of the spinal motorneurons affected in ALS and midbrain DA neurons in PD, butstill they are far from perfect. It may further be necessary toidentify culture conditions to produce specific subclasses ofthe desired cell type. Where we go after that depends on manythings. First and foremost will be some clinical trials, and ifthese trials will demonstrate hints of the effectiveness of stemcells in treating neurologic disease, we could decide a path.One cannot draw any final conclusion on the basis of theclinical trials performed to date, as they involve small num-bers of patients and often have an open-label design. Howev-er, these trials have some hopes, and the results may beconsidered to be ‘suggestive,’ therefore justifying larger, morecomplex clinical trials.

Conclusion

Stem cell research has revolutionized the approaches andefforts towards the generation of new and effective therapyfor these disorders. The promise of stem cell therapy in theCNS is to regenerate and reconstruct the original pathway topromote functional recovery. Although genetically engineer-ing cells has proven valuable to understand gene function and

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to deliver missing trophic factors or neurotransmitter synthe-sizing enzymes in the CNS, it will need the establishedmethods of translation from the laboratory to the clinic. Todate, it is just a hope and will progress with time. It is must tobe shown in the laboratory that the approach works and how itworks before it can even be considered for clinical use. Inrecent past, neurons and glia have been generated successfullyfrom stem cells in culture such as ESCs, mesenchymal stemcells, and NSCs. A new line of research is neurogenesis andprevention of neuronal/glial cell death using endogenous stemcells within the adult CNS. iPS cell-based models may alsoprovide a new opportunity to understand selective vulnerabil-ity of populations of neurons to discrete degenerative stimuli,a theme common to many neurological disorders.

Now, the major challenge to the researchers and cliniciansis to translate these exciting advances from the laboratory intoclinically useful therapies. Although successful in some cases,stem cell replacement therapy is still in its early days, andbefore envisaging any therapeutic application of such cells inhumans with neurological disorders, we need to confront withseveral key issues related to cell selection, targeting, andtiming.

Acknowledgments We thank our lab members for critical reading ofthe manuscript.

Conflicts of Interest The authors declare no conflicts of interest.

Authors’Contributions GUwrote themanuscript; SS and RKS editedthe manuscript. All authors read and approved the manuscript.

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