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Keywords:

  • functional recovery;
  • Huntington disease;
  • mesenchymal stem cell;
  • neural stem cell;
  • neurotrophic factors;
  • transplantation

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Huntington disease (HD) is a devastating neurodegenerative disorder and no proven medical therapy is currently available to mitigate its clinical manifestations. Although fetal neural transplantation has been tried in both preclinical and clinical investigations, the efficacy is not satisfactory. With the recent explosive progress of stem cell biology, application of stem cell-based therapy in HD is an exciting prospect. Three kinds of stem cells, embryonic stem cells, bone marrow mesenchymal stem cells and neural stem cells, have previously been utilized in cell therapy in animal models of neurological disorders. However, neural stem cells were preferably used by investigators in experimental HD studies, since they have a clear capacity to become neurons or glial cells after intracerebral or intravenous transplantation, and they induce functional recovery. In this review, we summarize the current state of cell therapy utilizing stem cells in experimental HD animal models, and discuss the future considerations for developing new therapeutic strategies using neural stem cells.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Huntington disease (HD), an autosomal dominant neurodegenerative disorder, is characterized clinically by progressive cognitive impairment, abnormalities of movement, and neuropsychiatric symptoms.1,2 Onset of HD usually occurs during the fourth or fifth decade of life, and the disease symptoms and signs progress with aging, with a mean survival of 15–20 years.

Recent progresses in stem cell biology have opened up an avenue to therapeutic strategies to replace lost neural cells by transplantation of stem/progenitor cells in various disorders in the CNS.3–9 Successful application of stem cell-based therapy in animal models of HD with functional recovery has been reported.10,11 However, there are still many obstacles to be overcome before clinical application of cell therapy in HD is adopted: (i) it is still uncertain what kind of stem/progenitor cells would be an ideal source for cellular grafts, and (ii) it needs to be better understood by what mechanism transplantation of stem/progenitor cells leads to an enhanced functional recovery. The aim of this review is to analyze the recently published studies on stem/progenitor cell transplantation in animal models of HD that have reported successful outcomes and propose possible strategies that can improve therapeutic efficacy of stem cell-based therapy in HD.

PATHOGENESIS OF HD

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Huntington disease is caused by a gene mutation by an abnormal expansion of CAG-encoded polyglutamine repeats in a protein called huntingtin.12–14 There are normally 10–29 (median 18) consecutive repetitions of the CAG triplet at 5′ end, which is translated into a corresponding polyglutamine stretch (polyQ). In contrast, HD patients have expanded CAG repeats that include from 36 to 121 repeats (median, 44), which makes medium spiny neurons in the striatum particularly vulnerable to cell death, and also leads to the dysfunction and death of neurons in other brain regions, including the cortex.15 The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset.16 Therefore, a higher number of expanded CAG repeat causes earlier onset disease, whereas the lower number of expansions result in first symptoms later in life. The disease progression is rapid in patients with higher numbers of CAG expansions.

Disease initiation and progression are thought to involve a conformational change in the mutant huntingtin protein due to the polyglutamine expansion,17 altered protein–protein interactions,18 abnormal protein aggregation19 and proteolysis, leading to transcriptional dysregulation,20–22 excitotoxicity,23 mitochondrial dysfunction,24 and culminating in extensive loss of neurons in the striatum and cerebral cortex.25 Although the extended polyglutamine stretch confers a deleterious gain-of-function to the protein, new results on the beneficial functions of normal huntingtin indicate that loss of the normal protein function might actually equally contribute to the pathology.13,26

RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Animal models of HD have been established using excitotoxic glutamic acid analogs such as kainic acid (KA),27 ibotenic acid (IA)28 and quinolinic acid (QA).29,30 Intrastriatal injection of KA, IA or QA in nanomolar quantities, result in the cell death of intrinsic neurons while sparing incoming nerve fibers, and the consequent neurochemical and pathological changes resemble the pathology of the HD brain.27,31–33 Among these excitotoxic amino acids, QA appears to induce a more selective cellular damage in striatum similar to HD patholgy than KA or IA.31,33

Rodents and primates with lesions of the striatum induced by 3-nitropropionic acid (3NP), KA or QA have been used to simulate HD in animals and to test efficacy of experimental therapeutics,31,34 or for experiments on neural transplantation.25,33,35 An excitotoxic animal model induced by QA, which stimulates glutamate receptors, resembles the histopathologic characteristics of HD patients,31 and another HD model with 3NP, a mitochondrial toxin, causes impairment of energy metabolism and activation of certain neuraonal cell death pathway as in mutated huntingtin.26,36 There have been two kinds of transplantation studies in HD animal models.5 One aims to prevent the degenerative changes of striatal neurons in HD models via provision of neurotrophic molecules. In these studies, cells that produce neurotrophic factors, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or ciliary neurotrophic factor (CNTF), have been transplanted into the striatum of HD animals. Excitotoxic amino acid QA or mitochondrial toxin 3NP are injected into the striatum followed by transplantation of growth factor-producing cells. Neuroprotection provided by neurotrophic factors secreted by grafted cells against neurotoxic insults is expected to reduce damage in striatum. The second type of experiment is neural transplantation, which aims at the reconstruction of damaged striatum. Medium-sized spiny projection neurons of caudate/putamen is the major population of neurons degenerating in HD,37 and these neurons form part of a complex circuit and presumably would have to be reconstructed to obtain therapeutic efficacy in HD. Damaged circuits include inputs from cerebral cortex and substantia nigra, and outputs to both globus pallidus and the substantia nigra. The particular circuit that is thought to be most important in the abnormal movements of HD involves the GABA-mediated inputs to the globus pallidus. Thus, repair of this circuitry component should result in functional recovery. For instance, a previous study has shown that subcutaneous application of basic fibroblast growth factor (FGF) promotes neurogenesis of GABAergic neurons with neuronal projections to the globus pallidus from caudate/putamen in the transgenic HD model,38 which implies the replacement of damaged neuronal cell types with operating connections is important.

CELLULAR THERAPY IN HD ANIMAL MODELS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Possible cellular therapy approach to the treatment of HD includes blocking neuronal dysfunction/cell death and replacing lost neurons in the striatum. The eaeliest transplantation study in animal model of HD appeared in 1983 in which fetal rat striatal tissue fragments were transplanted into the KA-lesioned striatum, and behavioral improvement was reported.39 Subsequently, numerous striatal (or other tissues) graft experiments have been performed in preclinical settings.33 Embryonic striatal tissues have been transplanted in the excitotoxic striatal lesion in animals including mice, rats and monkeys.25,33,34,36 Grafts have survived and expressed ranges of cellular markers of the normal striatum, alleviating behavioral deficits. Recovery has been observed in motor performance and cognitive tasks, which require restored cortical-subcortical networks and functional circuitry in the brain.25,32 Transplantation of appropriate cell types enabled new development of afferent and efferent functional connections with correct targets in the host brain.40 Neural transplantation in HD animal models could modify disease progression,41,42 improve functional outcome in these animals,10,11,25,32–34,43 restore electrophysiological sensitivity to dopamine, and induce neuronal differentiation with fiber outgrowth from the grafts.42

There have been only two studies so far of cell transplantation in transgenic HD mice, while striatal cell transplantation has been performed mostly in excitotoxic lesion models. Striatal or anterior cingulate graft exerted a small influence on several indices of behavioral function and did not result in any clinically relevant effect on the neurological deficiency in the transgenic mice.44,45 Further neural transplantation studies are called for in transgenic HD mice, since these animals represent authentic HD animal models.

CELLULAR THERAPY IN HD PATIENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

The first clinical study of cellular transplantation in HD patients was conducted as a pilot study in Mexico in 1990.46 The early trials in Cuba, Czechoslovakia, UK and in California provided brief clinical accounts of implantation protocols and reported that the procedure showed no major complication.47–54 Several reports have shown that the fetal striatal transplants could improve the cognitive symptoms associated with HD,54 and MRI of a recipient revealed the graft survival within the striatum without displacing the surrounding tissue.52 Studies initiated in France and NEST-UK (United Kingdom arm of European network for striatal transplantation) study, are now being proceeding to evaluate the safety, efficacy and the transplantation protocols for future clinical trials in cellular therapy involving HD patients.55,56 Most clinical trials used fetal striatal tissues from spontaneously aborted fetuses or elective abortions. However, there have been ethical and social and logistical issues associated with the use of human fetal tissues for brain transplantation. It is necessary to procure an alternative source of tissue for brain transplantation.

NEED FOR STEM CELL TRANSPLANTATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Although the striatal degeneration appears first and the subsequent destruction of the circuit involving both cortical and subcortical components is the cause of HD features, the human pathology encompasses neocortical and other areas of the brain as the disease progresses.25 Consequently, transplantation of neural tissue grafts into straitum is not expected to restore the whole brain pathology. Although stem cells are considered to be able to reconstitute the whole brain via the extensive migration and the remote paracrine effect, previous studies show that the prospect is somewhat premature. Mammalian neurogenesis persists in adult subventricular zone (SVZ) and dentate gyrus (DG) of the hippocampus. In HD, neurogenesis is reduced in the DG of transgenic HD mice,57 while increased neurogenesis is reported in the SVZ of HD patients.58,59 Whether the decline in neurogenesis itself causes the disease progression or increased neurogenesis is compensatory to the ongoing neurodegeneration, to supply neural progenitors with wild-type huntingtin, has not been clarified.

SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

During the last decade, there have been a number of studies reporting brain transplantation of stem cells in HD animal models (Table 1). In previous studies, rat neural stem/progenitor cells (NSCs) were genetically modified to continuously supply neurotrophic factors to counteract neural degeneration in the QA-HD model.60,63 Rats receiving NGF-secreting NSCs displayed a sparing of striatal neurons immunoreactive for glutamic acid decarboxylase (GAD), choline acetyltransferase (ChaT) or NADPH.60 In another study, pretreatment of human NSCs (neurospheres) with ciliary neurotrophic factor (CNTF) prior to transplantation improved the therapeutic efficacy.61 In the rat 3NP model, proactive transplantation of F3 immortalized human NSCs7,11 reduced damage induced by 3NP, while transplantation of NSCs subsequent to 3NP lesion failed to protect the striatal neurons.11 Transplanted F3 human NSCs were found to secrete a large amount of BDNF, which is the reason for neuroprotection observed in the HD pathology. This study suggests that NSCs can be used, without genetic modification, as graft cell source secreting trophic factors, in cellular therapy for HD.11 F3 human NSCs have also been transplanted systematically via the tail vein in QA model rats and induced functional recovery in these animals.10,43

Table 1.  Transplantation studies of stem cells in Huntington disease models
ModelCell typeCells methodLesion volumeHistologyDifferentiationFunctional outcomeCommentRef
  1. 3NP, 3-nitropropionic acid; BDNF, brain-derived neurotrophic factor; BM, bone marrow; ChAT, choline acetyltransferase; CNTF, ciliary neurotrophic factor; GAD, glutamic acid decarboxylase; GP, globus pallidus; IC, intracerebral injection; ICV, intracerebroventricular injection; IV, intravenous injection; NGF, nerve growth factor; NPC, neural progenitor cells; NSC, neural stem cells; PET, positron emission tomography; QA, quinolinic acid.

QAMouse fetal brain NSCs (Primary)5 × 105 × 2 (sites)/ICLesion vol. [DOWNWARDS ARROW] (NGF-NPCs only, 14 days)Preservation of GAD/ChAT/NADP+ cells, Glial proliferation[DOWNWARDS ARROW], Intact BBBNot doneNot testedNSCs from hNGF mouse60
QAHuman fetal brain NSCs (Primary)2 × 105/ICLesion vol. [DOWNWARDS ARROW] (CNTF-NSCs only, 56 days)No improvement in DARPP32+ cell survivalNeuN (1%), GFAP (3.4%), DARPP32/GAD+ (0%)Cylinder test [UPWARDS ARROW] (CNTF+ NSCs >naïve NSCs)Migration of NSCs to stiatum Proliferation of NSCs in situ61
QAHuman fetal brain NSCs (HB1.F3)5 × 106/IV 1 × 106/ICVNot testedSelective migration of NPCs into damaged striatumNeuN+, GFAP+Not testedNSC migration by intravenous injection43
QAHuman fetal brain NSCs (HB1.F3)5 × 106/IVLesion vol. [DOWNWARDS ARROW] (42 days)Preservation of Nissl+ cellsNeuN+, GFAP+Circling behavior [DOWNWARDS ARROW]Identification of human NSCs engraftment by ERV-3 PCR10
3NPHuman fetal brain NSCs (HB1.F3)1 × 105/ICLesion vol. [DOWNWARDS ARROW] (7 days)Preservation of NeuN/Calbindin/GAD+ cells (not NADPH+ cells)Nestin >>, GFAP, Calbindin, GADRotarod [UPWARDS ARROW]Proactive transplantation11
3NPHuman fetal hippocampal NPCs(MHP3)5 × 104 × 8/ICNo difference (14 weeks)NPC migration into the lesion Participation in the glial scarNeuN+, GFAP+Beam walking [UPWARDS ARROW]Striatal degeneration [DOWNWARDS ARROW] (serial MRI)62
QARat fetal NPCs (Primary)9 × 105/ICLesion vol. [DOWNWARDS ARROW] (NGF-NPCs only, 35 days)Preservation of DARPP32+/ChAT+ cells Astro/microglial density [DOWNWARDS ARROW]Not testedNot testedNGF/BDNF content [UPWARDS ARROW] by NGF- or BDNF-NPCs63
QARat fetal NPCs (ST14A)1.5 × 103 × 6 (sites)/ICNot testedPreservation of GABA+ cellsTubβIII/GABA/synapsin/ synaptotagmin (+)Circling [DOWNWARDS ARROW]GABA[UPWARDS ARROW] in NPCs by Retinoic acid+ KCl treatment34
QARat fetal brain NPCs (Primary)4 × 105/ICLesion vol. [DOWNWARDS ARROW]Preservation of Nissl+ cellsNeuN (0.8∼5.6%), GFAP (1.1∼2.4%)No improvementRecovered glucose metabolism in PET (2–3 week)64
QARat whole BM cells (Primary)3.5 × 106/ICNo difference (37 days)No difference<0.3% GAD+, <1% Nestin+No improvementNegative study70

Huntingtin mutation leads to selective death of GABAergic projection neurons in striatum,18,37 which affects GABA containing medium sized spiny neurons. These GABAergic neurons innervate the globus pallidus and substantia nigra pars reticulata and constitute critical parts of basal ganglia loop circuitry. Thus, intrastriatal transplantation of GABAergic neurons might replace the population of lost neurons and restore the functionality of the damaged circuit.25 One research group has generated a homogenous population of functional GABAergic neurons from an NSC line, using retinoic acid and potassium chloride depolarization. When transplanted in the QA model, these cells survived and improved functional deficits in vivo.34

Striatal or systematic transplantation of human NSCs produced behavioral as well as anatomical recovery in a rodent model of HD.10,11,34,41,43,61 The underlying mechanism of functional improvement induced by stem cell transplantation in the HD model is largely unknown. However, neuroprotection of host neurons by neurotrophic factors and increased neurogenesis and new circuit formation with reorganization, have been suggested in animal models of stroke in which bahavioral and anatomical recovery were seen following transplantation of NSCs,65–69 and an essentially similar mechanism should be at work in HD animal studies. In HD models, proactive transplantation of F3 human NSCs secreting BDNF induced behavioral as well as anatomical recovery,11 and the augmentation of NGF production by NSCs enhanced the neuroprotection afforded by NSCs.60 The decreased striatal atrophy and the improved functional recovery also suggest that NSC transplantation protects and exerts trophic action on the host brain, preventing further destruction10 and ongoing tissue loss.62 Intrastriatal transplantation of cultured rat neural progenitors resulted in improved metabolic function in the striatum and overlying cortex,64 which was likely the result of a trophic action of the transplanted cells on the host.

One research group tried autologous adult bone marrow mesenchymal stem cell transplantation in the QA model.70 HD rats receiving bone marrow stem cells showed an improved behavioral function; however, only a small number of cells expressed neural phenotype, suggesting that the release of the growth factors by the grafted cells allowed the host surviving cells to survive and function more efficiently and to facilitate other compensatory responses.70 Because transplantation of bone marrow cells has been successfully used in experimental stroke models,71,72 and also in a clinical study in stroke,73 application of bone marrow mesenchymal stem cells in HD is also feasible. However, autologous mesenchymal stem cell transplantation in the human clinical setting poses a problem that stem cells themselves also carry the mutant huntingtin gene. Thus, autologous mesenchymal stem cell transplantation in HD patients seems not to be a definite modality for curing the disease. Further studies of bone marrow mesenchymal stem cells for cell therapy in HD patients are called for.

SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Neural stem/progenitor cells can be transplanted systemically, that is, intravenously or intra-arterially, or intracerebrally in animal models of neurological disease. Target diseases include brain tumor,6,74–76 experimental allergic encephalomyelitis (EAE),77 global and focal ischemia,65,66 cerebral hemorrhage,68,69 temporal lobe epilepsy (TLE),78 Parkinson disease79,80 and the HD model.10,11,43,61 Although most HD animal studies used intrastriatal injection methods for transplantation, intravenous transplantation also has efficacy in functional recovery and neuroprotection of striatal neurons. Intravenous transplantation of F3 human NSCs reduced apomorphine-induced circling and striatal atrophy in the QA model; intravenously or intracerebrally injected human NSCs migrated into the brain and differentiated into neurons and astorytes as certified by the presence of grafted cells doubly labeled with human-specific cell marker and NeuN or human-specific cell marker and GFAP10,11

The systemic transplantation of NSCs is probably the least invasive method of cell administration.43 Neural transplantation into striatum requires an invasive surgical technique using a stereotaxic frame. Non-invasive transplantation via intravenous routes, if it is effective in humans, appears much more attractive. In rodents, in which the majority of experimentation has been done, the brain is comparatively small compared to the immense volume of the human brain. Thus, in humans, the local stereotaxic infusion of NSCs may be severely limited in terms of transplantation foci (spatial), and the infused cells have to migrate great distances to embrace entire disease sites (temporal). To overcome these obstacles, one must inject NSCs at numerous sites in the diseased brain. In contrast, intravascular injection can disperse NSCs according to natural cues and allow them to migrate along the “chemotactic gradients” of the host.68,81,82

The concept of intravascular NSC transplantation originated from the immense amount of clinical and experimental work conducted on hematopoietic stem cells (HSCs) and bone marrow transplantation. HSCs express many surface antigens and receptors. They react to homing signals (chemokines), attach to vascular endothelium (by interacting with adhesion molecules), and migrate to target tissues (e.g., bone marrow). NSCs also express many adhesion molecules and chemo/cytokine receptors,68,77,81 and this has led many researchers to consider the possibility of systemic NSC transplantation. In an experimental allergic encephalomyelitis (EAE) model, 2.5–3.5% of systemically infused NSCs was found to home to the brain one day after infusion,77 whereas others reported that the number of surviving donor cells increased 10-fold at 2 weeks after infusion.65–67 These findings suggest two possibilities, that is, the in situ proliferation of NSCs in the host brain,65 or the persistent and continuing homing of the circulating donor cells in host blood.38 Our preliminary study has shown that 24 h after the intravenous transplantation, most of the LacZ-labeled human NSCs were found in the kidney and only a small number were found in the brain; however, 4–5 days later, a large number of LacZ+ NSCs were found in the brain and only a small number of cells in the kidney (unpulished data). These results indicate that systematically administered cells initially lodge in the kidney, then are gradually released from kidney and migrate into the brain afterward via host blood circulation.

However, the migration of systemically administered NSCs into the damaged striatum may be due to the specific pathologic condition of the experimental animal model. Intrastriatal lesions created by excitatory amino acids, such as QA, mimic the neurochemical and neuropathological characteristics of HD.29,35 However, the effect of QA on tissue can cause acute damage and inflammation and cytokines and chemokines produced in the loci serve as chemoattractants for NSCs to migrate into the striatum. Thus, further studies using transgenic mice are warranted to clarify the question related to the migration of intravenously applied NSCs in HD animal models.

Although the mechanism by which NSCs migrate in a selective manner to the HD pathological lesions following systematic administration is unclear, it is suggested that the transplanted NSCs are recruited by certain chemoattractant signals produced at CNS injury sites, such as cytokines including stem cell factor (SCF),82 stromal cell derived factor-1 (SDF-1)83,84 or vascular endothelial cell growth factor (VEGF).81 In our previous HD animal studies, F3 immortalized human NSC line is demonstrated to express c-kit, the receptor for SCF, CXCR4, the receptor for SDF-1, and VEGFR1, the receptor for VEGF, and the pathways involving SCF/c-kit, SDF-2/CXCR4 and VEGF/VEGFR, are found to be involved in the migration of F3 human NSCs from the blood stream to the QA injury sites.10,43 Migration of NSCs toward sites of brain injury may represent a response of NSCs for the purpose of limiting tissue injury or to repair tissue damage in the brain.

CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

Because HD is inevitably fatal and there is no known treatment, there is little to be lost and much potential gain from even a small benefit from experimental therapeutics. However, an appropriately proven therapy in an animal model should be tried to avoid wasteful efforts. In HD, mitochondrial defects are thought to play a significant part in the pathomechanism for cell death in HD pathology. Administration of 3NP, which inhibits mitochondrial succinate dehydrogenase (SDH), can induce the behavioral and anatomical features of HD in rodents and primates.26,36 In the 3NP model, there are two types of important factors: one leads to cell death, such as c-Jun N-terminal kinase and Ca2+-activated protease calpains; and the others, such as glutamate, dopamine and adenosine, modulate the striatal degeneration induced by 3NP.26,36 Accordingly, 3NP animals are excellent HD models for the investigation of neuroprotection and molecular modification regarding toxicity from mitochondrial dysfunction.

Kainic acid, IA and QA can induce excitotoxic injury in the brain, and QA produces a selective neuronal loss in striatum resembling HD.28,29,35,43,63 Thus, transplantation of NSCs in these models can be used to determine the differentiation of NSCs into medium-sized spiny neurons, as well as to test the neuroprotective effect of NSCs. However, excitotoxic lesions of the striatum do not show sufficiently similar motor abnormality resembling human HD. Transgenic mice expressing human huntingtin with an expanded CAG/polyglutamine, such as R6/2, develop progressive clinical symptoms and pathology and inclusion formation, which are characteristic features of human HD.85,86 Thus, the transgenic mouse model can provide genetic similarity as well as the phenotypic similarity for stem cell transplantation studies.

To achieve clinically effective brain transplantation in HD transgenic mice and HD patients, many points should be clarified and warrant further studies. For instance, there is evidence that abnormal neurogenesis in the transgenic mouse is not attributable to an intrinsic impairment of the neural stem/progenitor cell itself but is attributable to the environment in which the cells are located.87 Accordingly, supplying wild-type stem cell itself might not be able to ameliorate the disease progression by surpassing the function of endogenous neural stem cells. Correction of the microenvironment of the host brain must also be achieved.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES

No proven medical therapy is currently available to mitigate the devastating clinical manifestations of HD. In the present review, we summarized the current state of stem cell-based cell therapy in experimental HD models. New therapeutic strategies are expected to block transcriptional dysregulation and the downstream cell death pathway, as well as replacing lost neurons. Until fundamental amelioration of mutant genes and complete reversal of disease progression are achieved, transplantation of NSCs or fetal neural tissues would be the major arm to fight the disease, along with neuroprotective strategies. With the recent explosive progress in the field of stem cell biology and its applications, one might hope that stem cell-based cell therapy would be one of the life-saving cures for HD patients in the near future.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATHOGENESIS OF HD
  5. RELEVANCE OF HD RODENT MODELS WITH CLINICAL HD FOR TRANSPLANTATION STUDY
  6. CELLULAR THERAPY IN HD ANIMAL MODELS
  7. CELLULAR THERAPY IN HD PATIENTS
  8. NEED FOR STEM CELL TRANSPLANTATION
  9. SUMMARY OF PRECLINICAL STUDIES OF STEM CELL TRANSPLANTATION
  10. SYSTEMIC TRANSPLANTATION OF NEURAL STEM CELLS
  11. CHOICE OF ANIMAL MODELS AND CONSIDERATIONS FOR FUTURE STUDIES
  12. CONCLUSIONS
  13. ACKNOWLEDGMENTS
  14. REFERENCES
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