Cell Medicine, Part B of Cell Transplantation, Vol. 1, pp. 15–46, 2010 Printed in the USA. All rights reserved.
Copyright  2010 Cognizant Comm. Corp.
Cell Therapy From Bench to Bedside Translation
in CNS Neurorestoratology Era
Hongyun Huang,* Lin Chen,* and Paul Sanberg† *Center for Neurorestoratology, Beijing Rehabilitation Center, Beijing, P.R. China †Department of Neurosurgery, University of South Florida, Tampa, FL, USA Recent advances in cell biology, neural injury and repair, and the progress towards development of neurorest-orative interventions are the basis for increased optimism. Based on the complexity of the processes ofdemyelination and remyelination, degeneration and regeneration, damage and repair, functional loss andrecovery, it would be expected that effective therapeutic approaches will require a combination of strategiesencompassing neuroplasticity, immunomodulation, neuroprotection, neurorepair, neuroreplacement, and neu-romodulation. Cell-based restorative treatment has become a new trend, and increasing data worldwide havestrongly proven that it has a pivotal therapeutic value in CNS disease. Moreover, functional neurorestorationhas been achieved to a certain extent in the CNS clinically. Up to now, the cells successfully used inpreclinical experiments and/or clinical trial/treatment include fetal/embryonic brain and spinal cord tissue,stem cells (embryonic stem cells, neural stem/progenitor cells, hematopoietic stem cells, adipose-derivedadult stem/precursor cells, skin-derived precursor, induced pluripotent stem cells), glial cells (Schwann cells,oligodendrocyte, olfactory ensheathing cells, astrocytes, microglia, tanycytes), neuronal cells (various pheno-typic neurons and Purkinje cells), mesenchymal stromal cells originating from bone marrow, umbilical cord,and umbilical cord blood, epithelial cells derived from the layer of retina and amnion, menstrual blood-derived stem cells, Sertoli cells, and active macrophages, etc. Proof-of-concept indicates that we have nowentered a new era in neurorestoratology.
Key words: Cell therapy; Translational medicine; Neurorestoratology; Central nervous system diseases BRIEF PROFILE OF NEURORESTORATOLOGY
neurodegeneration, cerebrovascular anoxia or ischemia,edema, demyelination, sensory and motor disorders, and neuropathic pain, as well as neural damage resulting Neurorestoratology, a distinct discipline within the from toxic, physical, and chemical factors, immune, in- neurosciences, has been clearly defined by the Interna- fectious, inflammatory, hereditary, congenital, develop- tional Association of Neurorestoratology as one subdis- mental, and other intractable neural lesions (376).
cipline and one new branch of neuroscience, which stud- Inexorable Law of Neuroscientific Innovation ies the therapeutic strategies for neural regeneration, repair,and replacement of damaged components of the nervous Thousands of years ago (approx 2500 B.C.), spinal system, neuroplasticity, neuroprotection, neuromodula- cord injuries were described as “crushed vertebra in his tion, angiogenesis, immunomodulation, and their mech- neck” as well as symptoms of neurological deterioration anisms to cause improvement. The core of neurorestora- without treatment in the ancient Egyptian medical papy- tology is to restore neurological function in humans. The rus known as the Edwin Smith Surgical Papyrus by the research field of neurorestoratology covers various neur- physician and architect of the Sakkara pyramids Imhotep orestorative treatments including transplantation of tis- (8). Nearly 90 years ago Ramon y Cajal (1926) stated sue and cells, biomaterials and bioengineering, neuro- with certainty: “Once the development was ended, the modulation by electrical and/or magnetic stimulation, founts of growth and regeneration of the axons and den- pharmaceutical or chemical therapies in neurotrauma, drites dried up irrevocably. In the adult centers, the Received February 19, 2010; final acceptance March 22, 2010.
Address correspondence to Hongyun Huang, Center for neurorestoratology, Beijing Rehabilitation Center, Beijing, 100144, P.R. China. Tel: 86-10-5882-3400; Fax: 86-10-5162-5950; E-mail: [email protected] nerve paths are something fixed, ended, and immutable.
potential to restore lost function. Intervention strategies Everything may die, nothing may be regenerated. It is include gene therapy, neurotrophic factors, and cell for the science of the future to change, if possible, this transplantation (195,248,321,377), tissue engineering harsh decree” (51). Regeneration and restoration of the (402), and neurostimulation (172,369).
central nervous system (CNS) was thought to be almost Neurorestorative Therapy or Surgery. Intervention an impossibility at that time, although scientists still strategies include cell-based and pharmacological thera- tried to study the special mystery of human life through pies (423) and electrostimulation (373).
transplanting brain tissues (374), electrical stimulation Restorative Neuroscience. Intervention strategies in- (156), nerve growth factor (NGF) administration (204), clude cell transplantation, stimulation, and medicine (11).
Together, all of the medical terms mentioned above Commonly, physicians of traditional clinical disci- were not considered as distinct disciplines, but instead a plines have believed that sequelae of stroke, CNS branch of neurology, neurosurgery, or a specific kind of trauma, neurodegenerative diseases, and damage lack ef- therapy. The emergence of the term “neurorestoratol- fective treatments. The majority of the medical commu- ogy,” however, signals the birth of a new discipline, nity now still think that: “Our knowledge of the patho- which is equally important in comparison with neurol- physiological processes, both the primary as well as the ogy and neurosurgery (59). The potential mechanisms of secondary, has increased tremendously. However, all action of neurorestoratology techniques are highlighted this knowledge has only led to improved medical care but not to any therapeutic methods to restore, even par-tially, the neurological function” (8). Unfortunately, the NEURORESTORATIVE MECHANISMS
majority of physicians remain ignorant or unaware of OF CELL THERAPY
the increasing quantity of published evidence concern- Neuroprotection by Neurotrophins and Immune ing CNS functional restoration by neuromodulation, neuroprotection, axon sprouting, neural circuit recon-struction, neurogenesis, neuroregeneration, neurorepair, Bone marrow mesenchymal stem cells (BM-MSCs) and neuroreplacement in animal models and patients have the capacity to modulate immune/inflammatory re- sponses in Alzheimer disease (AD) mice, ameliorating It is the eternal desire for humans to prolong and im- their pathophysiology, and improving the cognitive de- prove their quality of life, which, with no doubt, it cline associated with amyloid-β (Aβ) deposits (199).
should be the instinct and responsibility of physicians Neural stem/precursor cells (NSPCs) can be used as an and neuroscientists to search for effective methods. Ob- immune regulatory tool for autoimmune encephalomy- viously, it is inappropriate and overly pessimistic for elitis (300). In parallel, olfactory ensheathing cells (OECs) physicians to always say that there is no way to help play a role in neuroprotection through the secretion of patients with the sequelae of diseases and damage to the neurotrophins or growth factors (350). Studies by Chopp CNS. Therefore, the new discipline, Neurorestoratology, and colleagues have proven that transplanting MSCs is bound to arise from neuroscientific innovation, filling into the brain leads to secretion of neurotrophins, growth in the question-marked frame shown in Figure 1, which factors and other supportive substances after brain injury aims to create effective therapeutic strategies to benefit (307), which change the microenvironment in the dam- aged area and continually facilitate endogenous neuro-restorative mechanisms by reducing apoptotic cell death (55). Garbuzova-Davis et al. (114) and Zwart et al. (429)reported that an appropriate dose of mononuclear human Restorative Neurology. Dimitrijevic put forward this umbilical cord blood (MNC hUCB) cells may provide a term in 1985. It was defined as the branch of the neuro- neuroprotective effect for motor and optic neurons logical sciences that applied active procedures to im- through the active involvement of these cells in modu- prove the functioning of the impaired nervous system lating the host’s immune inflammatory system response.
through selective structural and functional modification Neural protection afforded by adipose-derived stromal of abnormal neurocontrol according to underlying mech- cells was found to be mostly attributable to activated anisms and clinically unrecognized residual functions; caspase-3 and Akt-mediated neuroprotective pathway its intervention strategies included neurostimulation, signaling through paracrine support provided by trophic neuromodulation, and neuroectomies (83), cell trans- plants (242), drugs (222), and so on.
Restorative Neurosurgery. This term was put for- ward by Liberson in 1987 (221). Then restorative neuro- In early animal studies using neural stem cell treat- surgery, as the frontier of neurosurgery, provided the ments, very few cells become neurons (53) and it was CELL THERAPY IN CNS NEURORESTORATOLOGY ERA Figure 1. Distribution of disease treated by clinical disciplines of neuroscience and relevant cross-
believed that there was no evidence that “new” neurons neuronal subtypes, establish synaptic contact with host could reinnervate muscle (256). More studies now indi- cells, increase the expression of synaptic markers, and cate that mesenchymal stromal cells (137,206) and neu- enhance axonal reorganization in the injured area. Initial ral stem cells could survive, migrate, and differentiate patch-clamp recording demonstrated that the MGE cells into endothelial cells or glia and neurons (173,427), received postsynaptic currents from the host cells. Func- form electrically active and functionally connected neu- tional recovery could be mediated by neurotrophic sup- rons (15) that form synapses between host and donor port, new synaptic circuit elaboration, and enhancement cells (396), and elicit further functional repair following of the stroke-induced neuroplasticity (74). Recent find- transplantation into the adult CNS (81,100,161,210,252, ings of transplanted embryonic dopamine (DA) neurons 349,382). Furthermore, evidence shows that bone mar- into the substantia nigra (SN) indicate that DA neurons row stromal cells are capable of remodeling the blood could extend neurites towards a desired target through the brain stem and caudal diencephalon to reconstructthe neural circuitry from grafted neurons in the host (315,355). Application of stem cells for neuroreplace- Many different cell types have been shown to have ment therapy is therefore no longer science fiction—it potential in the repair or remyelination of CNS diseases is science fact (367). OECs can promote neuroplasticity in neurodegenerative diseases (62), while NSCs can sup-press abnormal mossy fiber sprouting into the inner mo- lecular layer with subsequent reduction of hippocampal Schwann cells (SCs) can induce sprouting of motor and sensory axons in the adult rat spinal cord (214). Ac-cumulated studies show that OECs are capable of aiding Neuromodulation or Unmasking and Signaling Repair axon growth or sprouting following transplantation and continued regeneration of the denervated caudal host Our clinical study showed that patients with chronic tract resulting in the recovery of neurological functions spinal cord injury have rapid recovery of some functions in acute (44,211,312,314,409) as well as chronic spinal following OEC transplantation. The explanation is that they changed the local microenvironment by the secre- Neural Circuit or Network Reconstruction, tion of useful chemicals or growth factors, which can Neuroplasticity, and Neuroreplacement promote the nerve cell growth, unmasking the quiescent In the rat stroke model, a graft of medial ganglionic axons, and therefore restoring some of the lost functions eminence (MGE) cells may differentiate into multiple (147). Grafting dental pulp stem/stromal cells (DPSC) can promote proliferation, cell recruitment, and matura- alternative therapy for a variety of degenerative and tion of endogenous stem/progenitor cells by modulating traumatic disorders (Table 1). It has been argued that the local microenvironment through enhancing ciliary neural transplantation can promote functional recovery neurotrophic factor (CNTF), vascular endothelial growth by the replacement of damaged nerve cells, the reestab- factor (VEGF), and fibroblast growth factor (FGF) as lishment of specific nerve pathways lost as a result of stimulators and modulators of the local repair response injury, the release of specific neurotransmitters, or the in the CNS (142) and neuromodulation would likely be production of factors that promote neuronal growth necessary to realize the full potential of NSC grafts in restoring function (111). Another study also suggested Fetal/Embryonic Spinal Cord Tissue that the inhibitory neurotransmitters γ-aminobutyric acid(GABA) and glycine secreted by transplanted cells The first successful transplantation of fetal spinal could be an effective clinical tool for treating spinal cord cord into adult spinal cord was reported in 1983 (291).
injury (SCI)-associated neuropathic pain (91).
Some topographical features of the normal spinal cord Generally, the patient’s functional restoration origi- may be represented in mature spinal cord transplants nated from some or all of the mechanisms as listed (318). Embryonic spinal cord transplants are capable of above. But under many conditions, functional recovery replacing damaged intraspinal neuronal populations and is from neuromodulation or unmasking, neuroprotection, restoring some degree of anatomical continuity between sprouting, neural circuit reconstruction, and neuroplas- the isolated rostral and caudal stumps of the injured ticity by neurotrophins, immune or inflammatory modu- mammalian spinal cord (317). Improved hind limb be- lation and local microenvironment change, and in a few havioral deficits were observed after fetal spinal cord cases from neurogenesis or neuroregeneration, and neur- homografts (31). Moreover, the grafted fetal/embryonic orepair (378,409). Neuroreplacement may be an impor- tissue may stimulate partial regression of an established tant tool for Parkinson’s disease (PD), but may not be a glial scar (141), replace missing motoneurons (353), and major way for functional neurorestoration in most other form myelin (324). Data have shown that spinal cord CNS diseases or damage. It remains unclear how to ex- transplants support regrowth of adult host axons result- plain the exact mechanisms for clinical functional recov- ing in reconstitution of synaptic complexes within the ery; in the future mechanisms by which cell transplanta- transplant that in many respects resemble normal syn- tion enhances functional recovery need to be better apses. Transplants of fetal spinal cord may also contrib- understood following further experimental study.
ute to behavioral recovery by rescuing axotomized hostneurons that otherwise would have died. Electrophysio- PRECLINICAL STUDIES OF CELL-BASED
logical investigations of functional recovery after intras- NEURORESTORATOLOGY IN CNS DISEASES
pinal transplantation have been recorded (32,375).
Olfactory Ensheathing/Precursor Cells In 1977, the first evidence was presented that grafts of fetal brain tissue to the adult CNS could counteract an OECs are cells that display Schwann cell or astro- experimentally induced neurological deficit (279). Cell/ cyte-like properties. They are a source of growth factors tissue suspensions, dissociated from selected embryonic and adhesion molecules that play a very important role brain regions, can mediate considerable reinnervation of as a neuronal support enhancing cellular survival (179, a previously denervated brain or spinal cord region, and 292). Transplants of these cells have been shown to have they can replace neurons intrinsic to a particular target a neuroprotective effect, supporting axonal regeneration, after intracerebral or intraspinal grafting (277,294). Fetal remyelination of demyelinated axons, neuroplasticity, brain tissue, grafted into the CNS of neonatal and adult neuromodulation, neurogenesis, angiogenesis, anti-inflam- animals, has been shown to survive and differentiate (318).
matory response, reducing scar and cavity formation, In brain tissue grafts consisting of undifferentiated ma- and/or strong phagocytic activity (107,196,203,233,292, trix cells and few neuroblasts, good development was 293,311,341,388,397,398,419). The cellular composition observed both in the lateral ventricle and inside the pa- of the olfactory tissue and the evidence that equivalent renchyma, 30 and 110 days after transplant. They differ- cell types exist in both rodent and human olfactory mu- entiated into organotypical and histotypical structures cosa suggest that it is potentially a rich source of autolo- and cells similar to those formed in normal develop- gous cells for transplant-mediated repair of the CNS ment. Nerve and glial cells of these transplants were (224). Selected relevant studies are listed in Table 2.
well differentiated and tightly connected with the sur- rounding nervous tissue of the host (7). It has been con-vincingly shown that grafting of fetal/embryonic brain Schwann cells (SCs) play a pivotal role in the mainte- cells/tissue into the brain and/or spinal cord is a useful nance and regeneration of the axons in the peripheral CELL THERAPY IN CNS NEURORESTORATOLOGY ERA Table 1. Selected Literature in Preclinical Therapeutic Application of Fetal/Embryonic Brain Cells/Tissue
Spinal cord trauma
In vivo magnetic resonance imaging of fetal cat neural tissue trans-plants in the adult cat spinal cord Monoaminergic reinnervation of the transected spinal cord by ho-mologous fetal brain grafts Fetal locus coeruleus transplanted into the transected spinal cord ofthe adult rat: Some observations and implications Visual deficits
Fetal brain tissue transplants reduce visual deficits in adult rats withbilateral lesions of the occipital cortex Peripheral nerve injury
Viability, growth, and maturation of fetal brain and spinal cord inthe sciatic nerve of adult rat Parkinson’s disease
Brain grafts reduce motor abnormalities produced by destruction ofnigrostriatal dopamine system Cognitive deficits
Fetal brain transplant: Reduction of cognitive deficits in rats withfrontal cortex lesions Fetal brain transplants induce recuperation of taste aversion lear-ning Brain trauma
Fetal frontal cortex transplanted to injured motor/sensory cortex ofadult rats: Reciprocal connections with host thalamus demonstratedwith WGA-HRP The effects of intrahippocampal raphe and/or septal grafts in ratswith fimbria-fornix lesions depend on the origin of the grafted tis-sue and the behavioural task used Organization of host afferents to cerebellar grafts implanted intokainate lesioned cerebellum in adult rats Hypoxic hypoxia
Transplantation of embryonic brain tissue into the brain of adultrats after hypoxic hypoxia Neurotrophin-mediated neuroprotection by solid fetal telencephalicgraft in middle cerebral artery occlusion: A preventive approach Transplantation of human fetal brain cells into ischemic lesions of nervous system (PNS) due to their ability to dedifferenti- SC migration and myelination is mediated by interac- ate, migrate, proliferate, express growth-promoting fac- tions between sets of extracellular matrix molecules with tors, and myelinate-regenerating axons (197). Further, cell surface preoteins, genetic engineering of SCs to al- SCs have been shown to form myelin after transplanta- ter aspects of these interactions is a possible way for- tion into the demyelinated CNS. They can remyelinate ward. Efforts are, therefore, focused on enhancing their spinal cord lesions after experimental demyelination, migration and functional integration into the lesioned leading in some cases to functional recovery in rodent CNS. In addition, efforts are under way to use these and primate models (154). However, SCs do not nor- cells as tissue engineer seeds and gene delivery vehicles mally enter the CNS, and migration of SCs transplanted for an array of molecules with repair potential (33,282).
into the CNS white matter is inhibited by astrocytes. As The SCs ability to promote restorative efforts has led to Table 2. Selected Literature in Preclinical Therapeutic Application of Olfactory Ensheathing/Precursor Cells
Spinal cord trauma
Regeneration into the spinal cord of transected dorsal root axons ispromoted by ensheathing glia transplants Ensheathing glia transplants promote dorsal root regeneration andspinal reflex restitution after multiple lumbar rhizotomy Spinal implants of olfactory ensheathing cells promote axon regen-eration and bladder activity after bilateral lumbosacral dorsal rhi-zotomy in the adult rat Repair of adult rat corticospinal tract by transplants of olfactoryensheathing cells Phrenic rehabilitation and diaphragm recovery after cervical injuryand transplantation of olfactory ensheathing cells Xenotransplantation of transgenic pig olfactory ensheathing cellspromotes axonal regeneration in rat spinal cord Functional repair of the corticospinal tract by delayed transplanta-tion of olfactory ensheathing cells in adult rats Protection of corticospinal tract neurons after dorsal spinal cordtransection and engraftment of olfactory ensheathing cells Long-distance axonal regeneration in the transected adult rat spinalcord is promoted by olfactory ensheathing glia transplants Functional recovery of paraplegic rats and motor axon regenerationin their spinal cords by olfactory ensheathing glia Transplantation of nasal olfactory tissue promotes partial recoveryin paraplegic adult rats Olfactory ensheathing cells promote locomotor recovery after de-layed transplantation into transected spinal cord Olfactory ensheathing glias transplant improves axonal regenera-tion and functional recovery in spinal cord contusion injury Delayed transplantation of olfactory ensheathing glia promotessparing/regeneration of supraspinal axons in the contused adult ratspinal cord Regeneration of adult rat corticospinal axons induced by trans-planted olfactory ensheathing cells Effects of ensheathing cells transplanted into photochemically dam-aged spinal cord Increased expression of cyclo-oxygenase 2 and vascular endothelialgrowth factor in lesioned spinal cord by transplanted olfactory en-sheathing cells Schwann cell-like myelination following transplantation of an ol- factory bulb-ensheathing cell line into areas of demyelination in theadult CNS Transplanted olfactory ensheathing cells remyelinate and enhanceaxonal conduction in the demyelinated dorsal columns of the ratspinal cord CELL THERAPY IN CNS NEURORESTORATOLOGY ERA Table 2. Continued
Identification of a human olfactory ensheathing cell that can effecttransplant-mediated remyelination of demyelinated CNS axons Superparamagnetic iron oxide-labeled Schwann cells and olfactoryensheathing cells can be traced in vivo by magnetic resonance im-aging and retain functional properties after transplantation into theCNS Remyelination of the nonhuman primate spinal cord by transplanta-tion of H-transferase transgenic adult pig olfactory ensheathingcells Molecular reconstruction of nodes of Ranvier after remyelinationby transplanted olfactory ensheathing cells in the demyelinated spi-nal cord Olfactory bulb ensheathing cells enhance peripheral nerve regen-eration Effect of olfactory ensheathing cells transplantation on protectingspinal cord and neurons after peripheral nerve injury Transplantation of olfactory ensheathing cells stimulates the collat-eral sprouting from axotomized adult rat facial motoneurons Transplantation of olfactory mucosa minimizes axonal branchingand promotes the recovery of vibrissae motor performance afterfacial nerve repair in rats Optic nerve injury
Transplanted olfactory ensheathing cells promote regeneration ofcut adult rat optic nerve axons Glaucoma
Transplanted olfactory ensheathing cells incorporated into the opticnerve head ensheathe retinal ganglion cell axons: Possible rele-vance to glaucoma Parkinson’s disease
Olfactory ensheathing cell transplantation restores functional defi-cits in rat model of Parkinson’s disease: A cotransplantation ap-proach with fetal ventral mesencephalic cells Amyotrophic lateral sclerosis
Adult olfactory bulb neural precursor cell grafts provide temporaryprotection from motor neuron degeneration, improve motor func-tion, and extend survival in amyotrophic lateral sclerosis mice Cognitive dysfunction
Long-term functional restoration by neural progenitor cell trans-plantation in rat model of cognitive dysfunction: Eo-transplantationwith olfactory ensheathing cells for neurotrophic factor support A long term observation of olfactory ensheathing cells transplanta-tion to repair white matter and functional recovery in a focal ische-mia model in rat an increasing interest in using SC grafts for repair of and unusual antigenic phenotype. Evidence from post- mortem analysis implicates the involvement of microg-lia in the neurodegenerative process of several neurode- generative diseases, including AD and PD. Grafting of Remyelination by transplantation of myelin-forming activated microglia into the lesioned spinal cord may cells is possible in animal models; evidence suggests promote hind limb motor function recovery in rats and that both a precursor-type oligodendrocyte as well as an reduce the size of the liquefaction necrosis area (228, oligodendrocyte that previously formed a myelin sheath is able to remyelinate the CNS (126,386). Oligodendro-cytes or precursor cells are much more invasive and have been shown to migrate from the implantation site Monocytes/macrophages play an integral role in the to the lesion over a distance of several millimeters inflammatory process and angiogenesis as well as acting (72,387). Indeed, a number of studies have demonstrated as defense mechanisms by exerting microbiocidal and that transplanted oligodendrocytes survive in the host immunomodulatory activity. The recruited monocytes/ brain, migrate out of the graft, and synthesize myelin.
macrophages are capable of regulating angiogenesis in These cells, therefore, have potential for myelin repair ischemic tissue, tumors, and chronic inflammation. In after experimental demyelination and in human diseases, terms of neovascularization followed by tissue regenera- such as multiple sclerosis, though several findings sug- tion, monocytes/macrophages should be highly attrac- gest that OECs and SCs might be more effective than tive for cell-based therapy compared to other cells due oligodendrocytes induced from isolated CNS tissue (87, to their considerable advantages: nononcogenic, nonte- ratogenic, multiple secretory functions including proan-giogenic and growth factors and their straightforward cell harvesting procedure (348). Increasing the presence Cultured astrocytes have been reported to survive and of activated macrophage/microglial cells at a SCI site migrate following transplantation. Studies have indi- can provide an environment beneficial to the promotion cated that there are differences in the ability of immature of regeneration of sensory axons, possibly by the release and mature astrocytes to facilitate plastic changes in the of cytokines and interaction with other nonneuronal cells adult brain. Immature astrocytes can synthesize trophic in the immediate vicinity (117,305).
factors to support neuronal survival, produce a permis-sive environment for neurite extension, and reduce scar formation. In contrast, mature astrocytes produce a non- Purkinje cells have a therapeutic value for the re- permissive environment for axon growth and increase placement and reconstruction of a defective cerebellar scar formation. Purified astrocytes were capable of facil- circuitry in heredodegenerative ataxia. Insignificant itating behavioral recovery from frontal cortex ablation, amelioration of motor skills was found in mice after demyelinating lesions in spinal cord, and kainic acid solid cerebellar tissue transplantation, while the cell sus- (KA) lesions of the striatum (10,104,174,240,392). Im- pension application had no effect (344,357,358).
planted cultured immature astrocytes can stimulate axo-nal regeneration after injury of the postcommissural for- nix tract in the adult rat brain (406). In addition, Tanycytes (TAs) are the specialized ependymal glia behavior alleviation after astrocyte transplantation was in the CNS, which are located mostly in the ventral wall shown in rat models of memory deficit induced by of the third ventricle and median eminence (ME). They alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic closely interact with local cerebrospinal fluid, blood, and acid lesions, which is independent of cholinergic recov- neurons. TA is a common component of the brain bar- ery. The cultured astrocytes may exert their effects over rier system, the brain–cerebrospinal fluid (CSF) neuro- a short time period (less than 2 weeks) around the lesion humoral circuit, and the immune–neuroendocrine net- site. They can alter the microenvironment and as a result work. Recent data indicate that TAs transplanted into less scar tissue was formed followed by less of a barrier the adult rat spinal cord can support the regeneration of to the regrowth of nerve fibers (43). Furthermore, evi- lesioned axons and may represent a useful therapeutic dence indicates that astrocytes at an immature stage of differentiation are capable of inducing axon growth fromthe adult optic nerve (354).
Intracerebral transplantation of dopaminergic (DAer- Microglia are the principal immune cells in the CNS gic) neuron/cells is currently performed as a restorative and are characterized by a highly specific morphology therapy for PD (273). The success of cell therapy in PD CELL THERAPY IN CNS NEURORESTORATOLOGY ERA Table 3. Selected Literature in Preclinical Therapeutic Application of Schwann Cells
Spinal cord trauma
Reinnervation of peripheral nerve segments implanted into thehemisected spinal cord estimated by transgenic mice Schwann cells induce sprouting in motor and sensory axons in theadult rat spinal cord Influences of the glial environment on the elongation of axons after injury: Transplantation studies in adult rodents Axonal regeneration into Schwann cell-seeded guidance channelsgrafted into transected adult rat spinal cord Reconstruction of the contused cat spinal cord by the delayed nervegraft technique and cultured peripheral non-neuronal cells Syngeneic grafting of adult rat DRG-derived Schwann cells to theinjured spinal cord Transplantation of purified populations of Schwann cells into le-sioned adult rat spinal cord Chronic regenerative changes in the spinal cord after cord compres-sion injury in rats Remyelination by cells introduced into a stable demyelinating le-sion in the central nervous system Transplantation of rat Schwann cells grown in tissue culture intothe mouse spinal cord The use of cultured autologous Schwann cells to remyelinate areas of persistent demyelination in the central nervous system Schwann cell remyelination of CNS axons following injection ofcultures of CNS cells into areas of persistent demyelination Optic nerve injury
Schwann cells and the regrowth of axons in the mammalian CNS:A review of transplantation studies in the rat visual system Monocular deprivation
Schwann cells transplanted in the lateral ventricles prevent thefunctional and anatomical effects of monocular deprivation in therat Parkinson’s disease
Cografts of adrenal medulla with peripheral nerve enhance the sur-vivability of transplanted adrenal chromaffin cells and recovery ofthe host nigrostriatal dopaminergic system in MPTP-treated youngadult mice Peripheral nerve-dopamine neuron co-grafts in MPTP-treated mon-keys: Augmentation of tyrosine hydroxylase-positive fiber stainingand dopamine content in host systems Therapeutic study of autologous Schwann cells’ bridge graft into Brain trauma
Transplants of Schwann cell cultures promote axonal regenerationin the adult mammalian brain Reconstruction of transected postcommissural fornix in adult rat bySchwann cell suspension grafts Schwann cells transplantation promoted and the repair of brainstem injury in rats greatly relies on the discovery of an abundant source of cells capable of DAergic function in the brain. DAergic ES cells, in particular, possess a nearly unlimited neuron/precursor cells derived from human embryonic self-renewal capacity and developmental potential to stem (hES) cells, human-induced pluripotent stem (hiPS) differentiate into virtually any cell type of an organism.
cells, neural stem/progenitor cells, human mesenchymal They can efficiently differentiate into neural precursors, stem cells, and skin-derived stem cells could be increas- which can further generate functional neurons, astro- ingly considered as a pivotal choice for transplant (50, cytes, and oligodendrocytes (102,229,231). These cells 188,227,269,372). It is likely that cell replacement in also have the beneficial properties of secreting neuro- future will focus on not only ameliorating symptoms of trophic and neural growth factors (272). Along with di- the disease but also try to slow down the progression of rected differentiation, other current efforts are aimed at the disease by either neuroprotection or restoration of a efficient enrichment, avoidance of immune rejection, favorable microenvironment in the midbrain (319).
demonstration of functional integration, genetic modifi-cation to regulate neurotransmitter and factor release, and directed axon growth with these cells (125).
Transplantation of predifferentiated GABAergic neu- rons significantly induces recovery of sensorimotor func- tion in brain injury (25). A deficiency of GABAergic Neural stem/progenitor cells (NSPCs) are present neurons in the neocortex leads to the dysregulation of during embryonic development and in certain regions of cortical neuronal circuits, but this can be overcome by the adult CNS (264). Mobilizing adult NSCs to promote cell transplantation. Ventral neural stem cells transfected repair of injured or diseased parts of the CNS is a prom- with neurogenin 1 (Ngn1) are integrated as GABAergic ising approach (3). NSPCs in the adult CNS are capable neurons within a few days of transplantation into the of generating new neurons, astrocytes, and oligodendro- adult mouse neocortex, and the transplantation of com- cytes (381). Intraventricular transplantation of neural mitted neuronal progenitor cells has been demonstrated spheres attenuated brain inflammation in acute and to be an effective method for brain repair ( 268). In addi- chronic experimental autoimmune encephalomyelitis tion, transplants of neuronal cells bioengineered to syn- (EAE), reduced the clinical severity of disease, and re- thesize GABA may alleviate chronic neuropathic pain duced demyelination and axonal pathology. Intravenous (90). Fetal GABAergic neurons transplanted into the SN (IV) NSPCs injection also inhibited EAE and reduced might be an effective means of permanently blocking CNS inflammation and tissue injury (27). A recent study seizure generalization in kindling epilepsy and probably showed that adult NSCs transplanted at sites of injury also other types of epilepsy (101,234).
can differentiate into vascular cells (endothelial cells andvascular smooth muscle cells) for vasculogenesis (152).
Transplantation of NSCs or their derivatives into a host Transplanted cholinergic neurons may reinnervate the brain and the proliferation and differentiation of endoge- host hippocampus, although this reinnervation appears nous stem cells by pharmacological manipulations are to be different from that seen in the intact hippocampal promising treatments for many neurodegenerative dis- formation (9). Intraretrosplenial cortical grafts of cholin- eases and brain injuries, such as PD, brain ischemia, and ergic neurons can become functionally incorporated with the host neural circuitry, and the activity of the implanted cholinergic neurons can be modulated by thehost brain (216) and it can rectify spatial memory defi- Bone marrow stromal (also called “stem”) cells cits produced by the loss of intrinsic cholinergic afferents (BMSCs) can be easily amplified in vitro and their trans- from the medial septal nucleus (217). Reconstruction of differentiation into neural cells has been claimed in vitro the septohippocampal pathways by axons extending and in vivo (63,82,163,171). The possible mechanisms from embryonic cholinergic neuroblasts grafted into the responsible for the beneficial outcome observed after neuron-depleted septum has been confirmed in the neo- BMSC transplantation into neurodegenerating tissues in- natal rat (198). Intrahippocampal septal grafts are able clude cell replacement, trophic factor delivery, immuno- to reinnervate the hippocampal formation and ameliorate modulation, and anti-inflammatory, neuroprotection, and spatial learning and memory deficits, which are associ- angiogenesis (171,371,379). Transplantation of BMSCs ated with anatomical and functional incorporation into may have a therapeutic role after SCI (64). Adult BMSCs the circuitry of the host hippocampal formation. Auto- administered intravenously have been shown to migrate transplantation of peripheral cholinergic neurons into the into the brain and improve neurological outcome in rats cerebral cortex displayed amelioration of abnormal be- with traumatic brain injury (236). In parallel, data of intracerebral transplantation suggest that bone marrow CELL THERAPY IN CNS NEURORESTORATOLOGY ERA Table 4. Animal Model of CNS Diseases Treated Using Neural Stem/
Progenitor Cells
could potentially be used to induce plasticity in ischemic MSC therefore could be a viable alternative to human brain. Additionally, cotransplantation of BMSCs with ES cells or NSCs for transplantation therapy of CNS ES cell-derived graft cells may be useful for preventing trauma and neurodegenerative diseases (235) (Table 6).
the development of ES cell-derived tumors (253). Re- sults of this field are summarized in Table 5.
UCB is a rich source of stem cells with great prolifer- Umbilical Cord Mesenchymal Stromal Cells ative potential, besides the bone marrow and peripheral Mesenchymal stromal cells (MSCs) have now been blood; it has the advantage of being an easily accessible isolated from most tissues, including the umbilical cord stem cell source and is less immunogenic compared to (UC) and UC blood (UCB; see below). UC and UCB other sources for stem cells (334). There are at least MSCs are more primitive than those isolated from other three kinds of stem cells in UCB: hematopoietic, mesen- tissue sources and do not express the major histocompat- chymal, and embryonic-like stem cells, which are capa- ibility complex (MHC) class II human leukocyte anti- ble of differentiating across tissue lineage boundaries gen-D-related (HLA-DR) antigens. Studies have shown into neural, cardiac, epithelial, hepatocytic, and dermal that UC MSCs are still viable and are not rejected 4 tissue both in vitro and in vivo (132,325,383). Increasing months after transplantation as xenografts, without the evidence suggests that MSCs from UCB are present need for immune suppression, suggesting that they are a within a wide range of tissues and its therapeutic poten- favorable cell source for transplantation (422). UC in- tial extends beyond the hematopoietic component (34).
cluding arteries (UCA), veins (UCV), and Wharton’s The expanding population of NSPCs can be selected jelly (UCWJ) is a convenient, efficient source of MSCs from the human cord blood nonhematopoietic (CD34- that can be expanded easily in vitro for numerous clini- negative) mononuclear fraction (49). UCB can be a po- cal applications for the treatment of nonhematopoietic tential source for autologous or allogeneic monocytes/ diseases, and in studies of tissue regeneration and immu- macrophages. UCB monocytes should be considered as nosuppression (119,159). UC MSCs have proven to be a primary candidate owing to their easy isolation, low efficacious in reducing lesion sizes and enhancing be- immune rejection, and multiple characteristic advan- havioral recovery in animal models of ischemic and tages such as their anti-inflammatory properties by traumatic CNS injury. Recent findings also suggest that virtue of their unique immune and inflammatory imma- neurons derived from UC-MSC could alleviate move- turity, and their proangiogenic ability (333). The thera- ment disorders in hemiparkinsonian animal models. UC- peutic potential of UCB cells may be attributed to the Table 5. Animal Model of CNS Diseases Treated Using Bone Marrow Stromal Cells
Experimental autoimmune encephalomyelitis (EAE) inherent ability of stem cell populations to replace dam- 1995 based on favorable results in animal models in- aged tissues. Alternatively, various cell types within the cluding EAE (47). Recent studies show that transplanta- graft may promote neural repair by delivering neural tion of HSCs from bone marrow is an effective strategy protection and secretion of neurotrophic factors (284, for SCI after directly transplanting cells into the cord 334). In addition, evidence suggests that delivery of cir- 1 week after injury (185), with a similar potential in culating CD34+ human UCB cells can produce func- comparison with marrow stromal cells (180). An in- tional recovery in an animal stroke model with concur-rent angiogenesis and neurogenesis leading to somerestoration of cortical tissue (295). UCB cells have been Table 7. Animal Model of CNS Diseases Treated Using
used in preclinical models of brain injury and neurode- generative diseases, directed to differentiate into neural phenotypes, and have been related to functional recov- ery after engraftment in CNS lesion models (Table 7).
Hematopoietic stem cell transplantation (HSCT) was proposed as a treatment for multiple sclerosis (MS) in Table 6. Animal Model of CNS Diseases Treated Using
CELL THERAPY IN CNS NEURORESTORATOLOGY ERA creasing number of studies provide evidence that hema- myelinated endogenous host axons, recruited endoge- topoietic stem cells, either after stimulation of endoge- nous SCs into the injured cord, formation of a bridge nous stem cell pools or after exogenous hematopoietic across the lesion site, increased size of the spared tissue stem cell use, improve functional outcome after ische- rim, myelinated spared axons within the tissue rim, re- mic brain lesions. Various underlying mechanisms such duced reactive gliosis, and an environment that was as transdifferentiation into neural lineages, neuroprotec- highly conducive to axonal growth (35). In addition, tion through trophic support, and cell fusion have been SKPs transplanted into PD model rats sufficiently differ- deciphered (130). Furthermore, intracerebral peripheral entiated into dopamine neuron-like cells, and partially blood hematopoietic stem cell (CD34+) implantation in- but significantly corrected their behavior. The generated duces neuroplasticity by enhancing β1 integrin-mediated DA neuron-like cells are expected to serve as donor cells angiogenesis in chronic cerebral ischemia with signifi- for neuronal repair for PD (188). Thus, this cell line has cantly increased modulation of neurotrophic factor ex- been identified as novel, accessible, and a potentially pression in the ischemic hemisphere (352).
autologous source for future nervous system repair(35,192).
Adipose-Derived Adult Stem/Precursor Cells Adipose tissue is an abundant, accessible, and replen- The retinal pigment epithelium consists of a unicellu- ishable source of adult stem cells that can be isolated lar layer of neuroepithelial cells, retinal pigment epithe- from liposuction waste tissue by collagenase digestion lial (RPE) cells, which are essential for the maintenance and differential centrifugation (118). These adipose- of the normal function of the retina (139). Cultured hu- derived adult stem (ADAS) cells, which exhibit charac- man RPE cells have the capacity to synthesize neuro- teristics of multipotent adult stem cells, similar to those trophins, including NGF, brain-derived growth factor of MSCs, are multipotent, differentiating along the adi- (BDNF), glial cell-derived neurotrophic factor (GDNF), pocyte, chondrocyte, myocyte, neuronal, and osteoblast and neurotrophin-3 (NT-3) (158,262). Studies have lineages (124). ADAS cells have potential applications shown that, as an alternative cell source, RPE cells pos- for the repair and regeneration of acute and chronically sess DAergic replacement properties with neurotrophic damaged tissues (329). As an alternative stem cell support on primary cultures of rat striatal (enkephaliner- source for CNS therapies, ADAS cells labeled with su- gic) and mesencephalic (DAergic) neurons, and there- perparamagnetic iron oxide have been shown using MRI fore could exert a positive effect in parkinsonian animals to successfully transplant in vivo in unilateral middle by intrastriatal transplantation (247,257,365,366). RPE cerebral artery occluded (MCAo) mice (320). The study cells can be transduced with high efficiency using an of Ryu and colleagues indicate that improvement in neu- adenoviral vector, making them promising vehicles for rological function by the transplantation of ADAS in local delivery of therapeutic proteins for the treatment dogs with SCI may be partially due to the neural differ- of neurodegenerative diseases in a combined cell and entiation of the implanted stem cells (326). Furthermore, the transplantation of ADAS can promote the formationof a more robust nerve in rats with a sciatic nerve defect and produce a decrease in muscle atrophy (336).
Human amniotic epithelial cells (AEC) do not ex- press the HLA-A, -B, -C, or -DR antigens on their sur- face, which suggests no acute rejection in transplanta- Skin-derived precursors (SKPs) are a self-renewing, tion (6). The human amnion membrane serves as a multipotent precursor that are generated during embryo- bridge for axonal regeneration in vitro and in vivo; cells genesis and persist into adulthood in the dermis, share isolated from the amniotic membrane can differentiate characteristics with embryonic neural crest stem cells, into all three germ layers, have low immunogenicity and including their ability to differentiate into neural crest- anti-inflammatory function (76,417). Given their multi- derived cell types such as peripheral neurons, SCs, potent differentiation ability, capability of synthesizing astrocytes, and endothelium (26,149). After transplanta- catecholamines including DA, and neurotrophic and tion, the cells yield healthy cells that migrate to the le- neuroprotection effect, there is accumulating evidence sion site, and then differentiate mainly into cells ex- that suggests that AECs have therapeutic potential for pressing glia and neuronal markers (122). Recent multiple CNS disorders, such as PD, mucopolysacchari- evidence indicates that transplantation of SKP-derived dosis, SCI, stroke, brain trauma, etc. (Table 8).
SCs represent a viable alternative strategy for repairing the injured spinal cord, with the neuroanatomical neur-orestorative findings including good survival within the Endometrial cells supplied as a form of menstrual injured spinal cord, reduced size of the contusion cavity, blood–tissue mixture can be used for cell-based restor- Table 8. Selected Literatures in Preclinical Therapeutic Application of Amniotic Epithelial Cells
Parkinson’s disease
Human amniotic epithelial cells produce dopamine and surviveafter implantation into the striatum of a rat model of Parkinson’sdisease: A potential source of donor for transplantation therapy Implantation of human amniotic epithelial cells prevents the degen-eration of nigral dopamine neurons in rats with 6-hydroxydopaminelesions Transplantation of human amniotic cells exerts neuroprotection inMPTP-induced Parkinson disease mice Mucopolysaccharidosis
Engraftment of genetically engineered amniotic epithelial cells cor- rects lysosomal storage in multiple areas of the brain in mucopoly-saccharidosis type VII mice Brain ischemia
Amniotic epithelial cells transform into neuron-like cells in the is-chemic brain Amniotic fluid derived stem cells ameliorate focal cerebral isch-aemia-reperfusion injury induced behavioural deficits in mice Human amniotic epithelial cells ameliorate behavioral dysfunctionand reduce infarct size in the rat middle cerebral artery occlusionmodel Spinal cord trauma
Role of human amniotic epithelial cell transplantation in spinal cordinjury repair research Transplantation of human amniotic epithelial cells improves hind-limb function in rats with spinal cord injury Peripheral nerve injury
Bridging rat sciatic nerve defects with the composite nerve-muscleautografts wrapped with human amnion matrix membrane Brain injury
Treatment of traumatic brain injury in rats with transplantation ofhuman amniotic cells ative therapy in muscular dystrophy (380); subsequent evidence shows that populations of stromal stem cellsderived from menstrual blood are multipotent, being Transplanted testis-derived Sertoli cells, which create able to differentiate into chondrogenic, adipogenic, os- a localized immune “privileged” site, possess a modula- teogenic, neurogenic, and cardiogenic cell lineages (290).
tory function on graft rejection and survival and act as The cultured menstrual blood express embryonic like- a viable graft source for facilitating the use of xenotrans- stem cell phenotypic markers [Octamer-4 (Oct4), stage- plantation for diabetes, PD, Huntington’s disease, and specific embryonic antigen (SSEA), Nanog], and when other neurodegenerative diseases (41,331,332). In addi- grown in appropriate conditioned media, express neu- tion to producing immunoprotective factors, Sertoli cells ronal phenotypic markers [nestin, microtubule-associ- also secrete growth and trophic factors that appear to ated protein 2 (MAP2)] (40). Transplantation of men- enhance the posttransplantation viability of isolated cells strual blood-derived stem cells, either intracerebrally or and, likewise, the postthaw viability of isolated, cryopre- intravenously and without immunosuppression, signifi- served cells (52). Sertoli cells grafted into adult rat cantly reduces behavioral and histological impairments brains ameliorated behavioral deficits and enhanced DAergic neuronal survival and outgrowth (331). Cotrans- CELL THERAPY IN CNS NEURORESTORATOLOGY ERA planting of Sertoli cells may be useful as a combination younger, but not in older patients (108). Furthermore, therapy in CNS lesions, a strategy that could enhance pathologic findings suggest that grafts of fetal mesence- the recovery benefits associated with transplantation and phalic DA neurons could survive long term with or with- decrease the need for, and the risks associated with, out α-synuclein-positive Lewy bodies (184,205,259).
long-term systemic immunosuppression (399). Further, Bachoud-Le´vi and coworkers indicated motor and recent research has shown that implantation of a Sertoli cognitive recovery in patients with Huntington’s disease cell-enriched preparation has a significant neuroprotec- after neural transplantation (17), which continued during tive benefit to vulnerable motor neurons in a superoxide long-term follow-up (16). The therapeutic value of hu- dismutase 1 (SOD1) transgenic mouse model of amyo- man striatal neuroblasts in Huntington’s disease was trophic lateral sclerosis (ALS) (136).
identified by Gallina and colleagues (112).
Human Neural Stem/Progenitor Cells Induced pluripotent stem (iPS) cells are derived from somatic cells by ectopic expression of a few transcrip- The clinical regimes of intracranial implant of human tion factors. iPS cells appear to be able to self-renew neuronal cells in stroke patients have proven safe and indefinitely and to differentiate into all types of cells feasible, though there is a lack of evidence for a signifi- in the body, and are almost identical to ES cells. The cant benefit in motor function (181,182). Data suggest generation of patient-derived pluripotent cells applicable that cell therapy is a safe method and can be effectively to autologous cell-based therapies has the potential to used for stroke (308), acute brain injury (346,347), and revolutionize medicine (60). Since the first report from cerebral palsy (345). In addition, neurological function Takahashi and Yamanaka on the reprogramming of has been restored after autologous neural stem cell trans- mouse fibroblasts into pluripotent stem cells by defined plantation in patients with brain trauma (428).
factors in 2006 (370), various new methods have beendeveloped to refine and improve reprogramming tech- Umbilical Cord Mesenchymal Stem Cells nology (281). The current demonstration of DAergic dif-ferentiation of human induced pluripotent stem cells Therapy of UC-MSCs could stabilize the disease (hiPSCs), replacement of segmental losses of interneur- course of refractory progressive MS (218).
ons and motorneurons due to gray matter damage andrestoration of auditory spiral ganglion neurons suggest a Umbilical Cord Blood Mesenchymal Stem Cells new avenue for highly effective, tumor-free, and im- Kang and colleagues report that UCB-MSC trans- mune rejection-free cell therapy for PD, SCI, and hear- plantation may play a role in the treatment of SCI pa- ing disturbance in the near future (151,276,323).
Olfactory Ensheathing Cell and Olfactory NEURORESTORATOLOGY
Early OEC/olfactory mucosa autograft transplants for Adrenal Medullary Tissue, Substantia Nigra, patients with chronic SCI were reported by Huang et al.
in 2003 (143), Rabinovich et al. in 2003 (309), and Lima Positive findings had initially been observed by et al. in 2006 (223), and the results were safe, feasible, Backlund et al. (19) and Lindvall et al. (225) concerning and positive. Mackay-Sim and colleagues reported au- the transplantation of autologous adrenal medullary tis- tologous OEC transplantation for three patients with sue into the striatum of patients with severe parkinson- chronic SCI with 3-year follow-up was safe, feasible, ism. Subsequently, Hitchcock et al. (138), Lindvall and and one patient showed sensory improvement (243). The colleagues (226,395), and Madrazo et al. (244) have sep- therapeutic value of OEC transplantation has been arately reported that fetal nigral implants might have shown in chronic SCI, ALS, cerebral palsy, stroke, MS, provided a modest improvement in motor function and and other neurodegenerative diseases and traumatic have clinically valuable improvements in most recipi- brain insults in 1,255 patients (144,145).
ents within a period of long-term follow-up after trans-plantation into the brain of patients with PD. Freed and colleagues randomly assigned patients to receive nervecell transplants or sham surgery with double-blind fol- Data from Arjmand and colleagues suggested that au- low-up. The result showed that transplanted human em- tologous SC transplantation is safe for spinal cord in- bryonic DA neurons survive with clinical benefit in jured patients but had no beneficial effects (327).
Table 9. Selected Recent Articles of Clinical Studies Related to Cell-Based CNS Neurorestoratology
lateral sclerosis, cerebral palsy,multiple sclerosis, stoke, etc.
by Farge et al. (98), Fassas et al. (99), Portaccio et al.
(304), and Saccardi et al. (328) as well as in studies for Knoller et al. reported that autologous macrophages malignant or severe MS (54,177,246).
Nonmyeloablative autologous haemopoietic stem cell Bone Marrow Stromal Cell/Hematopoietic Stem transplantation in patients with relapsing-remitting MS reverses neurological deficits (48). Also autologous pe-ripheral blood stem cell transplantation has promoted Research of Appel et al. indicated that peripheral obvious neurologic improvement for patients with poly- cells derived from donor hematopoietic stem cells were neuropathy, organomegaly, endocrinopathy, M-protein, able to enter the human CNS primarily at sites of moto- and skin changes syndrome (190,191).
neuron pathology and engrafted as immunomodulatorycells, but they did not provide benefit in sporadic ALS SUMMARY AND PROSPECTS
patients (12). On the contrary, autologous anti-humanCD133+ mononuclear cell transplantation in the motor When entering the 21st century, numerous centers cortex delays ALS progression and improves quality of have globally started clinical trials or experimental treat- life (251). Furthermore, many studies showed that this ments to investigate the utilization of cells, such as neu- kind of cell therapy was feasible, safe, and effective for rons, OECs, bone marrow-derived cells, NSPCs, SCs, ALS (78), stroke (21,364), chronic SCI patients (61,77, etc., for intractable CNS diseases. Despite their diversity 266,287,368), and there was also improvement in the in number, clinical status of subjects, route of cell ad- acute and subacute phase of chronic SCI (416). Different ministration, and criteria to evaluate efficacy, the main routes of cell transplantation such as by direct injection conclusion drawn from these clinical studies was that into spinal cord, intravenous and intrathecal injection such therapies were safe, feasible, and had some neuro- have proven to be equally effective in SCI (116) and logical functional improvement or restorative effect that traumatic brain injury (424). Evidence shows that autol- improved the patient’s quality of life to a varying extent.
ogous hematopoietic stem cell transplantation cannot be These achievements had already answered YES or NO deemed a curative treatment but instead may give rise to the question of whether the degeneration and damage to prolonged stabilization or change the aggressive in the CNS could be functionally restored.
course of diseases (330). Similar results were reported But from the cellular biology viewpoint, there are CELL THERAPY IN CNS NEURORESTORATOLOGY ERA jury-scientific challenges for the unknown future. Ups. J.
several unanswered questions for cell transplantation: what kind of cells would be the best ideal source, the 9. Anderson, K. J.; Gibbs, R. B.; Salvaterra, P. M.; Cotman, best therapeutic time window, the most suitable selec- C. W. Ultrastructural characterization of identified cho- tion for patients and diseases of different kinds, and the linergic neurons transplanted to the hippocampal forma- optimal route. Consequently, emphasis should be placed tion of the rat. J. Comp. Neurol. 249(2):279–292; 1986.
10. Andersson, C.; Tytell, M.; Brunso-Bechtold, J. Trans- on solving these questions and evaluating the efficacy plantation of cultured type 1 astrocyte cell suspensions of each particular treatment modality in detail.
into young, adult and aged rat cortex: Cell migration and On the other hand, from a clinical neurorestoratology survival. Int. J. Dev. Neurosci. 11(5):555–568; 1993.
viewpoint, the current treatment results are far from an 11. Andres, R. H.; Meyer, M.; Ducray, A. D.; Widmer, effective cure or the miracle effect, as the majority of H. R. Restorative neuroscience: Concepts and perspec-tives. Swiss Med. Wkly. 138(11–12):155–172; 2008.
people expect; however, therapeutic strategies to retard 12. Appel, S. H.; Engelhardt, J. I.; Henkel, J. S.; Siklos, L.; disease progression for neurodegenerative diseases or to Beers, D. R.; Yen, A. A.; Simpson, E. P.; Luo, Y.; improve some functions from acquired damages seem to Carrum, G.; Heslop, H. E.; Brenner, M. K.; Popat, U.
be a more realistic clinical aim compared with expecting Hematopoietic stem cell transplantation in patients with a cure or complete recovery in the present or near future.
sporadic amyotrophic lateral sclerosis. Neurology 71(17):1326–1334; 2008.
Patients, scientists, and doctors should value highly the 13. Armengol, J. A.; Sotelo, C.; Angaut, P.; Alvarado- patients’ achievements from effective treatment strate- Mallart, R. M. Organization of host afferents to cerebel- gies that are currently still thought by some to not be lar grafts implanted into kainate lesioned cerebellum in adult rats. Eur. J. Neurosci. 1(1):75–93; 1989.
So far, the pleasurable reality is that landmark ad- 14. Arnhold, S.; Semkova, I.; Andressen, C.; Lenartz, D.; Meissner, G.; Sturm, V.; Kochanek, S.; Addicks, K.; vances and the results of preclinical and clinical studies Schraermeyer, U. Iris pigment epithelial cells: A possible in neurorestoratolgy have been driving our traditional cell source for the future treatment of neurodegenerative concept from the passive reaction to disease to active diseases. Exp. Neurol. 187(2):410–417; 2004.
attempts to restore the lost functions of the CNS. Now 15. Auerbach, J. M.; Eiden, M. V.; McKay, R. D. Trans- people are more interested in and pay more attention planted CNS stem cells form functional synapses in vivo.
Eur. J. Neurosci. 12(5):1696–1704; 2000.
to functional neurorestoration rather than the anatomical Lefaucheur, J. P.; Boisse´, M. F.; Maison, P.; Baudic, S.;Ribeiro, M. J.; Bourdet, C.; Remy, P.; Cesaro, P.; REFERENCES
Hantraye, P.; Peschanski, M. Effect of fetal neural trans- 1. Agrawal, A. K.; Shukla, S.; Chaturvedi, R. K.; Seth, K.; plants in patients with Huntington’s disease 6 years after Srivastava, N.; Ahmad, A.; Seth, P. K. Olfactory en- surgery: A long-term follow-up study. Lancet Neurol.
sheathing cell transplantation restores functional deficits in rat model of Parkinson’s disease: A cotransplantation 17. Bachoud-Le´vi, A. C.; Re´my, P.; Nguyen, J. P.; approach with fetal ventral mesencephalic cells. Neuro- Brugie`res, P.; Lefaucheur, J. P.; Bourdet, C.; Baudic, S.; Gaura, V.; Maison, P.; Haddad, B.; Boisse´, M. F.; 2. Aguayo, A. J.; David, S.; Bray, G. M. Influences of the Grandmougin, T.; Je´ny, R.; Bartolomeo, P.; Dalla Barba, glial environment on the elongation of axons after injury: G.; Degos, J. D.; Lisovoski, F.; Ergis, A. M.; Pailhous, Transplantation studies in adult rodents. J. Exp. Biol. 95: E.; Cesaro, P.; Hantraye, P.; Peschanski, M. Motor and cognitive improvements in patients with Huntington’s 3. Ahmed, S. The culture of neural stem cells. J. Cell. Bio- disease after neural transplantation. Lancet 356(9246): 4. Akerud, P.; Canals, J. M.; Snyder, E. Y.; Arenas, E.
18. Bachstetter, A. D.; Pabon, M. M.; Cole, M. J.; Hudson, Neuroprotection through delivery of glial cell line- C. E.; Sanberg, P. R.; Willing, A. E.; Bickford, P. C.; derived neurotrophic factor by neural stem cells in a Gemma, C. Peripheral injection of human umbilical cord mouse model of Parkinson’s disease. J. Neurosci.
blood stimulates neurogenesis in the aged rat brain. BMC 5. Akiyama, Y.; Radtke, C.; Kocsis, J. D. Remyelination of 19. Backlund, E. O.; Granberg, P. O.; Hamberger, B.; Knuts- the rat spinal cord by transplantation of identified bone son, E.; Ma˚rtensson, A.; Sedvall, G.; Seiger, A.; Olson, marrow stromal cells. J. Neurosci. 22(15):6623–6630; L. Transplantation of adrenal medullary tissue to stria- tum in parkinsonism. First clinical trials. J. Neurosurg.
6. Akle, C. A.; Adinolfi, M.; Welsh, K. I.; Leibowitz, S.; McColl, I. Immunogenicity of human amniotic epithelial 20. Bakshi, A.; Barshinger, A. L.; Swanger, S. A.; Madha- vani, V.; Shumsky, J. S.; Neuhuber, B.; Fischer, I. Lum- bar puncture delivery of bone marrow stromal cells in 7. Alexandrova, M. A.; Polezhaev, L. V. Transplantation of spinal cord contusion: A novel method for minimally in- various regions of embryonic brain tissue into the brain vasive cell transplantation. J. Neurotrauma 23(1):55–65; of adult rats. J. Hirnforsch. 25(1):89–98; 1984.
8. Anderberg, L.; Aldskogius, H.; Holtz, A. Spinal cord in- 21. Bang, O. Y.; Lee, J. S.; Lee, P. H.; Lee, G. Autologous mesenchymal stem cell transplantation in stroke patients.
Schwann cell remyelination of CNS axons following in- jection of cultures of CNS cells into areas of persistent 22. Bantubungi, K.; Blum, D.; Cuvelier, L.; Wislet-Gende- demyelination. Neurosci. Lett. 77(1):20–24; 1987.
bien, S.; Rogister, B.; Brouillet, E.; Schiffmann, S. N.
38. Blo¨mer, U.; Naldini, L.; Verma, I. M.; Trono, D.; Gage, Stem cell factor and mesenchymal and neural stem cell F. H. Applications of gene therapy to the CNS. Hum.
transplantation in a rat model of Huntington’s disease.
Mol. Cell. Neurosci. 37(3):454–470; 2008.
39. Borlongan, C. V.; Hadman, M.; Sanberg, C. D.; Sanberg, 23. Barami, K.; Hao, H. N.; Lotoczky, G. A.; Diaz, F. G.; P. R. Central nervous system entry of peripherally in- Lyman, W. D. Transplantation of human fetal brain cells jected umbilical cord blood cells is not required for neu- into ischemic lesions of adult gerbil hippocampus. J.
roprotection in stroke. Stroke 35(10):2385–2389; 2004.
40. Borlongan, C. V.; Kaneko, Y.; Maki, M.; Yu, S.; Ali, 24. Barnett, S. C.; Alexander, C. L.; Iwashita, Y.; Gilson, M. M.; Allickson, J.; Sanberg, C.; Kuzmin-Nichols, N.; J. M.; Crowther, J.; Clark, L.; Dunn, L. T.; Papanastas- Sanberg, P. R. Menstrual blood cells display stem cell- siou, V.; Kennedy, P. G.; Franklin, R. J. Identification of like phenotypic markers and exert neuroprotection fol- a human olfactory ensheathing cell that can effect trans- lowing transplantation in experimental stroke. Stem Cells plant-mediated remyelination of demyelinated CNS ax- ons. Brain 123(Pt. 8):1581–1588; 2000.
41. Borlongan, C. V.; Stahl, C. E.; Cameron, D. F.; Saporta, 25. Becerra, G. D.; Tatko, L. M.; Pak, E. S.; Murashov, S.; Freeman, T. B.; Cahill, D. W.; Sanberg, P. R. CNS A. K.; Hoane, M. R. Transplantation of GABAergic neu- immunological modulation of neural graft rejection and rons but not astrocytes induces recovery of sensorimotor survival. Neurol. Res. 18(4):297–304; 1996.
function in the traumatically injured brain. Behav. Brain 42. Bottai, D.; Madaschi, L.; Di Giulio, A. M.; Gorio, A.
Viability-dependent promoting action of adult neural 26. Belicchi, M.; Pisati, F.; Lopa, R.; Porretti, L.; Fortunato, precursors in spinal cord injury. Mol. Med. 14(9–10): F.; Sironi, M.; Scalamogna, M.; Parati, E. A.; Bresolin, N.; Torrente, Y. Human skin-derived stem cells migrate 43. Bradbury, E. J.; Kershaw, T. R.; Marchbanks, R. M.; throughout forebrain and differentiate into astrocytes Sinden, J. D. Astrocyte transplants alleviate lesion in- after injection into adult mouse brain. J. Neurosci. Res.
duced memory deficits independently of cholinergic re- covery. Neuroscience 65(4):955–972; 1995.
27. Ben-Hur, T. Immunomodulation by neural stem cells. J.
44. Bretzner, F.; Liu, J.; Currie, E.; Roskams, A. J.; Tetzlaff, Neurol. Sci. 265(1–2):102–104; 2008.
W. Undesired effects of a combinatorial treatment for 28. Ben-Hur, T.; Goldman, S. A. Prospects of cell therapy spinal cord injury-transplantation of olfactory ensheath- for disorders of myelin. Ann. NY Acad. Sci. 1142:218– ing cells and BDNF infusion to the red nucleus. Eur. J.
29. Bermu´dez-Rattoni, F.; Ferna´ndez, J.; Sa´nchez, M. A.; 45. Brunet, J. F.; Redmond, Jr., D. E.; Bloch, J. Primate Aguilar-Roblero, R.; Drucker-Colı´n, R. Fetal brain trans- adult brain cell autotransplantation, a pilot study in plants induce recuperation of taste aversion learning.
asymptomatic MPTP-treated monkeys. Cell Transplant.
30. Bernstein, J. J. Viability, growth, and maturation of fetal 46. Bunge, M. B. Transplantation of purified populations of brain and spinal cord in the sciatic nerve of adult rat. J.
Schwann cells into lesioned adult rat spinal cord. J. Neu- Neurosci. Res. 10(4):343–350; 1983.
rol. 242(1 Suppl. 1):S36–S39; 1994.
31. Bernstein, J. J.; Goldberg, W. J. Fetal spinal cord homo- 47. Burt, R. K.; Burns, W.; Hess, A. Bone marrow transplan- grafts ameliorate the severity of lesion-induced hind limb tation for multiple sclerosis. Bone Marrow Transplant.
behavioral deficits. Exp. Neurol. 98(3):633–644; 1987.
32. Bernstein-Goral, H.; Bregman, B. S. Spinal cord trans- 48. Burt, R. K.; Loh, Y.; Cohen, B.; Stefoski, D.; Balabanov, plants support the regeneration of axotomized neurons R.; Katsamakis, G.; Oyama, Y.; Russell, E. J.; Stern, J.; after spinal cord lesions at birth: A quantitative double- Muraro, P.; Rose, J.; Testori, A.; Bucha, J.; Jovanovic, labeling study. Exp. Neurol. 123(1):118–132; 1993.
B.; Milanetti, F.; Storek, J.; Voltarelli, J. C.; Burns, 33. Bhatheja, K.; Field, J. Schwann cells: Origins and role W. H. Autologous non-myeloablative haemopoietic stem in axonal maintenance and regeneration. Int. J. Biochem.
cell transplantation in relapsing-remitting multiple scle- Cell Biol. 38(12):1995–1999; 2006.
rosis: A phase I/II study. Lancet Neurol. 8(3):244–253; 34. Bieback, K.; Klu¨ter, H. Mesenchymal stromal cells from umbilical cord blood. Curr. Stem Cell Res. Ther. 2(4): 49. Buzan´ska, L.; Jurga, M.; Doman´ska-Janik, K. Neuronal differentiation of human umbilical cord blood neural 35. Biernaskie, J.; Sparling, J. S.; Liu, J.; Shannon, C. P.; stem-like cell line. Neurodegener. Dis. 3(1–2):19–26; Plemel, J. R.; Xie, Y.; Miller, F. D.; Tetzlaff, W. Skin- derived precursors generate myelinating Schwann cells 50. Cai, J.; Yang, M.; Poremsky, E.; Kidd, S.; Schneider, that promote remyelination and functional recovery after J. S.; Iacovitti, L. Dopaminergic neurons derived from contusion spinal cord injury. J. Neurosci. 27(36):9545– human induced pluripotent stem cells survive and inte- grate into 6-OHDA lesioned rats. Stem Cells Dev. in 36. Blakemore, W. F.; Crang, A. J. The use of cultured au- tologous Schwann cells to remyelinate areas of persistent 51. Cajal, S. R. Y. Degeneration and regeneration of the ner- demyelination in the central nervous system. J. Neurol.
vous system (R. M. May, Trans.). London: Oxford Uni- 37. Blakemore, W. F.; Crang, A. J.; Patterson, R. C.
52. Cameron, D. F.; Othberg, A. I.; Borlongan, C. V.; CELL THERAPY IN CNS NEURORESTORATOLOGY ERA Rashed, S.; Anton, A.; Saporta, S.; Sanberg, P. R. Post- J. H.; Hwang, S. H.; Han, H.; Lee, J. H.; Choe, B. Y.; thaw viability and functionality of cryopreserved rat fetal Lee, S. Y.; Kim, H. Y. Intraarterially delivered human brain cells cocultured with Sertoli cells. Cell Transplant.
umbilical cord blood-derived mesenchymal stem cells in canine cerebral ischemia. J. Neurosci. Res. 87(16):3554– 53. Cao, Q. L.; Zhang, Y. P.; Howard, R. M.; Walters, W. M.; Tsoulfas, P.; Whittemore, S. R. Pluripotent stem 66. Cicchetti, F.; Saporta, S.; Hauser, R. A.; Parent, M.; cells engrafted into the normal or lesioned adult rat spi- Saint-Pierre, M.; Sanberg, P. R.; Li, X. J.; Parker, J. R.; nal cord are restricted to a glial lineage. Exp. Neurol.
Chu, Y.; Mufson, E. J.; Kordower, J. H.; Freeman, T. B.
Neural transplants in patients with Huntington’s disease 54. Capello, E.; Saccardi, R.; Murialdo, A.; Gualandi, F.; undergo disease-like neuronal degeneration. Proc. Natl.
Pagliai, F.; Bacigalupo, A.; Marmont, A.; Uccelli, A.; Acad. Sci. USA 106(30):12483–12488; 2009.
Inglese, M.; Bruzzi, P.; Sormani, M. P.; Cocco, E.; 67. Collier, T. J.; Elsworth, J. D.; Taylor, J. R.; Sladek, Jr., Meucci, G.; Massacesi, L.; Bertolotto, A.; Lugaresi, A.; J. R.; Roth, R. H.; Redmond, Jr., D. E. Peripheral nerve- Merelli, E.; Solari, A.; Filippi, M.; Mancardi, G. L.; Ital- dopamine neuron co-grafts in MPTP-treated monkeys: ian GITMO-Neuro Intergroup on ASCT for Multiple Augmentation of tyrosine hydroxylase-positive fiber Sclerosis. Intense immunosuppression followed by autol- staining and dopamine content in host systems. Neuro- ogous stem cell transplantation in severe multiple sclero- sis. Neurol. Sci. 26(Suppl. 4):S200–S203; 2005.
68. Commissiong, J. W. Fetal locus coeruleus transplanted 55. Chen, J.; Li, Y.; Katakowski, M.; Chen, X.; Wang, L.; into the transected spinal cord of the adult rat: Some ob- Lu, D.; Lu, M.; Gautam, S. C.; Chopp, M. Intravenous servations and implications. Neuroscience 12(3):839– bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in fe- 69. Coronel, M. F.; Musolino, P. L.; Villar, M. J. Selective male rat. J. Neurosci. Res. 73(6):778–786; 2003.
migration and engraftment of bone marrow mesenchy- 56. Chen, J.; Li, Y.; Wang, L.; Zhang, Z.; Lu, D.; Lu, M.; mal stem cells in rat lumbar dorsal root ganglia after sci- Chopp, M. Therapeutic benefit of intravenous adminis- atic nerve constriction. Neurosci. Lett. 405(1–2):5–9; tration of bone marrow stromal cells after cerebral ische- mia in rats. Stroke 32(4):1005–1011; 2001.
70. Corti, S.; Locatelli, F.; Donadoni, C.; Guglieri, M.; 57. Chen, J.; Sanberg, P. R.; Li, Y.; Wang, L.; Lu, M.; Will- Papadimitriou, D.; Strazzer, S.; Del Bo, R.; Comi, G. P.
ing, A. E.; Sanchez-Ramos, J.; Chopp, M. Intravenous Wild-type bone marrow cells ameliorate the phenotype administration of human umbilical cord blood reduces of SOD1-G93A ALS mice and contribute to CNS, heart behavioral deficits after stroke in rats. Stroke 32(11): and skeletal muscle tissues. Brain 127(Pt. 11):2518– 58. Chen, J.; Zhang, Z. G.; Li, Y.; Wang, L.; Xu, Y. X.; 71. Corti, S.; Nizzardo, M.; Nardini, M.; Donadoni, C.; Gautam, S. C.; Lu, M.; Zhu, Z.; Chopp, M. Intravenous Salani, S.; Ronchi, D.; Saladino, F.; Bordoni, A.; Fortu- administration of human bone marrow stromal cells in- nato, F.; Del Bo, R.; Papadimitriou, D.; Locatelli, F.; duces angiogenesis in the ischemic boundary zone after Menozzi, G.; Strazzer, S.; Bresolin, N.; Comi, G. P. Neu- stroke in rats. Circ. Res. 92:692–699; 2003.
ral stem cell transplantation can ameliorate the pheno- 59. Chen, L.; Huang, H. Neurorestoratology: New concept type of a mouse model of spinal muscular atrophy. J.
and bridge from bench to bedside. Zhongguo Xiu Fu Clin. Invest. 118(10):3316–3330; 2008.
Chong Jian Wai Ke Za Zhi 23(3):366–370; 2009.
72. Crang, A. J.; Blakemore, W. F. Remyelination of demye- 60. Chen, L.; Liu, L. Current progress and prospects of in- linated rat axons by transplanted mouse oligodendro- duced pluripotent stem cells. Sci. China C. Life Sci.
73. Cristante, A. F.; Barros-Filho, T. E.; Tatsui, N.; 61. Chernykh, E. R.; Stupak, V. V.; Muradov, G. M.; Sizi- Mendrone, A.; Caldas, J. G.; Camargo, A.; Alexandre, kov, M. Y.; Shevela, E. Y.; Leplina, O. Y.; Tikhonova, A.; Teixeira, W. G.; Oliveira, R. P.; Marcon, R. M. Stem M. A.; Kulagin, A. D.; Lisukov, I. A.; Ostanin, A. A.; cells in the treatment of chronic spinal cord injury: Eval- Kozlov, V. A. Application of autologous bone marrow uation of somatosensitive evoked potentials in 39 pa- stem cells in the therapy of spinal cord injury patients.
tients. Spinal Cord 47(10):733–738; 2009.
Bull. Exp. Biol. Med. 143(4):543–547; 2007.
74. Daadi, M. M.; Lee, S. H.; Arac, A.; Grueter, B. A.; Bhat- 62. Chiu, S. C.; Hung, H. S.; Lin, S. Z.; Chiang, E.; Liu, nagar, R.; Maag, A. L.; Schaar, B.; Malenka, R. C.; D. D. Therapeutic potential of olfactory ensheathing cells Palmer, T. D.; Steinberg, G. K. Functional engraftment in neurodegenerative diseases. J. Mol. Med. 87(12): of the medial ganglionic eminence cells in experimental stroke model. Cell Transplant. 18(7):815–826; 2009.
63. Cho, S. R.; Kim, Y. R.; Kang, H. S.; Yim, S. H.; Park, 75. Date, I.; Felten, S. Y.; Felten, D. L. Cografts of adrenal C. I.; Min, Y. H.; Lee, B. H.; Shin, J. C.; Lim, J. B.
medulla with peripheral nerve enhance the survivability Functional recovery after the transplantation of neurally of transplanted adrenal chromaffin cells and recovery of differentiated mesenchymal stem cells derived from bone the host nigrostriatal dopaminergic system in MPTP- marrow in a rat model of spinal cord injury. Cell Trans- treated young adult mice. Brain Res. 537(1–2):33–39; 64. Chopp, M.; Zhang, X. H.; Li, Y.; Wang, L.; Chen, J.; 76. Davis, G. E.; Blaker, S. N.; Engvall, E.; Varon, S.; Lu, D.; Lu, M.; Rosenblum, M. Spinal cord injury in rat: Manthorpe, M.; Gage, F. H. Human amnion membrane Treatment with bone marrow stromal cell transplanta- serves as a substratum for growing axons in vitro and in tion. Neuroreport 11(13):3001–3005; 2000.
vivo. Science 236(4805):1106–1109; 1987.
65. Chung, D. J.; Choi, C. B.; Lee, S. H.; Kang, E. H.; Lee, 77. Deda, H.; Inci, M. C.; Ku¨rekc¸i, A. E.; Kayihan, K.; Ozgu¨n, E.; Ustu¨nsoy, G. E.; Kocabay, S. Treatment of after transplantation into the CNS. J. Neurosci. 24(44): chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 90. Eaton, M. J.; Plunkett, J. A.; Martinez, M. A.; Lopez, T.; 1-year follow-up. Cytotherapy 10(6):565–574; 2008.
Karmally, S.; Cejas, P.; Whittemore, S. R. Transplants 78. Deda, H.; Inci, M. C.; Ku¨rekc¸i, A. E.; Sav, A.; Kayihan, of neuronal cells bioengineered to synthesize GABA al- K.; Ozgu¨n, E.; Ustu¨nsoy, G. E.; Kocabay, S. Treatment leviate chronic neuropathic pain. Cell Transplant. 8(1): of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplan- 91. Eaton, M. J.; Wolfe, S. Q. Clinical feasibility for cell tation: A 1-year follow-up. Cytotherapy 11(1):18–25; therapy using human neuronal cell line to treat neuro- pathic behavioral hypersensitivity following spinal cord 79. de Haro, J.; Zurita, M.; Ayllo´n, L.; Vaquero, J. Detection injury in rats. J. Rehabil. Res. Dev. 46(1):145–165; 2009.
of 111In-oxine-labeled bone marrow stromal cells after 92. Einstein, O.; Friedman-Levi, Y.; Grigoriadis, N.; Ben- intravenous or intralesional administration in chronic Hur, T. Transplanted neural precursors enhance host paraplegic rats. Neurosci. Lett. 377(1):7–11; 2005.
brain-derived myelin regeneration. J. Neurosci. 29(50): 80. de Paula, S.; Vitola, A. S.; Greggio, S.; de Paula, D.; Mello, P. B.; Lubianca, J. M.; Xavier, L. L.; Fiori, H. H.; 93. Emborg, M. E.; Ebert, A. D.; Moirano, J.; Peng, S.; Dacosta, J. C. Hemispheric brain injury and behavioral Suzuki, M.; Capowski, E.; Joers, V.; Roitberg, B. Z.; deficits induced by severe neonatal hypoxia-ischemia in Aebischer, P.; Svendsen, C. N. GDNF-secreting human rats are not attenuated by intravenous administration of neural progenitor cells increase tyrosine hydroxylase and human umbilical cord blood cells. Pediatr. Res. 65(6): VMAT2 expression in MPTP-treated cynomolgus mon- keys. Cell Transplant. 17(4):383–395; 2008.
81. Detante, O.; Moisan, A.; Dimastromatteo, J.; Richard, 94. Ende, N.; Chen, R. Human umbilical cord blood cells M. J.; Riou, L.; Grillon, E.; Barbier, E.; Desruet, M. D.; ameliorate Huntington’s disease in transgenic mice. J.
De, Fraipont, F.; Segebarth, C.; Jaillard, A.; Hommel, M.; Ghezzi, C.; Remy, C. Intravenous administration of 95. Ende, N.; Chen, R. Parkinson’s disease mice and human 99mTc-HMPAO-labeled human mesenchymal stem cells umbilical cord blood. J. Med. 33(1–4):173–180; 2002.
after stroke: In vivo imaging and biodistribution. Cell 96. Ende, N.; Chen, R.; Ende-Harris, D. Human umbilical Transplant. 18(12):1369–1379; 2009.
cord blood cells ameliorate Alzheimer’s disease in trans- 82. Dezawa, M. Systematic neuronal and muscle induction genic mice. J. Med. 32(3–4):241–247; 2001.
systems in bone marrow stromal cells: The potential for 97. Ende, N.; Weinstein, F.; Chen, R.; Ende, M. Human um- tissue reconstruction in neurodegenerative and muscle bilical cord blood effect on sod mice (amyotrophic lat- degenerative diseases. Med. Mol. Morphol. 41(1):14–19; eral sclerosis). Life Sci. 67(1):53–59; 2000.
98. Farge, D.; Labopin, M.; Tyndall, A.; Fassas, A.; Manc- 83. Dimitrijevic, M. R. Recent achievements of restorative ardi, G. L.; Van Laar, J.; Ouyang, J.; Kozak, T.; Moore, neurology. Switzerland: Karger; 1985.
J.; Ko¨tter, I.; Chesnel, V.; Marmont, A.; Gratwohl, A.; 84. Ding, D. C.; Shyu, W. C.; Chiang, M. F.; Lin, S. Z.; Saccardi, R. Autologous hematopoietic stem cell trans- Chang, Y. C.; Wang, H. J.; Su, C. Y.; Li, H. Enhance- plantation (HSCT) for autoimmune diseases: An obser- ment of neuroplasticity through upregulation of beta1- vational study on 12 years of experience from the Euro- integrin in human umbilical cord-derived stromal cell pean Group for Blood and Marrow Transplantation implanted stroke model. Neurobiol. Dis. 27(3):339–353; (EBMT) Working Party on Autoimmune Diseases.
Haematologica 95(2):284–292; 2010.
85. Duan, X. L.; Xu, Y. Z.; Zeng, Z. C. Bridging rat sciatic 99. Fassas, A.; Passweg, J. R.; Anagnostopoulos, A.; Kazis, nerve defects with the composite nerve-muscle auto- A.; Kozak, T.; Havrdova, E.; Carreras, E.; Graus, F.; grafts wrapped with human amnion matrix membrane.
Kashyap, A.; Openshaw, H.; Schipperus, M.; Deconinck, Zhong Nan Da Xue Xue Bao Yi Xue Ban 29(3):279– E.; Mancardi, G.; Marmont, A.; Hansz, J.; Rabusin, M.; Zuazu, Nagore, F. J.; Besalduch, J.; Dentamaro, T.; 86. Dunbar, G. L.; Sandstrom, M. I.; Rossignol, J.; Lescau- Fouillard, L.; Hertenstein, B.; La, Nasa, G.; Musso, M.; dron, L. Neurotrophic enhancers as therapy for behav- Papineschi, F.; Rowe, J. M.; Saccardi, R.; Steck, A.; ioral deficits in rodent models of Huntington’s disease: Kappos, L.; Gratwohl, A.; Tyndall, A.; Samijn, J.; Auto- Use of gangliosides, substituted pyrimidines, and mesen- immune Disease Working Party of the EBMT (European chymal stem cells. Behav. Cogn. Neurosci. Rev. 5(2): Group for Blood and Marrow Transplantation). Hemato- poietic stem cell transplantation for multiple sclerosis. A 87. Duncan, I. D. Glial cell transplantation and remyelina- retrospective multicenter study. J. Neurol. 249(8):1088– tion of the central nervous system. Neuropathol. Appl.
100. Ferrari, D.; Sanchez-Pernaute, R.; Lee, H.; Studer, L.; 88. Duncan, I. D.; Aguayo, A. J.; Bunge, R. P.; Wood, Isacson, O. Transplanted dopamine neurons derived from P. M. Transplantation of rat Schwann cells grown in tis- primate ES cells preferentially innervate DARPP-32 stri- sue culture into the mouse spinal cord. J. Neurol. Sci.
atal progenitors within the graft. Eur. J. Neurosci. 24(7): 89. Dunning, M. D.; Lakatos, A.; Loizou, L.; Kettunen, M.; 101. Fine, A.; Meldrum, B. S.; Patel, S. Modulation of experi- ffrench-Constant, C.; Brindle, K. M.; Franklin, R. J. Su- mentally induced epilepsy by intracerebral grafts of fetal perparamagnetic iron oxide-labeled Schwann cells and GABAergic neurons. Neuropsychologia 28(6):627–634; olfactory ensheathing cells can be traced in vivo by mag- netic resonance imaging and retain functional properties 102. Fluckiger, A. C.; Dehay, C.; Savatier, P. Embryonic stem CELL THERAPY IN CNS NEURORESTORATOLOGY ERA cells and cell replacement therapies in the nervous sys- C.; Rossi, R.; Sanberg, P. R. Human umbilical cord tem. Med. Sci (Paris) 19(6–7):699–708; 2003.
blood treatment in a mouse model of ALS: Optimization 103. Franklin, R. J.; Bayley, S. A.; Milner, R.; Ffrench- of cell dose. PLoS ONE 3(6):e2494; 2008.
Constant, C.; Blakemore, W. F. Differentiation of the O- 115. Garbuzova-Davis, S.; Willing, A. E.; Zigova, T.; 2A progenitor cell line CG-4 into oligodendrocytes and Saporta, S.; Justen, E. B.; Lane, J. C.; Hudson, J. E.; astrocytes following transplantation into glia-deficient Chen, N.; Davis, C. D.; Sanberg, P. R. Intravenous ad- areas of CNS white matter. Glia 13(1):39–44; 1995.
ministration of human umbilical cord blood cells in a 104. Franklin, R. J.; Crang, A. J.; Blakemore, W. F. Trans- mouse model of amyotrophic lateral sclerosis: Distribu- planted type-1 astrocytes facilitate repair of demyelinat- tion, migration, and differentiation. J. Hematother. Stem ing lesions by host oligodendrocytes in adult rat spinal cord. J. Neurocytol. 20(5):420–430; 1991.
116. Geffner, L. F.; Santacruz, P.; Izurieta, M.; Flor, L.; 105. Franklin, R. J.; Ffrench-Constant, C. Remyelination in Maldonado, B.; Auad, A. H.; Montenegro, X.; Gonzalez, the CNS: From biology to therapy. Nat. Rev. Neurosci.
R.; Silva, F. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple 106. Franklin, R. J.; Gilson, J. M.; Franceschini, I. A.; routes is safe and improves their quality of life: Compre- Barnett, S. C. Schwann cell-like myelination following hensive case studies. Cell Transplant. 17(12):1277–1293; transplantation of an olfactory bulb-ensheathing cell line into areas of demyelination in the adult CNS. Glia 17(3): 117. Gensel, J. C.; Nakamura, S.; Guan, Z.; van, Rooijen, N.; Ankeny, D. P.; Popovich, P. G. Macrophages promote 107. Franssen, E. H.; De Bree, F. M.; Essing, A. H.; Ramon- axon regeneration with concurrent neurotoxicity. J. Neu- Cueto, A.; Verhaagen, J. Comparative gene expression profiling of olfactory ensheathing glia and Schwann cells 118. Gimble, J.; Guilak, F. Adipose-derived adult stem cells: indicates distinct tissue repair characteristics of olfactory Isolation, characterization, and differentiation potential.
ensheathing glia. Glia 56(12):1285–1298; 2008.
108. Freed, C. R.; Greene, P. E.; Breeze, R. E.; Tsai, W. Y.; 119. Girdlestone, J.; Limbani, V. A.; Cutler, A. J.; Navarrete, DuMouchel, W.; Kao, R.; Dillon, S.; Winfield, H.; C. V. Efficient expansion of mesenchymal stromal cells Culver, S.; Trojanowski, J. Q.; Eidelberg, D.; Fahn, S.
from umbilical cord under low serum conditions. Cytoth- Transplantation of embryonic dopamine neurons for se- vere Parkinson’s disease. N. Engl. J. Med. 344(10):710– 120. Glavaski-Joksimovic, A.; Virag, T.; Chang, Q. A.; West, N. C.; Mangatu, T. A.; McGrogan, M. P.; Dugich-Djord- 109. Freedman, M. S.; Bar-Or, A.; Atkins, H. L.; Karussis, jevic, M.; Bohn, M. C. Reversal of dopaminergic degen- D.; Frassoni, F.; Lazarus, H.; Scolding, N.; Slavin, S.; eration in a parkinsonian rat following micrografting of Le Blanc, K.; Uccelli, A. The therapeutic potential of human bone marrow-derived neural progenitors. Cell mesenchymal stem cell transplantation as a treatment for multiple sclerosis: Consensus report of the International 121. Gonzalez, M. F.; Sharp, F. R.; Loken, J. E. Fetal frontal MSCT Study Group. Mult. Scler. 16(4):503–510; 2010.
cortex transplanted to injured motor/sensory cortex of 110. Fu, Y. S.; Cheng, Y. C.; Lin, M. Y.; Cheng, H.; Chu, adult rats: Reciprocal connections with host thalamus P. M.; Chou, S. C.; Shih, Y. H.; Ko, M. H.; Sung, M. S.
demonstrated with WGA-HRP. Exp. Neurol. 99(1):154– Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: 122. Gorio, A.; Torrente, Y.; Madaschi, L.; Di Stefano, A. B.; Potential therapeutic application for parkinsonism. Stem Pisati, F.; Marchesi, C.; Belicchi, M.; Di Giulio, A. M.; Bresolin, N. Fate of autologous dermal stem cells trans- 111. Furmanski, O.; Gajavelli, S.; Lee, J. W.; Collado, M. E.; planted into the spinal cord after traumatic injury (TSCI).
Jergova, S.; Sagen, J. Combined extrinsic and intrinsic Neuroscience 125(1):179–189; 2004.
manipulations exert complementary neuronal enrichment 123. Guan, X. Q.; Yu, J. L.; Li, L. Q.; Liu, G. X. Study on in embryonic rat neural precursor cultures: An in vitro mesenchymal stem cells entering the brain through the and in vivo analysis. J. Comp. Neurol. 515(1):56–71; blood–brain barrier. Zhonghua Er Ke Za Zhi 42(12): 112. Gallina, P.; Paganini, M.; Lombardini, L.; Mascalchi, 124. Guilak, F.; Awad, H. A.; Fermor, B.; Leddy, H. A.; M.; Porfirio, B.; Gadda, D.; Marini, M.; Pinzani, P.; Gimble, J. M. Adipose-derived adult stem cells for carti- Salvianti, F.; Crescioli, C.; Bucciantini, S.; Mechi, C.; lage tissue engineering. Biorheology 41(3–4):389–399; Sarchielli, E.; Romoli, A. M.; Bertini, E.; Urbani, S.; Bartolozzi, B.; De Cristofaro, M. T.; Piacentini, S.; 125. Guillaume, D. J.; Zhang, S. C. Human embryonic stem Saccardi, R.; Pupi, A.; Vannelli, G. B.; Di Lorenzo, N.
cells: A potential source of transplantable neural progeni- Human striatal neuroblasts develop and build a striatal- tor cells. Neurosurg. Focus 24(3–4):E3; 2008.
like structure into the brain of Huntington’s disease pa- 126. Gumpel, M.; Gout, O.; Lubetzki, C.; Gansmuller, A.; tients after transplantation. Exp. Neurol. 222(1):30–41; Baumann, N. Myelination and remyelination in the cen- tral nervous system by transplanted oligodendrocytes us- 113. Garbuzova-Davis, S.; Klasko, S. K.; Sanberg, P. R. Intra- ing the shiverer model. Discussion on the remyelinating venous administration of human umbilical cord blood cell population in adult mammals. Dev. Neurosci. 11(2): cells in an animal model of MPS III B. J. Comp. Neurol.
127. Guntinas-Lichius, O.; Angelov, D. N.; Tomov, T. L.; 114. Garbuzova-Davis, S.; Sanberg, C. D.; Kuzmin-Nichols, Dramiga, J.; Neiss, W. F.; Wewetzer, K. Transplantation N.; Willing, A. E.; Gemma, C.; Bickford, P. C.; Miller, of olfactory ensheathing cells stimulates the collateral sprouting from axotomized adult rat facial motoneurons.
Putative dental pulp-derived stem/stromal cells promote proliferation and differentiation of endogenous neural 128. Guntinas-Lichius, O.; Wewetzer, K.; Tomov, T. L.; cells in the hippocampus of mice. Stem Cells 26(10): Azzolin, N.; Kazemi, S.; Streppel, M.; Neiss, W. F.; Angelov, D. N. Transplantation of olfactory mucosa 143. Huang, H.; Chen, L.; Wang, H.; Xiu, B.; Li, B.; Wang, minimizes axonal branching and promotes the recovery R.; Zhang, J.; Zhang, F.; Gu, Z.; Li, Y.; Song, Y.; Hao, of vibrissae motor performance after facial nerve repair W.; Pang, S.; Sun, J. Influence of patients’ age on func- in rats. J. Neurosci. 22(16):7121–7131; 2002.
tional recovery after transplantation of olfactory en- 129. Guzman, R.; De Los, Angeles, A.; Cheshier, S.; Choi, sheathing cells into injured spinal cord injury. Chin.
R.; Hoang, S.; Liauw, J.; Schaar, B.; Steinberg, G. Intra- Med. J. (Engl.) 116(10):1488–1491; 2003.
carotid injection of fluorescence activated cell-sorted 144. Huang, H.; Chen, L.; Xi, H.; Wang, H.; Zhang, J.; CD49d-positive neural stem cells improves targeted cell Zhang, F.; Liu, Y. Fetal olfactory ensheathing cells trans- delivery and behavior after stroke in a mouse stroke plantation in amyotrophic lateral sclerosis patients: A model. Stroke 39(4):1300–1306; 2008.
controlled pilot study. Clin. Transplant. 22(6):710–718; 130. Haas, S.; Weidner, N.; Winkler, J. Adult stem cell ther- apy in stroke. Curr. Opin. Neurol. 18(1):59–64; 2005.
145. Huang, H.; Chen, L.; Xi, H.; Wang, Q.; Zhang, J.; Liu, 131. Habisch, H. J.; Janowski, M.; Binder, D.; Kuzma-Koza- Y.; Zhang, F. Olfactory ensheathing cells transplantation kiewicz, M.; Widmann, A.; Habich, A.; Schwalens- for central nervous system diseases in 1,255 patients.
to¨cker, B.; Hermann, A.; Brenner, R.; Lukomska, B.; Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 23(1):14– Domanska-Janik, K.; Ludolph, A. C.; Storch, A. In- trathecal application of neuroectodermally converted 146. Huang, H.; Liu, K.; Huang, W.; Liu, Z.; Young, W. Ol- stem cells into a mouse model of ALS: Limited intrapar- factory ensheathing glias transplant improves axonal re- enchymal migration and survival narrows therapeutic ef- generation and functional recovery in spinal cord contu- fects. J. Neural Transm. 114(11):1395–1406; 2007.
sion injury. J. Naval Gen. Hosp. 14(2):65–67; 2001.
132. Harris, D. T.; Rogers, I. Umbilical cord blood: A unique 147. Huang, H.; Wang, H.; Chen, L.; Gu, Z.; Zhang, J.; source of pluripotent stem cells for regenerative medi- Zhang, F.; Song, Y.; Li, Y.; Tan, K.; Liu, Y.; Xi, H.
cine. Curr. Stem Cell Res. Ther. 2(4):301–309; 2007.
Influence factors for functional improvement after olfac- 133. Harrison, B. M. Remyelination by cells introduced into tory ensheathing cell transplantation for chronic spinal a stable demyelinating lesion in the central nervous sys- cord injury. Zhongguo Xiu Fu Chong Jian Wai Ke Za tem. J. Neurol. Sci. 46(1):63–81; 1980.
134. Harting, M. T.; Sloan, L. E.; Jimenez, F.; Baumgartner, 148. Hunt, D. P.; Irvine, K. A.; Webber, D. J.; Compston, J.; Cox, Jr., C. S. Subacute neural stem cell therapy for D. A.; Blakemore, W. F.; Chandran, S. Effects of direct traumatic brain injury. J. Surg. Res. 153(2):188–194; 2009.
transplantation of multipotent mesenchymal stromal/ 135. Harvey, A. R.; Plant, G. W.; Tan, M. M. Schwann cells stem cells into the demyelinated spinal cord. Cell Trans- and the regrowth of axons in the mammalian CNS: A review of transplantation studies in the rat visual system.
149. Hunt, D. P.; Jahoda, C.; Chandran, S. Multipotent skin- Clin. Exp. Pharmacol. Physiol. 22(8):569–579; 1995.
derived precursors: From biology to clinical translation.
136. Hemendinger, R.; Wang, J.; Malik, S.; Persinski, R.; Curr. Opin. Biotechnol. 20(5):522–530; 2009.
Copeland, J.; Emerich, D.; Gores, P.; Halberstadt, C.; 150. Hwang, D. H.; Lee, H. J.; Park, I. H.; Seok, J. I.; Kim, Rosenfeld, J. Sertoli cells improve survival of motor neu- B. G.; Joo, I. S.; Kim, S. U. Intrathecal transplantation of rons in SOD1 transgenic mice, a model of amyotrophic human neural stem cells overexpressing VEGF provide lateral sclerosis. Exp. Neurol. 196(2):235–243; 2005.
behavioral improvement, disease onset delay and sur- 137. Hess, D. C.; Hill, W. D.; Martin-Studdard, A.; Carroll, vival extension in transgenic ALS mice. Gene Ther.
J.; Brailer, J.; Carothers, J. Bone marrow as a source of endothelial cells and NeuN-expressing cells after stroke.
151. Hwang, D. Y.; Kim, D. S.; Kim, D. W. Human ES and iPS cells as cell sources for the treatment of Parkinson’s 138. Hitchcock, E. R.; Kenny, B. G.; Clough, C. G.; Hughes, disease: Current state and problems. J. Cell. Biochem.
R. C.; Henderson, B. T.; Detta, A. Stereotactic implanta- tion of fetal mesencephalon. Stereotact. Funct. Neuro- 152. Ii, M.; Nishimura, H.; Sekiguchi, H.; Kamei, N.; Yokoy- ama, A.; Horii, M.; Asahara, T. Concurrent vasculogen- 139. Hooks, J. J.; Detrick, B.; Percopo, C.; Hamel, C.; Sira- esis and neurogenesis from adult neural stem cells. Circ.
ganian, R. P. Development and characterization of mono- clonal antibodies directed against the retinal pigment 153. Imaizumi, T.; Lankford, K. L.; Burton, W. V.; Fodor, epithelial cell. Invest. Ophthalmol. Vis. Sci. 30(10): W. L.; Kocsis, J. D. Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regener- 140. Hortoba´gyi, T.; Harkany, T.; Reisch, R.; Urbanics, R.; ation in rat spinal cord. Nat. Biotechnol. 18(9):949–953; Ka´lma´n, M.; Nyakas, C.; Nagy, Z. Neurotrophin-medi- ated neuroprotection by solid fetal telencephalic graft in 154. Imaizumi, T.; Lankford, K. L.; Kocsis, J. D.; Sasaki, M.; middle cerebral artery occlusion: A preventive approach.
Akiyama, Y.; Hashi, K. Comparison of myelin-forming Brain Res. Bull. 47(2):185–191; 1998.
cells as candidates for therapeutic transplantation in de- 141. Houle´, J. D.; Reier, P. J. Transplantation of fetal spinal myelinated CNS axons. No To Shinkei 52(7):609–615; cord tissue into the chronically injured adult rat spinal cord. J. Comp. Neurol. 269(4):535–547; 1988.
155. Imaizumi, T.; Lankford, K. L.; Waxman, S. G.; Greer, 142. Huang, A. H.; Snyder, B. R.; Cheng, P. H.; Chan, A. W.
C. A.; Kocsis, J. D. Transplanted olfactory ensheathing CELL THERAPY IN CNS NEURORESTORATOLOGY ERA cells remyelinate and enhance axonal conduction in the of donor for transplantation therapy. Exp. Neurol.
demyelinated dorsal columns of the rat spinal cord. J.
168. Kakishita, K.; Nakao, N.; Sakuragawa, N.; Itakura, T.
156. Ingvar, S. Reactions of cells to the galvanic current in Implantation of human amniotic epithelial cells prevents tissue cultures. Proc. Soc. Exp. Biol. Med. 17:198–199; the degeneration of nigral dopamine neurons in rats with 6-hydroxydopamine lesions. Brain Res. 980(1):48–56; 157. Inoue, M.; Honmou, O.; Oka, S.; Houkin, K.; Hashi, K.; Kocsis, J. D. Comparative analysis of remyelinating po- 169. Kang, K. S.; Kim, S. W.; Oh, Y. H.; Yu, J. W.; Kim, tential of focal and intravenous administration of autolo- K. Y.; Park, H. K.; Song, C. H.; Han, H. A 37-year-old gous bone marrow cells into the rat demyelinated spinal spinal cord-injured female patient, transplanted of multi- potent stem cells from human UC blood, with improved 158. Ishida, K.; Yoshimura, N.; Yoshida, M.; Honda, Y.; sensory perception and mobility, both functionally and Murase, K.; Hayashi, K. Expression of neurotrophic fac- morphologically: A case study. Cytotherapy 7(4):368– tors in cultured human retinal pigment epithelial cells.
Curr. Eye Res. 16(2):96–101; 1997.
170. Kao, C. H.; Chen, S. H.; Chio, C. C.; Lin, M. T. Human 159. Ishige, I.; Nagamura-Inoue, T.; Honda, M. J.; Harnpra- umbilical cord blood-derived CD34+ cells may attenuate sopwat, R.; Kido, M.; Sugimoto, M.; Nakauchi, H.; Tojo, spinal cord injury by stimulating vascular endothelial and A. Comparison of mesenchymal stem cells derived neurotrophic factors. Shock 29(1):49–55; 2008.
from arterial, venous, and Wharton’s jelly explants of 171. Karussis, D.; Kassis, I.; Kurkalli, B. G.; Slavin, S. Immu- human umbilical cord. Int. J. Hematol. 90(2):261–269; nomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): A proposed treatment 160. Itakura, T.; Yokote, H.; Yukawa, S.; Nakai, M.; Komai, for multiple sclerosis and other neuroimmunological/ N.; Umemoto, M. Transplantation of peripheral choliner- neurodegenerative diseases. J. Neurol. Sci. 265(1–2): gic neurons into Alzheimer model rat brain. Stereotact.
Funct. Neurosurg. 54–55:368–372; 1990.
172. Katayama, Y. Deep brain stimulation therapy: Control of 161. Jacquet, B. V.; Patel, M.; Iyengar, M.; Liang, H.; Therit, human brain function by chronically implanted elec- B.; Salinas-Mondragon, R.; Lai, C.; Olsen, J. C.; Anton, trodes. No To Shinkei 52(4):297–305; 2000.
E. S.; Ghashghaei, H. T. Analysis of neuronal prolifera- 173. Kelly, S.; Bliss, T. M.; Shah, A. K.; Sun, G. H.; Ma, M.; tion, migration and differentiation in the postnatal brain Foo, W. C.; Masel, J.; Yenari, M. A.; Weissman, I. L.; using equine infectious anemia virus-based lentiviral Uchida, N.; Palmer, T.; Steinberg, G. K. Transplanted vectors. Gene Ther. 16(8):1021–1033; 2009.
human fetal neural stem cells survive, migrate, and dif- 162. Jeltsch, H.; Cassel, J. C.; Neufang, B.; Kelche, C.; Hert- ferentiate in ischemic rat cerebral cortex. Proc. Natl.
ting, G.; Jackisch, R.; Will, B. The effects of intrahippo- Acad. Sci. USA 101(32):11839–11844; 2004.
campal raphe and/or septal grafts in rats with fimbria- 174. Kesslak, J. P.; Nieto-Sampedro, M.; Globus, J.; Cotman, fornix lesions depend on the origin of the grafted tissue C. W. Transplants of purified astrocytes promote behav- and the behavioural task used. Neuroscience 63(1):19– ioral recovery after frontal cortex ablation. Exp. Neurol.
163. Jiang, Y.; Jahagirdar, B. N.; Reinhardt, R. L.; Schwartz, 175. Keyvan-Fouladi, N.; Raisman, G.; Li, Y. Functional re- R. E.; Keene, C. D.; Ortiz-Gonzalez, X. R.; Reyes, M.; pair of the corticospinal tract by delayed transplantation Lenvik, T.; Lund, T.; Blackstad, M.; Du, J.; Aldrich, S.;

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