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web focus imaging in cell biology
Review

Nature Medicine 10, S42–S50 (2004)

Stem cell therapy for human neurodegenerative disorders–how to make it work

Recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. These findings raise hope for the development of stem cell therapies in human neurodegenerative disorders. Before clinical trials are initiated, we need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.

Olle Lindvall1, 2, Zaal Kokaia2, 3, 5 & Alberto Martinez-Serrano4, 5

1 Laboratory of Neurogenesis and Cell Therapy, Section of Restorative Neurology, Department of Clinical Neuroscience, Wallenberg Neuroscience Center, University Hospital, SE-221 84 Lund, Sweden.

2 Lund Strategic Research Center for Stem Cell biology and Cell Therapy, Lund, Sweden.

3 Laboratory of Neural Stem Cell Biology, Section of Restorative Neurology, Department of Clinical Neuroscience, University Hospital, SE-221 84 Lund, Sweden.

4 Human Neural Stem Cell Biology and Gene Therapy Group, Center of Molecular Biology Severo Ochoa, Autonomous University of Madrid, Cantoblanco, 28049-Madrid, Spain.

5 These authors contributed equally to this work.



Correspondence should be addressed to Olle Lindvall olle.lindvall@neurol.lu.se or Zaal Kokaia zaal.kokaia@neurol.lu.se or Alberto Martinez-Serrano amserrano@cbm.uam.es

Published online: 1 July 2004
doi:10.1038/nm1064


Stem cells are immature cells with prolonged self-renewal capacity and, depending on their origin, ability to differentiate into multiple cell types or all cells of the body. Transplantation of stem cells or their derivatives, and mobilization of endogenous stem cells within the adult brain, have been proposed as future therapies for neurodegenerative diseases. It may seem unrealistic, though, to induce functional recovery by replacing cells lost through disease, considering the complexity of human brain structure and function. Studies in animal models have nevertheless demonstrated that neuronal replacement and partial reconstruction of damaged neuronal circuitry is possible. There is also evidence from clinical trials that cell replacement in the diseased human brain can lead to symptomatic relief.

Here we review the scientific basis of stem cell therapies and discuss their prospects in Parkinson's disease, stroke, amyotrophic lateral sclerosis (ALS) and Huntington's disease. In each of these neurodegenerative diseases, a different spectrum of cell types is affected; therefore, different types of neurons are required for replacement. We argue that long-term survival of new, functionally integrated neurons is the main goal to achieve maximum symptomatic relief through stem cell therapy. Stem cell transplantation may also lead to clinically valuable improvements through other mechanisms as well (Box 1).

Can cell therapy work in patients with Parkinson's disease?
The main pathology in Parkinson's disease (PD) is a degeneration of nigrostriatal dopaminergic neurons. Studies in patients with PD after intrastriatal transplantation of human fetal mesencephalic tissue, rich in postmitotic dopaminergic neurons, have provided proof of principle that neuronal replacement can work in the human brain. The grafted neurons survive and reinnervate the striatum for as long as 10 years despite an ongoing disease process, which destroys the patient's own dopaminergic neurons1, 2. The grafts are able to normalize striatal dopamine release2 and to reverse the impairment of cortical activation underlying AKINESIA3. Thus, grafted dopaminergic neurons can become functionally integrated into neuronal circuitries in the brain3. Several open-label trials have reported clinical benefit (see refs. 4,5). Some patients have been able to withdraw from L-dopa treatment for several years and resume an independent life2.

Two recent sham surgery-controlled trials showed only modest improvement6, 7, which illustrates that present cell replacement procedures are far from optimal. The poor response in one study could be explained by markedly fewer surviving grafted dopaminergic neurons6 as compared with that in open-label trials1, 8, 9. In the other study, patients were more severely disabled at the time of transplantation (compare refs. 7 and 10), indicating extensive degenerative changes. No or short-term immunosuppression was given in these studies6, 7, which may be necessary to avoid immune reactions causing dysfunctional grafts7.

DYSKINESIAS can develop after transplantation7, 10 and become troublesome in 7–15% of grafted patients6, 7, 10. This adverse effect is not due to dopaminergic overgrowth7, 10, 11. It may be caused by uneven and patchy reinnervation11, giving rise to low or intermediate amounts of striatal dopamine, or by chronic inflammatory and immune responses around the graft7. Alternatively, graft-induced dyskinesias could be explained by unfavorable composition of the graft with respect to the predominant type of mesencephalic dopaminergic neurons from the substantia nigra or ventral tegmental area12 and the proportion of cells that are not dopaminergic.

Neurons from stem cells for Parkinson's disease
It is improbable that transplantation of human fetal mesencephalic tissue will become routine treatment for persons with PD because of problems with tissue availability and too much variation in functional outcome. Stem cell technology (Fig. 1) has the potential to generate large numbers of dopaminergic neurons in standardized preparations. On the basis of results with fetal transplants in animals and humans, it is possible to identify a set of requirements that probably also need to be fulfilled by stem cell–derived cells to induce marked clinical improvement: (i) the cells should release dopamine in a regulated manner and should show the molecular, morphological and electrophysiological properties of substantia nigra neurons12; (ii) the cells must be able to reverse in animals those motor deficits that resemble the symptoms in persons with PD; (iii) the yield of cells should allow for at least 100,000 grafted dopaminergic neurons to survive over the long term in each human putamen13; (iv) the grafted dopaminergic neurons should re-establish a dense terminal network throughout the striatum; (v) the grafts must become functionally integrated into host neural circuitries3.

Fig. 1
Figure 1 | Generation of neurons in vitro from stem cells. Figure 1

Fig. 2
Figure 2 | Generation of dopaminergic neurons for Parkinson's disease. Figure 2


Only 5–10% of cells in fetal mesencephalic grafts are dopaminergic neurons. It is not yet known whether it is favorable to implant a pure population of dopaminergic neurons or whether the graft should also contain a specific composition of other neuron types and glial cells to induce maximum symptomatic relief. Recent studies indicate a major role of astrocytes in specifying neuronal phenotypes during embryonic development, suggesting that glial cells are important for fate decision by NSCs and precursors before or after transplantation18, 19.

The protocols for generation of dopaminergic neurons (Fig. 2 and Supplementary Table 1 online) give rise to mixed cell populations. FLUORESCENCE-ACTIVATED CELL SORTING (FACS) of mesencephalic dopaminergic precursors has had limited success because of difficulties in finding specific surface antigens. HOMOLOGOUS RECOMBINATION20 may make it possible to generate transgenic human ESCs, expressing reporter genes that allow for purification of dopaminergic neuroblasts.

Whether new dopaminergic neurons are generated from endogenous NSCs in the adult brain is controversial. Zhao et al.21 reported continuous formation of dopaminergic neurons in the adult mouse substantia nigra (Fig. 2). The rate of neurogenesis doubled after a lesion of the dopamine system. In contrast, other investigators observed only a glial response and failed to detect any neurogenesis following dopaminergic lesions22, 23 (Y. Chen, Y. Ai and D.M. Gash, personal communication; D.K. Morris-Irvin et al., personal communication). In the study of Zhao et al.21, evidence for neurogenesis was mainly based on bromodeoxyuridine incorporation, which, however, may have also other explanations24, 25.

How to develop a stem-cell therapy for Parkinson's disease
A clinically competitive cell therapy must provide advantages over current treatments for PD. Cell-based approaches should induce long-lasting, major improvements of mobility and suppression of dyskinesias. Alternatively, the new cells should improve symptoms that are resistant to other treatments, such as balance problems. Improvements after fetal grafts4, 6, 7 have not exceeded those found with deep brain stimulation26, and there is no convincing evidence for reversal of drug-resistant symptoms4. Incomplete recovery could be due to only part of the striatum having been reinnervated4, 9. Even in animals with good reinnervation, however, improvements are only partial27, indicating that the ectopic graft placement in the striatum may be of crucial importance. Grafts implanted in the substantia nigra give some improvements in animals27, 28 and have been tested clinically29, but they are not able to reconstruct the nigrostriatal pathway27.

Even if stem cell technology can generate large numbers of dopaminergic neurons, the development of effective cell therapy for PD will require three additional advances. First, better criteria for selecting the patients suitable for cell therapy have to be defined. Dopaminergic cell therapy will most likely be successful only in those affected individuals who show marked symptomatic benefit in response to L-dopa and in whom the main pathology is a loss of dopaminergic neurons. Debilitating symptoms in PD and related disorders are also caused by pathological changes in non-dopaminergic systems. Until we know how to repair these systems, enrollment of individuals with such symptoms in clinical trials with dopaminergic cell therapy should be carefully considered.

Second, the functional efficacy of grafts must be improved. On the basis of imaging before surgery, the transplantation procedure should be customized with respect to the dose and location of grafted cells so that the repair of the dopamine system will be as complete as possible in each patient's brain. There is so far no evidence that stem cell–derived dopaminergic neurons will induce more pronounced improvement as compared with primary neurons in fetal grafts. One advantage with stem cells is the possibility for controlled genetic modification, which, for example, could be used to increase survival, differentiation, migration and function of their progeny19, 30, 31, 32. For more complete reversal of Parkinson's symptoms, it may be necessary to stimulate regrowth of axons from grafts in the substantia nigra to the striatum; this would probably require modulation of host growth-inhibitory mechanisms33. The ability of grafted NSCs to rescue dysfunctional dopaminergic neurons34, through release of neurotrophic molecules, could also promote symptomatic relief (Box 1). It is unknown whether immunosuppressive treatment is needed in patients with human stem cell grafts. Results with ALLOGENEIC fetal grafts7 suggest that effective immunosuppression, at least for 1 year after transplantation, is necessary to optimize functional outcome. If immune reactions constitute a substantial problem, alternative solutions could be to generate transgenic ESCs or NSCs. ISOGENIC stem cells seem ideal but require therapeutic cloning or the use of adult stem cells from the patient.

Third, strategies to avoid adverse effects must be developed. New animal models are needed to reveal the pathophysiological mechanisms of graft-induced dyskinesias35. The risk for teratoma from ESCs as well as the consequences of introducing new genes in stem cell–derived neurons should be carefully evaluated. Implantation of mouse ESCs into rat striatum caused teratomas in 20% of the animals36. However, the risk is reduced if the cells are differentiated beforehand in vitro. Importantly, ESCs seem more prone to generate tumors when implanted into the same species from which they were derived37. Thus, an absence of tumors after implantation of human ESCs into rodents does not exclude their occurrence in the human brain. To improve safety it may be necessary to engineer ESCs with regulatable suicide genes.

Can cell therapy work in stroke?
In stroke, occlusion of a cerebral artery leads to focal ischemia in a restricted CNS region. Many different types of neurons and glial cells degenerate in stroke. It has not yet been convincingly demonstrated that neuronal replacement induces symptomatic relief in individuals who have suffered strokes. In the only reported clinical trial, persons with stroke affecting basal ganglia received implants of neurons generated from the human NT-2 teratocarcinoma cell line into the infarcted area38. Improvements in some affected individuals correlated with increased metabolic activity at the graft site39. This finding could be interpreted as graft function but might as well reflect inflammation or increased activity in host neurons. Autopsy in one individual who had suffered a stroke revealed a population of grafted cells expressing a neuronal marker 2 years after surgery40.

Neurons from stem cells for stroke
Cells from different sources have been tested for their ability to reconstruct the forebrain and improve function after transplantation in animals subjected to stroke (Supplementary Table 2 online). Although the transplanted cells can survive and partly reverse some behavioral deficits, the mechanisms underlying the observed improvements are unclear and there is little evidence for neuronal replacement. In most cases, only a few grafted cells survived, and these did not show the phenotype of the dead neurons. Moreover, it is unknown whether these cells are functional neurons and establish connections with host neurons. Bone marrow–derived cells were also described to give rise to neurons in the stroke-damaged brain (Supplementary Table 2 online). However, two recent reports challenge this interpretation by demonstrating that fusion is responsible for the appearance of donor-derived neurons after systemic administration of bone marrow cells41, 42.

Recent findings in rodents suggest an alternative approach to cell therapy in stroke based on self-repair (Fig. 3). Stroke leads to increased generation of neurons from NSCs in the subventricular zone (SVZ)43, 44, 45. These immature neurons migrate into the damaged striatum, where they express markers of striatal medium spiny projection neurons. Thus, the new neurons seem to differentiate into the phenotype of most neurons destroyed by the ischemic lesion. However, because >80% of the new neurons die during the first weeks after stroke, they only replace a small fraction (0.2%) of the mature striatal neurons that have died44. Several factors can increase adult neurogenesis by stimulating formation and/or improving survival of new neurons, including fibroblast growth factor 2 (FGF-2)46, 47, epidermal growth factor (EGF)48, stem cell factor46, erythropoietin49, brain-derived neurotrophic factor50, 51, caspase inhibitors52 and anti-inflammatory drugs53, 54.

Fig. 3
Figure 3 | Generation of striatal neurons from endogenous stem cells after stroke. Figure 3

There is no substantial formation of new neurons in the cerebral cortex after stroke43, 44, 56. Notably, targeted apoptotic degeneration of cortical neurons in mice, leaving tissue architecture intact, leads to formation of new cortical neurons extending axons to the thalamus57. Thus, restricted self-repair capacity in ischemically damaged cortex is probably due to lack of cues necessary to trigger neurogenesis from putative local parenchymal NSCs or migration of neuroblasts from the SVZ.

How to develop a stem cell therapy for stroke
To repair the stroke-damaged brain may seem unrealistic because of atrophy and loss of many cell types. However, even re-establishment of only a fraction of damaged neuronal circuitries could have important implications. In the ideal scenario, NSCs implanted in the damaged area will differentiate in situ into those cells that have died. This strategy requires that the largely unknown developmental mechanisms instructing stem cells to differentiate into specific cell types will work also in the brain of the affected individual. For maximum functional recovery, transplantation should probably be combined with stimulation of neurogenesis from endogenous NSCs. Neurogenesis occurs from NSCs in the human SVZ58, 59, and neuronal precursors are found in human subcortical white matter60.

Adequate blood supply will be crucial for survival and development of the new neurons. Neurogenesis is closely associated with angiogenesis from endothelial precursors61. Angiogenesis occurs in the human brain after stroke but may have to be further stimulated to increase the yield of surviving new neurons. Administration of vascular endothelial growth factor (VEGF) promotes SVZ neurogenesis and angiogenesis in the penumbra region (region at risk) after stroke62. VEGF can also guide directed migration of undifferentiated SVZ neural progenitors63. For efficient repair it may be necessary to provide NSCs with a platform so that they can re-form appropriate brain structure. In neonatal mice64, NSCs seeded on synthetic extracellular matrix and implanted into the ischemia-damaged area generated new vascularized parenchyma comprising neurons and glia.

Research should now aim to identify and improve efficacy of different mechanisms, which may underlie the benefit of stem cells after stroke (Box 1). For developing the neuronal replacement strategy toward clinical application, three different tasks can be distinguished: (i) Proof of principle should be obtained that neurons generated from NSCs can survive in large numbers in animals subjected to stroke, migrate to appropriate locations, show morphological and functional properties of those neurons that have died and establish afferent and efferent synaptic interactions with neurons that survived the insult. Magnetic resonance imaging seems ideal for noninvasive imaging at high spatial and temporal resolution of the survival, migration and differentiation of grafted cells65. (ii) Behavioral recovery must be optimized in animal models. Strategies to improve survival, differentiation and integration of NSCs will require detailed knowledge of the regulation of these processes. The time window after the insult when the generation of new neurons will lead to maximum restitution of neuronal circuitries and functional recovery should be determined. (iii) There is a need to define which patients are suitable for stem cell therapy. The occurrence of striatal neurogenesis after stroke43, 44, 48 focuses the interest on individuals with basal ganglia infarcts. If stem cells can also generate cortical neurons and repair axonal damage, individuals with lesions in the cerebral cortex may be included. A strategy for repair of infarcted white matter was suggested recently by the observation that NEUROSPHERES derived from adult tissue injected intravenously or intraventricularly in mice66 gave rise to cells that migrated to demyelinated areas and remyelinated axons.

Stem cell therapy for amyotrophic lateral sclerosis?
In its common form, ALS is characterized by progressive dysfunction and degeneration of motor neurons in cerebral cortex, brain stem and spinal cord. Muscle weakness progresses rapidly and causes death within a few years. To have long-term value, stem cell therapy must restore function of both upper and lower motor neurons. Successful replacement of cortical motor neurons requires not only re-establishment of spinal cord connections but also precise functional integration of the new neurons into cortical circuitries. Corticospinal or corticobulbar systems are not reconstructed after implantation of fetal cortical tissue into adult neocortex67. Late-stage fetal cortical neurons, however, replace apoptotic neurons when grafted into adult mouse neocortex, receive afferents from host brain and project to the contralateral hemisphere68. This finding supports the strategy of differentiating stem cells along specific cortical neuronal lineages in vitro and transplanting them so as to reconstruct cortical circuitry. It is unknown, though, if such cortical neuronal replacement will work in the brains of individuals with ALS.

Is it then possible to replace spinal motor neurons in ALS? Fetal motor neurons grafted to the adult rat spinal cord lacking motor neurons migrate to the ventral horn and make functional connections with skeletal muscle69, 70. Whether these neurons are integrated in neuronal circuits and restore reflexes and voluntary movements is unclear.

Functional benefits have been detected after cell implantation in ALS models, although it is unlikely that the observed effects were due to neuronal replacement and re-establishment of connectivity. Spinal grafts of neurons generated from the human NT-2 cell line71 and intravenous administration of human umbilical cord blood cells72 delayed disease progression in mice. Human embryonic germ cell derivatives delivered into the CSF of rats with motor neuron injury were distributed over the spinal cord and migrated into the parenchyma73. The paralyzed rats showed partial motor recovery, probably because the grafted cells protected host neurons and facilitated their reafferentation by secreting growth factors.

A great deal of basic research should be done before persons with ALS should be considered for clinical trials. Cells with characteristics of cholinergic neurons have been generated from stem cells of various sources (Fig. 4), but their functional properties and ability to repair the spinal cord in ALS models are unknown. In the shorter term, strategies to retard disease progression seem to be a more realistic clinical approach as compared with neuronal replacement.

Fig. 4
Figure 4 | Generation of cholinergic motor neurons for ALS. Figure 1

Can stem cell therapy be developed for Huntington's disease?
Huntington's disease is a fatal disorder characterized by chorea and progressive dementia. The main pathology is a loss of medium spiny projection neurons in the striatum due to a mutation in the huntingtin gene. Cell therapy in Huntington's disease aims at restoring brain function by replacing these neurons. In animal models, intrastriatal grafts of fetal striatal tissue containing projection neurons re-establish connections with the globus pallidus and receive inputs from host cerebral cortex74. This level of reconstruction of corticostriatopallidal circuitry is sufficient to reverse motor and cognitive deficits in rats and monkeys74, 75, 76.

Clinical trials with intrastriatal transplantation of human fetal striatal tissue support the cell replacement strategy in Huntington's disease. The grafts survived without typical pathology, contained striatal projection neurons and interneurons, and received afferents from the patient's brain77. However, the extent of clinical benefit was unclear. One open-label trial indicated cognitive and motor improvements78, whereas outcome was unchanged in the other79. Clinical improvement was associated with reduction of striatal and cortical hypometabolism, suggesting that the grafts had restored function in striato-cortical neural loops80.

Substantial benefit following cell therapy will require that many more grafted striatal neurons survive than the low numbers achieved in the trials with fetal tissue77. The stem cell technology could markedly increase the availability of such cells. It is notable that most stem cell sources generate cells in vitro that stain for gamma-aminobutyric acid (GABA). The mechanisms governing this default GABAergic differentiation are unknown, and there is no evidence that other striatal neuronal markers are expressed by these cells. Mouse ESC derivatives81, autologous bone marrow cells82 and human forebrain neurosphere cells83 have been transplanted into rat striatum. Expression of markers for striatal projection neurons was described83 but could not be confirmed by others84.

Basic research should now explore how to generate and select striatal projection neurons from stem cells. Subsequent studies should be able to show that these neurons survive transplantation, become anatomically and functionally integrated, and improve motor and cognitive function in Huntington's models. Recently, neural proliferation was reported to be increased in the subependymal layer adjacent to the caudate nucleus in patients with Huntington's disease85. This finding suggests that in the brain of someone affected with Huntington's, there is an ineffective neuroregenerative response that, if the generated neurons can survive over the long term and are functional despite carrying the mutation, may become a future therapeutic target.

The ability of stem cell–derived striatal neurons to maintain a stable clinical condition over a long period of time will be essential for their therapeutic value in Huntington's disease. Reconstruction of striatal circuitry alone may be insufficient, because the progressive neocortical degeneration in Huntington's disease is probably not secondary to neuronal loss in the striatum. Functional restoration through neuronal replacement probably has to be combined with neuroprotective strategies for optimum clinical benefit.

Perspectives
The development of stem cell–based therapies for neurodegenerative disorders is still at an early stage. Many basic issues remain to be resolved, and we need to move forward with caution and avoid scientifically ill-founded trials in affected individuals. One challenge now is to identify molecular determinants of stem cell proliferation so as to control undesired growth and genetic alterations of ESCs, as well as to better manage the expansion of NSCs. We also need to know how to pattern stem cells to obtain a more complete repertoire of various types of cells for replacement, and how to induce effective functional integration of stem cell–derived neurons into existing neural and synaptic networks. Technological advances will be needed to make precise genetic modifications of stem cells or their progeny that will enhance their capacity for migration, integration and pathway reconstruction.

The potential of the brain's self-repair mechanisms is virtually unexplored. We need to develop technologies for genetic labeling of stem cell progeny so that we can firmly establish where neurogenesis occurs and which cell types are generated following damage. The functional properties of the new neurons and their ability to form appropriate afferent and efferent connections should be determined. We also need to identify, with the aid of genomic and proteomic approaches, the cellular and molecular players that, in a concerted action, regulate different steps of neurogenesis. On the basis of this knowledge, we should design strategies to deliver molecules that improve the yield of new functional neurons and other cells in the damaged area.

To aid in further progress toward the clinic, we also need to develop animal models that closely mimic the human disease. Such models will allow us to assess and balance potential risks and benefits of stem cell therapies before their application in humans. Likewise, we need to improve noninvasive imaging technologies so that we can monitor regenerative processes subsequent to stem cell–based approaches in animals and humans.

The time and the scientific effort required should not dampen our enthusiasm for developing stem cell therapies. For the first time, there is real hope that in the future we will be able to offer persons with currently intractable neurodegenerative diseases effective cell-based treatments to restore brain function.

HOW TO CITE THIS ARTICLE

Please cite this article as supplement to volume 10 of Nature Medicine, pages S42–S50.

Received 10 February 2004; Accepted 30 March 2004; Published online 1 July 2004.

Acknowledgements

We thank Bengt Mattsson for illustrations. Our own work was supported by grants from the Swedish Research Council, Swedish Foundation for Strategic Research, the Kock, Söderberg, Crafoord and Segerfalk Foundations, EU (BIO04-CT98-0530 and QLK3-CT-2001-02120), Foundation La Caixa, and Spanish Ministry of Science and Technology (MCYT SAF2001-1038-C02-02). The Lund Stem Cell Center is supported by a Center of Excellence grant in life sciences from the Swedish Foundation for Strategic Research.

Competing interests statement

The authors declare that they have no competing financial interests.

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