Zusammenfassung
Der Einsatz von Stammzellen hat sich als attraktive Strategie zum Ersatz verloren gegangener Zell- und Gewebefunktionen erwiesen. Stammzelltherapie gehört in vielen Fachgebieten mittlerweile zum klinischen Alltag. Die Komplexität des Gewebes im zentralen Nervensystem (ZNS) beschränkt die therapeutischen Anstrengungen bisher häufig auf die Rekonstitution umschriebener, gut bekannter Neurotransmitterdefizite, wie beispielsweise die Rekonstitution des nigro-striatalen Systems beim idiopathischen Parkinsonsyndrom. Die Entwicklung der letzten Jahre erbrachten allerdings neben der klassischen Zellersatztherapie verschiedene Möglichkeiten und Alternativen einer Stammzelltherapie verschiedenster neurologischer Erkrankungen, wie z. B. der Einsatz neuraler Stammzellen als Neuroprotektiva oder auch als Vektoren für den Transfer von Genen. Durch den Nachweis von neuralen Stammzellen auch im adulten Gehirn stellt sich zudem die Frage nach deren physiologischer und pathophysiologischer Rolle im Laufe des Lebens sowie deren Potenzial zur endogenen Regeneration. Die Kultivierung dieser Zellen hat darüber hinaus das Ziel, Mechanismen der neuronalen Degeneration und Regeneration zu studieren und daraus Therapiemöglichkeiten abzuleiten, wie z. B. die Stimulation endogener Stammzellen durch Medikamente. In dieser Arbeit möchten wir verschiedene Strategien der Nutzung von Stammzellen zur Therapie der häufigsten neurologischen Erkrankungen vorstellen und deren mögliche klinische Anwendung kritisch diskutieren.
Abstract
The use of stem cells has proven to be an attractive strategy for restoring lost cell or tissue functions. Stem cell therapy is nowadays routinely used in many clinical applications. The complexity of the tissue in the central nervous system, however, often limits the use of stem cells as yet for reconstructions of defined well-known neurotransmitter deficits, for example the reconstitution of the nigro-striatal system in Parkinson's disease. The ongoing developments during the recent years have shown alternative applications of stem cells in neurological diseases, for example, the use of neural stem cells as neuroprotective agents or as vectors for transferring genes of interest. Due to the discovery of neural stem cell also in the adult brain, the questions concerning their role in physiological and pathophysiological conditions as well as their potential for endogenous regeneration have to be further investigated. The cultivation and characterisation of these cells is aimed to improve our understanding of the mechanisms of neuronal degeneration and regeneration and could help in the development of therapeutic strategies such as, for example, the stimulation of endogenous stem cells by pharmacological compounds. In this review we present different strategies for the use of stem cells to treat various acute and chronic neurological diseases and discuss possible clinical applications.
Literatur
-
1
Dunnett S B, Bjorklund A.
Prospects for new restorative and neuroprotective treatments in Parkinson's disease.
Nature.
1999;
399
A32-39
-
2
Kordower J H, Freeman T B, Snow B J. et al .
Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease.
N Engl J Med.
1995;
332
1118-1124
-
3
Kordower J H, Goetz C G, Freeman T B, Olanow C W.
Dopaminergic transplants in patients with Parkinson's disease: neuroanatomical correlates of clinical recovery.
Exp Neurol.
1997;
144
41-46
-
4
Lindvall O, Brundin P, Widner H. et al .
Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease.
Science.
1990;
247
574-577
-
5
Gaiano N, Fishell G.
Transplantation as a tool to study progenitors within the vertebrate nervous system.
J Neurobiol.
1998;
36
152-161
-
6
Temple S.
Division and differentiation of isolated CNS blast cells in microculture.
Nature.
1989;
340
471-473
-
7
Hermann A, Gerlach M, Schwarz J, Storch A.
Neurorestoration in Parkinson's disease by cell replacement and endogenous regeneration.
Expert Opin Biol Ther.
2004;
4
131-143
-
8
Storch A, Schwarz J.
Neural stem cells and neurodegeneration.
Curr Opin Investig Drugs.
2002;
3
774-781
-
9
Martinez-Serrano A, Bjorklund A.
Immortalized neural progenitor cells for CNS gene transfer and repair.
Trends Neurosci.
1997;
20
530-538
-
10 Ohmoto Y WK. Immunology. Mechanisms of rejection. In: Dunnett SB BA, Baker GB (eds) Neural Transplantation Methods. Totowa NJ, USA; Humana Press 2000: 461-476
-
11
Schwarz S C, Wittlinger J, Schober R. et al .
Transplantation of human neural precursor cells in the 6-OHDA lesioned rats: Effect of immunosuppression with cyclosporine A.
Parkinsonism Relat Disord.
2006;
12
302-308
-
12
Bjorklund A, Lindvall O.
Cell replacement therapies for central nervous system disorders.
Nat Neurosci.
2000;
3
537-544
-
13
Gage F H.
Mammalian neural stem cells.
Science.
2000;
287
1433-1438
-
14
McKay R.
Stem cells in the central nervous system.
Science.
1997;
276
66-71
-
15
Stemple D L, Anderson D J.
Isolation of a stem cell for neurons and glia from the mammalian neural crest.
Cell.
1992;
71
973-985
-
16
Reynolds B A, Weiss S.
Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.
Science.
1992;
255
1707-1710
-
17
Lois C, Alvarez-Buylla A.
Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia.
Proc Natl Acad Sci USA.
1993;
90
2074-2077
-
18
Mayer-Proschel M, Kalyani A J, Mujtaba T, Rao M S.
Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells.
Neuron.
1997;
19
773-785
-
19
Rao M S, Mayer-Proschel M.
Glial-restricted precursors are derived from multipotent neuroepithelial stem cells.
Dev Biol.
1997;
188
48-63
-
20
Lie D C, Dziewczapolski G, Willhoite A R. et al .
The adult substantia nigra contains progenitor cells with neurogenic potential.
J Neurosci.
2002;
22
6639-6649
-
21
Zhao M, Momma S, Delfani K. et al .
Evidence for neurogenesis in the adult mammalian substantia nigra.
Proc Natl Acad Sci USA.
2003;
100
7925-7930
-
22
Kornack D R, Rakic P.
The generation, migration, and differentiation of olfactory neurons in the adult primate brain.
Proc Natl Acad Sci USA.
2001;
98
4752-4757
-
23
Koketsu D, Mikami A, Miyamoto Y, Hisatsune T.
Nonrenewal of neurons in the cerebral neocortex of adult macaque monkeys.
J Neurosci.
2003;
23
937-942
-
24
Gould E, Gross C G.
Neurogenesis in adult mammals: some progress and problems.
J Neurosci.
2002;
22
619-623
-
25
Frielingsdorf H, Schwarz K, Brundin P, Mohapel P.
No evidence for new dopaminergic neurons in the adult mammalian substantia nigra.
Proc Natl Acad Sci USA.
2004;
101
10177-10182
-
26
Tsai C H, Lo S K, See L C. et al .
Environmental risk factors of young onset Parkinson's disease: a case-control study.
Clin Neurol Neurosurg.
2002;
104
328-333
-
27
Brustle O, McKay R D.
Neuronal progenitors as tools for cell replacement in the nervous system.
Curr Opin Neurobiol.
1996;
6
688-695
-
28
Abe K.
Cognitive function in amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Other Motor Neuron Disord.
2000;
1
343-347
-
29
Akiyama Y, Honmou O, Kato T. et al .
Transplantation of clonal neural precursor cells derived from adult human brain establishes functional peripheral myelin in the rat spinal cord.
Exp Neurol.
2001;
167
27-39
-
30
Arsenijevic Y, Villemure J G, Brunet J F. et al .
Isolation of multipotent neural precursors residing in the cortex of the adult human brain.
Exp Neurol.
2001;
170
48-62
-
31
Cattaneo E, McKay R.
Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor.
Nature.
1990;
347
762-765
-
32
Brustle O, Jones K N, Learish R D. et al .
Embryonic stem cell-derived glial precursors: a source of myelinating transplants.
Science.
1999;
285
754-756
-
33
Kawasaki H, Mizuseki K, Nishikawa S. et al .
Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity.
Neuron.
2000;
28
31-40
-
34
Lee S H, Lumelsky N, Studer L. et al .
Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells.
Nat Biotechnol.
2000;
18
675-679
-
35
Li M, Pevny L, Lovell-Badge R, Smith A.
Generation of purified neural precursors from embryonic stem cells by lineage selection.
Curr Biol.
1998;
8
971-974
-
36
Kawasaki H, Suemori H, Mizuseki K. et al .
Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity.
Proc Natl Acad Sci USA.
2002;
99
1580-1585
-
37
Amit M, Carpenter M K, Inokuma M S. et al .
Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture.
Dev Biol.
2000;
227
271-278
-
38
Bjorklund L M, Sanchez-Pernaute R, Chung S. et al .
Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model.
Proc Natl Acad Sci USA.
2002;
99
2344-2349
-
39
Kilpatrick T J, Bartlett P F.
Cloning and growth of multipotential neural precursors: requirements for proliferation and differentiation.
Neuron.
1993;
10
255-265
-
40
Svendsen C N, Caldwell M A, Ostenfeld T.
Human neural stem cells: isolation, expansion and transplantation.
Brain Pathol.
1999;
9
499-513
-
41
Vescovi A L, Parati E A, Gritti A. et al .
Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation.
Exp Neurol.
1999;
156
71-83
-
42
Rietze R L, Valcanis H, Brooker G F. et al .
Purification of a pluripotent neural stem cell from the adult mouse brain.
Nature.
2001;
412
736-739
-
43
Schuldiner M, Eiges R, Eden A. et al .
Induced neuronal differentiation of human embryonic stem cells.
Brain Res.
2001;
913
201-205
-
44
Johansson C B, Svensson M, Wallstedt L. et al .
Neural stem cells in the adult human brain.
Exp Cell Res.
1999;
253
733-736
-
45
Kukekov V G, Laywell E D, Suslov O. et al .
Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain.
Exp Neurol.
1999;
156
333-344
-
46
Roy N S, Wang S, Jiang L. et al .
In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus.
Nat Med.
2000;
6
271-277
-
47
Hermann A, Maisel M, Liebau S. et al .
Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells.
J Neurochem.
2006;
98
629-640
-
48
Lee J, Elkahloun A G, Messina S A. et al .
Cellular and genetic characterization of human adult bone marrow-derived neural stem-like cells: a potential antiglioma cellular vector.
Cancer Res.
2003;
63
8877-8889
-
49
Aboody K S, Brown A, Rainov N G. et al .
Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas.
Proc Natl Acad Sci USA.
2000;
97
12846-12851
-
50
Lees K R, Zivin J A, Ashwood T. et al .
NXY-059 for acute ischemic stroke.
N Engl J Med.
2006;
354
588-600
-
51
Lindvall O, Kokaia Z, Martinez-Serrano A.
Stem cell therapy for human neurodegenerative disorders - how to make it work.
Nat Med.
2004;
10
S42-50
-
52
Hayashi J, Takagi Y, Fukuda H. et al .
Primate embryonic stem cell-derived neuronal progenitors transplanted into ischemic brain.
J Cereb Blood Flow Metab.
2006;
26
906-914
-
53
Ikeda R, Kurokawa M S, Chiba S. et al .
Transplantation of neural cells derived from retinoic acid-treated cynomolgus monkey embryonic stem cells successfully improved motor function of hemiplegic mice with experimental brain injury.
Neurobiol Dis.
2005;
20
38-48
-
54
Wei L, Cui L, Snider B J. et al .
Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia.
Neurobiol Dis.
2005;
19
183-193
-
55
Lindvall O, Kokaia Z.
Stem cells for the treatment of neurological disorders.
Nature.
2006;
441
1094-1096
-
56
Kondziolka D, Wechsler L, Goldstein S. et al .
Transplantation of cultured human neuronal cells for patients with stroke.
Neurology.
2000;
55
565-569
-
57
Meltzer C C, Kondziolka D, Villemagne V L. et al .
Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke.
Neurosurgery.
2001;
49
586-591; discussion 591 - 592
-
58
Nelson P T, Kondziolka D, Wechsler L. et al .
Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation.
Am J Pathol.
2002;
160
1201-1206
-
59
Arvidsson A, Collin T, Kirik D. et al .
Neuronal replacement from endogenous precursors in the adult brain after stroke.
Nat Med.
2002;
8
963-970
-
60
Yamashita T, Ninomiya M, Hernandez Acosta P. et al .
Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum.
J Neurosci.
2006;
26
6627-6636
-
61
Thored P, Arvidsson A, Cacci E. et al .
Persistent production of neurons from adult brain stem cells during recovery after stroke.
Stem Cells.
2006;
24
739-747
-
62
Nistor G I, Totoiu M O, Haque N. et al .
Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation.
Glia.
2005;
49
385-396
-
63
Windrem M S, Nunes M C, Rashbaum W K. et al .
Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain.
Nat Med.
2004;
10
93-97
-
64
Pluchino S, Quattrini A, Brambilla E. et al .
Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis.
Nature.
2003;
422
688-694
-
65
Pluchino S, Zanotti L, Rossi B. et al .
Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism.
Nature.
2005;
436
266-271
-
66
Scolding N, Franklin R, Stevens S. et al .
Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis.
Brain.
1998;
121
2221-2228
-
67
Back S A, Tuohy T M, Chen H. et al .
Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation.
Nat Med.
2005;
11
966-972
-
68
Li X J, Du Z W, Zarnowska E D. et al .
Specification of motoneurons from human embryonic stem cells.
Nat Biotechnol.
2005;
23
215-221
-
69
Wichterle H, Lieberam I, Porter J A, Jessell T M.
Directed differentiation of embryonic stem cells into motor neurons.
Cell.
2002;
110
385-397
-
70
Harper J M, Krishnan C, Darman J S. et al .
Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats.
Proc Natl Acad Sci USA.
2004;
101
7123-7128
-
71
Miles G B, Yohn D C, Wichterle H. et al .
Functional properties of motoneurons derived from mouse embryonic stem cells.
J Neurosci.
2004;
24
7848-7858
-
72
Kerr D A, Llado J, Shamblott M J. et al .
Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury.
J Neurosci.
2003;
23
5131-5140
-
73
Klein S M, Behrstock S, McHugh J. et al .
GDNF delivery using human neural progenitor cells in a rat model of ALS.
Hum Gene Ther.
2005;
16
509-521
-
74
Clement A M, Nguyen M D, Roberts E A. et al .
Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice.
Science.
2003;
302
113-117
-
75
Corti S, Locatelli F, Donadoni C. et al .
Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues.
Brain.
2004;
127
2518-2532
-
76
Ende N, Weinstein F, Chen R, Ende M.
Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis).
Life Sci.
2000;
67
53-59
-
77
Garbuzova-Davis S, Willing A E, Zigova T. et al .
Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation.
J Hematother Stem Cell Res.
2003;
12
255-270
-
78 Habisch H J, Janowski M, Binder D. et al .Intrathecal application of neuroectodermally converted stem cells into a mouse model of ALS: Limited intraparenchymal migrations narrows therapeutic effects. Eingereicht bei J Neural Transm
-
79
Ludolph A C.
Matrix metalloproteinases - A conceptional alternative for disease-modifying strategies in ALS/MND?.
Exp Neurol.
2006;
201
277-280
-
80
Silani V, Cova L, Corbo M. et al .
Stem-cell therapy for amyotrophic lateral sclerosis.
Lancet.
2004;
364
200-202
-
81
Janson C G, Ramesh T M, During M J. et al .
Human intrathecal transplantation of peripheral blood stem cells in amyotrophic lateral sclerosis.
J Hematother Stem Cell Res.
2001;
10
913-915
-
82
Huang H, Chen L, Wang H. et al .
Influence of patients' age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury.
Chin Med J (Engl).
2003;
116
1488-1491
-
83
Cyranoski D.
Fetal-cell therapy: paper chase.
Nature.
2005;
437
810-811
-
84
Watts J.
Controversy in China.
Lancet.
2005;
365
109-110
-
85
Dobkin B H, Curt A, Guest J.
Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury.
Neurorehabil Neural Repair.
2006;
20
5-13
-
86
Chi L, Ke Y, Luo C. et al .
Motor neuron degeneration promotes neural progenitor cell proliferation, migration, and neurogenesis in the spinal cords of amyotrophic lateral sclerosis mice.
Stem Cells.
2006;
24
34-43
-
87
Tuszynski M H, Blesch A.
Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer's disease.
Prog Brain Res.
2004;
146
441-449
-
88
Tuszynski M H, Thal L, Pay M. et al .
A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease.
Nat Med.
2005;
11
551-555
-
89
Freed C R, Greene P E, Breeze R E. et al .
Transplantation of embryonic dopamine neurons for severe Parkinson's disease.
N Engl J Med.
2001;
344
710-719
-
90
Olanow C W, Goetz C G, Kordower J H. et al .
A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease.
Ann Neurol.
2003;
54
403-414
-
91
Hagell P, Piccini P, Bjorklund A. et al .
Dyskinesias following neural transplantation in Parkinson's disease.
Nat Neurosci.
2002;
5
627-628
-
92
Ling Z D, Potter E D, Lipton J W, Carvey P M.
Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines.
Exp Neurol.
1998;
149
411-423
-
93
Storch A, Lester H A, Boehm B O, Schwarz J.
Functional characterization of dopaminergic neurons derived from rodent mesencephalic progenitor cells.
J Chem Neuroanat.
2003;
26
133-142
-
94
Storch A, Paul G, Csete M. et al .
Long-term proliferation and dopaminergic differentiation of human mesencephalic neural precursor cells.
Exp Neurol.
2001;
170
317-325
-
95
Kim J H, Auerbach J M, Rodriguez-Gomez J A. et al .
Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease.
Nature.
2002;
418
50-56
-
96
Hermann A, Maisel M, Wegner F. et al .
Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons.
Stem Cells.
2006;
24
949-964
-
97
Dezawa M, Kanno H, Hoshino M. et al .
Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation.
J Clin Invest.
2004;
113
1701-1710
-
98
Hermann A, Gastl R, Liebau S. et al .
Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells.
J Cell Sci.
2004;
117
4411-4422
-
99
Hermann A, Liebau S, Gastl R. et al .
Comparative analysis of neuroectodermal differentiation capacity of human bone marrow stromal cells using various conversion protocols.
J Neurosci Res.
2006;
83
1502-1514
-
100
Studer L, Tabar V, McKay R D.
Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats.
Nat Neurosci.
1998;
1
290-295
-
101
Perrier A L, Tabar V, Barberi T. et al .
Derivation of midbrain dopamine neurons from human embryonic stem cells.
Proc Natl Acad Sci USA.
2004;
101
12543-12548
-
102
Carvey P M, Ling Z D, Sortwell C E. et al .
A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease.
Exp Neurol.
2001;
171
98-108
Prof. Dr. med. Alexander Storch
Klinik und Poliklinik für Neurologie, Technische Universität Dresden
Fetscherstraße 74
01307 Dresden
eMail: alexander.storch@neuro.med.tu-dresden.de
