Cellular transplantation strategies for spinal cord injury and translational neurobiology.
Basic science advances in spinal cord injury and regeneration research have led to a variety of novel experimental therapeutics designed to promote functionally effective axonal regrowth and sprouting. Among these interventions are cell-based approaches involving transplantation of neural and non-neural tissue elements that have potential for restoring damaged neural pathways or reconstructing intraspinal synaptic circuitries by either regeneration or neuronal/glial replacement. Notably, some of these strategies (e.g., grafts of peripheral nerve tissue, olfactory ensheathing glia, activated macrophages, marrow stromal cells, myelin-forming oligodendrocyte precursors or stem cells, and fetal spinal cord tissue) have already been translated to the clinical arena, whereas others have imminent likelihood of bench-to-bedside application. Although this progress has generated considerable enthusiasm about treating what once was thought to be a totally incurable condition, there are many issues to be considered relative to treatment safety and efficacy. The following review reflects on different experimental applications of intraspinal transplantation with consideration of the underlying pathological, pathophysiological, functional, and neuroplastic responses to spinal trauma that such treatments may target along with related issues of procedural and biological safety. The discussion then moves to an overview of ongoing and completed clinical trials to date. The pros and cons of these endeavors are considered, as well as what has been learned from them. Attention is primarily directed at preclinical animal modeling and the importance of patterning clinical trials, as much as possible, according to laboratory experiences.
Reier
Paul J
PJ
College of Medicine and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. reier@mbi.ufl.edu
D000818:Animals; D017690:Cell Transplantation; D002986:Clinical Trials as Topic; D016332:Fetal Tissue Transplantation; D006801:Humans; D009186:Myelin Sheath / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D009446:Neurobiology / Q000639:trends*; D009473:Neuronal Plasticity; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000628:therapy*
J Neurotrauma. 2004 Oct;21(10):1371-83
15672628
J Neurosci. 1998 May 15;18(10):3803-15
9570810
Glia. 2000 May;30(3):209-18
10756071
Mol Med Today. 1997 Dec;3(12):554-61
9449127
Neurosci Lett. 1993 Jul 9;157(1):115-9
8233021
Neuropathology. 2003 Sep;23(3):169-80
14570283
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2199-204
11854516
J Neurophysiol. 1995 Mar;73(3):1020-30
7608752
Brain Res. 2001 Jan 19;889(1-2):344-57
11166728
Neurobiol Dis. 2004 Aug;16(3):638-53
15262276
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3908-13
9520466
J Neurotrauma. 1999 Aug;16(8):695-703
10511242
J Neurosurg. 2000 Oct;93(2 Suppl):266-75
11012058
Adv Neurol. 1988;47:361-85
3278523
Exp Neurol. 1993 Sep;123(1):35-50
8405278
Prog Brain Res. 2002;137:83-95
12440361
Int J Dev Neurosci. 1993 Oct;11(5):603-12
8116473
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17066-71
12477938
J Neurotrauma. 2004 Apr;21(4):441-9
15115593
Glia. 2000 Dec;32(3):214-25
11102963
Exp Neurol. 2003 Aug;182(2):247-60
12895437
Neuroscientist. 2002 Oct;8(5):457-88
12374430
Neuron. 2000 Feb;25(2):425-35
10719896
J Spinal Cord Med. 2004;27(4):311-8
15484661
J Neurosci Res. 2000 Aug 15;61(4):364-70
10931522
N Engl J Med. 1995 Apr 27;332(17):1118-24
7700284
Exp Brain Res. 1999 May;126(1):93-108
10333010
FASEB J. 1996 Sep;10(11):1296-302
8836043
Exp Neurol. 1997 Dec;148(2):495-501
9417828
Exp Neurol. 1998 Jan;149(1):262-76
9454636
J Neurotrauma. 1991 Summer;8(2):103-19
1870134
J Neurotrauma. 2002 Oct;19(10):1231-49
12427331
J Neurotrauma. 2002 Jun;19(6):787-800
12165138
Neurologist. 2003 Jan;9(1):1-15
12801427
Science. 1979 Jun 8;204(4397):1117-9
451560
Curr Opin Neurobiol. 1998 Dec;8(6):800-7
9914245
J Neurosci. 1998 Dec 15;18(24):10514-24
9852589
Cell Transplant. 2002;11(6):593-613
12428749
Phys Ther. 2000 Aug;80(8):808-17
10911417
Exp Neurol. 1974 Sep;44(3):424-39
4621072
Exp Neurol. 2002 Oct;177(2):349-59
12429182
J Spinal Cord Med. 1999 Summer;22(2):119-24
10826269
Mol Cell Neurosci. 2001 Mar;17(3):471-87
11273643
J Neuropathol Exp Neurol. 2002 Jul;61(7):623-33
12125741
Glia. 2002 Sep;39(3):229-36
12203389
NeuroRehabilitation. 2003;18(4):339-51
14757930
Brain Res Bull. 2002 Apr;57(6):827-32
12031280
J Neurotrauma. 2003 Aug;20(8):707-16
12965050
J Neuroimmunol. 2003 Sep;142(1-2):10-6
14512160
Neuropharmacology. 2000 Mar 3;39(5):777-87
10699444
Glia. 1997 Mar;19(3):247-58
9063731
Annu Rev Neurosci. 1981;4:127-62
7013633
J Neurosci. 1998 Jan 15;18(2):763-78
9425018
Neurobiol Dis. 2001 Feb;8(1):11-8
11162236
Brain. 2002 Jan;125(Pt 1):14-21
11834589
Brain Res Bull. 1998 Jun;46(3):175-87
9667810
Cent Nerv Syst Trauma. 1984 Winter;1(2):117-29
6545680
J Neurosci. 2003 Feb 1;23(3):727-31
12574399
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4089-94
10097168
Behav Brain Res. 2003 Sep 15;144(1-2):143-56
12946605
Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S137-45
11805621
J Neurotrauma. 2001 Sep;18(9):931-45
11565604
Science. 2000 Dec 1;290(5497):1775-9
11099418
J Neurotrauma. 2000 Oct;17(10):915-25
11063057
Exp Neurol. 1992 Apr;116(1):40-51
1559563
Exp Neurol. 1996 Jan;137(1):1-14
8566201
Science. 2002 Feb 8;295(5557):1029-31
11834824
Anat Rec B New Anat. 2003 Mar;271(1):71-6
12619088
Acta Neurobiol Exp (Wars). 1996;56(1):449-63
8787206
Cell Prolif. 2004 Feb;37(1):55-65
14871237
Spine (Phila Pa 1976). 2002 Apr 15;27(8):887-92
11935115
Exp Neurol. 1995 Nov;136(1):64-72
7589335
J Neurotrauma. 2000 Sep;17(9):781-8
11011818
Nature. 2000 Oct 26;407(6807):963-70
11069169
Lancet. 2004 May 1;363(9419):1432-7
15121406
J Neurotrauma. 2002 Feb;19(2):239-56
11893025
Eur J Neurosci. 2000 Jul;12(7):2414-24
10947820
J Neuropathol Exp Neurol. 1996 Mar;55(3):280-9
8786386
Spinal Cord. 1998 Dec;36(12):811-7
9881728
Neurosci Res. 1987 Oct;5(1):68-73
3431751
Nat Neurosci. 2004 Mar;7(3):269-77
14966523
Exp Neurol. 1996 Nov;142(1):128-43
8912904
J Neural Transplant Plast. 1995;5(4):233-43
7578439
Prog Neurobiol. 2001 Dec;65(5):489-96
11689283
Exp Neurol. 1997 Dec;148(2):453-63
9417825
J Exp Biol. 1990 Oct;153:199-224
2280221
Nat Rev Neurosci. 2003 Sep;4(9):703-13
12951563
Trends Neurosci. 2003 Oct;26(10):555-63
14522149
Restor Neurol Neurosci. 1991 Jan 1;2(4):309-25
21551618
Anat Rec B New Anat. 2003 Mar;271(1):49-60
12619086
J Clin Invest. 2001 Aug;108(4):591-9
11518733
J Neurosci. 2001 Dec 1;21(23):9334-44
11717367
J Neurosci. 2001 Jun 1;21(11):3740-8
11356861
Exp Neurol. 1992 Jan;115(1):177-88
1370221
Nat Med. 1997 Jan;3(1):73-6
8986744
Behav Brain Res. 1993 Jul 30;56(1):59-76
7691077
J Neurotrauma. 2002 Jun;19(6):753-61
12165135
Dev Biol. 1993 Mar;156(1):34-48
7680631
Ann Neurol. 1994 Feb;35(2):172-80
8109898
J Neurotrauma. 2003 Feb;20(2):179-93
12675971
Exp Brain Res. 1988;73(2):329-42
3215309
Exp Neurol. 1991 Nov;114(2):193-205
1748194
J Neurosci Res. 2000 Aug 1;61(3):288-94
10900075
Electroencephalogr Clin Neurophysiol. 1993 Jun;89(3):177-86
7686850
Neurosurgery. 2004 Apr;54(4):950-5; discussion 955
15046663
Exp Neurol. 2002 Jan;173(1):153-67
11771948
Clin Neuropharmacol. 2001 Sep-Oct;24(5):254-64
11586110
Cell Tissue Res. 1983;230(1):15-35
6850760
Exp Neurol. 1985 Apr;88(1):1-12
3979504
J Comp Neurol. 1988 Mar 22;269(4):612-7
3372730
J Neurosci Res. 1997 Dec 1;50(5):798-808
9418967
Muscle Nerve. 1994 Dec;17(12):1466-8
7969249
Exp Neurol. 1995 Oct;135(2):123-45
7589324
J Neuroimmunol. 1995 Aug;61(1):89-96
7560018
Prog Brain Res. 2002;138:401-9
12432780
Brain Pathol. 1995 Oct;5(4):451-57
8974628
J Neurotrauma. 1997 Apr;14(4):235-48
9151772
Pain. 1996 Dec;68(2-3):185-94
9121805
Neuroscientist. 2001 Aug;7(4):325-39
11488398
Adv Neurol. 1993;59:75-89
8420126
Sci Am. 1999 Sep;281(3):64-73
10467750
Cell Transplant. 1998 Mar-Apr;7(2):187-96
9588600
J Neurosci Res. 2002 May 15;68(4):406-23
11992467
Exp Neurol. 2001 Sep;171(1):153-69
11520130
Chin Med J (Engl). 2003 Oct;116(10):1488-91
14570607
N Engl J Med. 1999 Sep 23;341(13):992-6
10498498
Exp Neurol. 2003 Nov;184(1):97-113
14637084
Nat Rev Neurosci. 2001 Apr;2(4):263-73
11283749
Science. 1981 Nov 20;214(4523):931-3
6171034
J Neurocytol. 1994 Jul;23(7):433-52
7964912
Science. 2002 Aug 23;297(5585):1299
12193778
Brain Res. 1982 Apr 8;237(1):147-62
6176289
Mol Psychiatry. 2002;7(1):9-11
11803438
Int J Dev Neurosci. 1993 Oct;11(5):641-9
8116476
Nat Biotechnol. 2001 Dec;19(12):1129-33
11731781
Exp Neurol. 1985 Apr;88(1):108-22
3979505
Science. 1999 Jul 30;285(5428):754-6
10427001
Exp Brain Res. 2000 Jul;133(2):233-41
10968224
J Neurosci. 1994 Jul;14(7):4050-63
8027762
J Neurotrauma. 1999 Jun;16(6):533-41
10391369
Physiol Genomics. 2001 Dec 21;7(2):201-13
11773606
J Spinal Cord Med. 1999 Fall;22(3):173-81
10685382
Lancet Neurol. 2003 Jul;2(7):437-45
12849125
J Neurotrauma. 2003 Jan;20(1):1-16
12614584
Exp Neurol. 1991 Nov;114(2):254-7
1748200
Science. 1997 Sep 26;277(5334):2000-2
9302296
Adv Neurol. 1988;47:87-138
3278533
Nat Rev Neurosci. 2004 Feb;5(2):146-56
14735117
Exp Neurol. 1997 Dec;148(2):523-43
9417830
J Neurosci Res. 2003 May 1;72(3):343-51
12692901
Neurosci Res. 1990 Jun;8(2):124-30
2170872
Exp Neurol. 2001 Sep;171(1):11-21
11520117
J Comp Neurol. 1997 Jan 20;377(3):443-64
8989657
J Comp Neurol. 2000 Apr 10;419(3):286-96
10723005
Nat Med. 2004 Jan;10(1):93-7
14702638
Rev Neurol (Paris). 1997 Sep;153(8-9):521-5
9684002
Nat Med. 1998 Jul;4(7):814-21
9662373
Nat Med. 1999 Aug;5(8):943-6
10426320
Acad Radiol. 2002 Aug;9 Suppl 2:S332-5
12188266
Cell Transplant. 2001;10(8):661-4
11814107
Exp Neurol. 1997 Dec;148(2):502-22
9417829
J Physiol. 2001 May 15;533(Pt 1):83-9
11351016
Prog Brain Res. 2000;128:265-72
11105686
Acta Neuropathol. 1984;64(3):203-12
6496037
Exp Neurol. 1993 Sep;123(1):17-34
8405276
J Appl Physiol (1985). 2003 Feb;94(2):795-810
12531916
Exp Neurol. 1999 Aug;158(2):351-65
10415142
Science. 2000 Dec 1;290(5497):1779-82
11099419
J Child Neurol. 2001 Jan;16(1):2-9
11225952
J Neurotrauma. 2004 Apr;21(4):383-93
15115588
Science. 1999 Apr 2;284(5411):143-7
10102814
Exp Neurol. 2003 Nov;184(1):237-46
14637095
Eur J Neurosci. 2001 Jan;13(2):257-68
11168530
J Neurosci. 2001 Nov 1;21(21):8680-9
11606656
Prog Brain Res. 2002;137:125-39
12440364
J Neurobiol. 1995 Oct;28(2):171-89
8537823
Nat Med. 2004 Jun;10(6):570-3
15170195
Nature. 2002 Apr 4;416(6880):542-5
11932747
J Neuroimmunol. 2000 Nov 1;111(1-2):210-4
11063840
Exp Neurol. 1996 Apr;138(2):261-76
8620925
Exp Brain Res. 1990;80(1):1-11
2358020
Science. 1987 Aug 7;237(4815):642-5
3603044
Exp Neurol. 1997 Jun;145(2 Pt 1):397-411
9217076
Nature. 1997 Dec 18-25;390(6661):680-3
9414159
J Appl Physiol (1985). 1998 Nov;85(5):1786-92
9804582
J Neurosci. 2002 Apr 1;22(7):2690-700
11923434
Arch Phys Med Rehabil. 1998 Jan;79(1):107-12
9440427
Exp Neurol. 1995 Dec;136(2):149-61
7498405
Neuroreport. 2004 May 19;15(7):1105-8
15129154
Nat Med. 2004 Jun;10(6):610-6
15156204
J Neurosci. 2004 Sep 29;24(39):8562-76
15456830
J Neurosci. 2003 Sep 24;23(25):8682-91
14507967
J Neurosurg. 2002 Mar;96(2 Suppl):197-205
12450283
J Neurosci. 2002 Aug 1;22(15):6670-81
12151546
Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8786-90
15173585
Spinal Cord. 2002 Mar;40(3):101-9
11859436
Exp Neurol. 2002 Oct;177(2):575-80
12429203
J Neurosci. 2004 Mar 3;24(9):2090-101
14999060
J Neurotrauma. 1998 Jul;15(7):459-72
9674550
J Neurophysiol. 1992 Nov;68(5):1473-86
1479425
Ann Emerg Med. 1993 Jun;22(6):987-92
8503537
J Neurotrauma. 2004 Apr;21(4):429-40
15115592
Am J Phys Med Rehabil. 2003 Oct;82(10 Suppl):S38-49
14502038
J Comp Neurol. 2004 May 17;473(1):1-15
15067714
Lancet Neurol. 2002 Sep;1(5):269
12849411
J Neurotrauma. 2003 May;20(5):477-82
12803979
Prog Brain Res. 2002;137:401-6
12440382
Trends Pharmacol Sci. 2003 Jan;24(1):7-12
12498724
Adv Neurol. 1993;59:175-84
8420104
Neurobiol Dis. 2004 Apr;15(3):415-36
15056450
J Neurosurg. 1992 Feb;76(2):261-74
1730955
J Neurosci. 2001 Feb 1;21(3):944-50
11157080
J Neurotrauma. 1993 Spring;10(1):19-24
8320729
Neurosci Lett. 1991 Mar 11;124(1):44-8
1857542
Inj Prev. 2002 Dec;8 Suppl 4:IV33-6
12460955
Exp Neurol. 2001 Jan;167(1):27-39
11161590
J Neurobiol. 1995 Oct;28(2):190-201
8537824
Neuropathol Appl Neurobiol. 1978 May-Jun;4(3):165-76
360094
Exp Neurol. 1997 Sep;147(1):172-82
9294414
Pain. 1998 Mar;75(1):141-155
9539683
Exp Neurol. 1992 Sep;117(3):287-98
1397165
J Neurotrauma. 2004 Apr;21(4):375-82
15115587
J Neurosci. 2002 Jan 1;22(1):315-23
11756515
Cell Transplant. 1997 May-Jun;6(3):339-46
9171166
J Neurosci Res. 1996 Sep 01;45(5):588-97
8875323
Nat Neurosci. 2000 Jun;3(6):537-44
10816308
J Neurotrauma. 1994 Aug;11(4):369-77
7837278
Nat Rev Neurosci. 2001 Nov;2(11):831-4
11715059
J Neurosci. 2003 Mar 15;23(6):2494-501
12657710
Nat Rev Neurosci. 2001 May;2(5):365-9
11331920
J Neurotrauma. 2001 Oct;18(10):1091-105
11686495
Neuroscience. 1983 Oct;10(2):521-43
6633870
Dev Neurosci. 1992;14(2):73-84
1396177
Zh Vopr Neirokhir Im N N Burdenko. 1994 Jul-Sep;(3):27-9
7985441
J Neurochem. 2001 Nov;79(4):804-15
11723173
Can J Physiol Pharmacol. 1996 Apr;74(4):518-30
8828897
Restor Neurol Neurosci. 2002;20(5):189-218
12515895
Eur J Neurosci. 2003 Jul;18(2):412-22
12887423
J Neurophysiol. 1999 Sep;82(3):1381-9
10482756
J Neurotrauma. 1992 Summer;9(2):123-6; discussion 126-8
1404425
J Neurosci. 1997 Jul 15;17(14):5395-406
9204923
J Neurosci Res. 1998 Jul 1;53(1):51-65
9670992
Exp Neurol. 1992 Apr;116(1):1-12
1559561
Exp Neurol. 1991 Jul;113(1):1-9
2044676
Exp Neurol. 1999 Mar;156(1):191-204
10192790
Neuroreport. 2001 Aug 8;12(11):2303-9
11496100
Ann Neurol. 1991 Feb;29(2):115-23
2012382
J Neurotrauma. 2004 Feb;21(2):195-204
15000760
Nat Rev Neurosci. 2001 May;2(5):369-75
11331921
Acta Neuropathol. 1982;57(1):59-69
7090743
J Neurotrauma. 1997 Nov;14(11):875-84
9421458
Glia. 1998 Nov;24(3):329-37
9775984
Brain. 2002 Jan;125(Pt 1):2-3
11834587
Exp Neurol. 1993 Apr;120(2):264-76
8491282
Ann Neurol. 2003 Apr;53(4):454-68
12666113
Science. 1996 Jul 26;273(5274):510-3
8662542
J Neurotrauma. 2002 Oct;19(10):1203-16
12427329
Neurosci Lett. 2002 Jul 19;327(2):133-7
12098653
Eur J Neurosci. 1998 Feb;10(2):607-21
9749723
Histol Histopathol. 1995 Apr;10(2):503-7
7599444
J Neurosci Res. 2002 Oct 1;70(1):65-81
12237865
Exp Neurol. 2000 Dec;166(2):213-26
11085887
J Spinal Cord Med. 2003 Winter;26(4):323-8
14992331
Glia. 2003 Jan 15;41(2):191-8
12509809
Neuron. 2000 Oct;28(1):15-8
11086978
Brain Res Bull. 1989 Jan;22(1):47-52
2540887
Eur J Neurosci. 1999 Oct;11(10):3648-58
10564372
FASEB J. 2004 Feb;18(2):335-7
14657003
J Neurosci. 2004 Apr 14;24(15):3752-61
15084655
J Exp Biol. 1987 Sep;132:5-19
3323406
J Neurosci. 2000 Sep 1;20(17):6421-30
10964948
J Neurosci. 2002 Jul 15;22(14):6083-91
12122069
Nat Med. 1999 Dec;5(12):1410-2
10581084
J Neurotrauma. 1992 Summer;9(2):129-31; discussion 131-4
1404426
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6126-31
10823956
Neuroreport. 2000 Sep 11;11(13):3001-5
11006983
Exp Neurol. 2001 Jan;167(1):48-58
11161592
Neurochem Res. 2003 Nov;28(11):1659-76
14584820
Adv Physiol Educ. 2002 Dec;26(1-4):238-55
12443996
Prog Brain Res. 2002;137:49-70
12440359
Nat Biotechnol. 2000 Sep;18(9):949-53
10973214
J Neurosci Res. 2004 Apr 15;76(2):232-43
15048921
J Neurotrauma. 2001 Sep;18(9):911-29
11565603
J Neurosci. 2000 Jul 1;20(13):5144-52
10864971
Nature. 2002 Apr 11;416(6881):636-40
11948352
Eur J Neurosci. 2000 Sep;12(9):3079-86
10998091
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3513-8
11248109
Eur J Neurosci. 1999 May;11(5):1723-40
10215926
Exp Brain Res. 1990;81(1):25-34
2394228
Neuroreport. 1992 Dec;3(12):1045-8
1493215
Brain Res. 2000 Jan 31;854(1-2):70-8
10784108
J Neurol. 1994 Dec;242(1 Suppl 1):S36-9
7699407
Brain Pathol. 1995 Oct;5(4):407-13
8974623
Adv Neurol. 1997;72:305-15
8993707
Annu Rev Neurosci. 1984;7:279-308
6370080
Prog Brain Res. 2002;137:257-73
12440372
N Engl J Med. 1999 Sep 23;341(13):988-92
10498497
Exp Brain Res. 1991;84(3):561-8
1864327
Exp Brain Res. 1988;73(2):343-53
3215310
J Neurotrauma. 2001 Aug;18(8):743-56
11526981