title: Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model.
abstract: BACKGROUND
  Traumatic spinal cord injury (SCI) results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns) were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+) and CD24(-/lo) population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.
  
  
  RESULTS
  hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.
  
  
  CONCLUSIONS
  The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.
authors.affiliation: Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Desirée L
authors.initials: DL
authors.lastname: Salazar
authors.forename: Nobuko
authors.initials: N
authors.lastname: Uchida
authors.forename: Frank P T
authors.initials: FP
authors.lastname: Hamers
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Cummings
authors.forename: Aileen J
authors.initials: AJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology*; D002454:Cell Differentiation; D002465:Cell Movement; D002470:Cell Survival; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008124:Locomotion / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors
references.citation: J Neurotrauma. 2006 Mar-Apr;23(3-4):371-83
references.pmid: 16629623
references.citation: J Neurosci Res. 2009 Feb;87(2):307-17
references.pmid: 18972448
references.citation: Diabetes. 1992 Jan;41(1):98-106
references.pmid: 1727742
references.citation: Brain Res Bull. 1989 Jan;22(1):47-52
references.pmid: 2540887
references.citation: Exp Neurol. 2004 Jul;188(1):33-42
references.pmid: 15191800
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2199-204
references.pmid: 11854516
references.citation: Glia. 2007 May;55(7):698-711
references.pmid: 17330874
references.citation: Cell Transplant. 2005;14(4):225-40
references.pmid: 15929557
references.citation: Nat Rev Neurosci. 2003 Dec;4(12):968-80
references.pmid: 14682359
references.citation: J Neurosci Res. 2006 Aug 15;84(3):471-82
references.pmid: 16721767
references.citation: J Neurosci. 2003 Oct 15;23(28):9428-34
references.pmid: 14561871
references.citation: Exp Neurol. 2003 Aug;182(2):247-60
references.pmid: 12895437
references.citation: J Neurotrauma. 2007 Apr;24(4):674-89
references.pmid: 17439350
references.citation: J Neurosci. 2005 May 11;25(19):4694-705
references.pmid: 15888645
references.citation: Exp Neurol. 1997 Dec;148(2):495-501
references.pmid: 9417828
references.citation: Exp Neurol. 2006 Oct;201(2):335-48
references.pmid: 16839548
references.citation: Exp Neurol. 2005 Apr;192(2):384-93
references.pmid: 15755556
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14069-74
references.pmid: 16172374
references.citation: Stem Cells. 1998;16(3):166-77
references.pmid: 9617892
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14720-5
references.pmid: 11121071
references.citation: Exp Neurol. 2002 Oct;177(2):349-59
references.pmid: 12429182
references.citation: J Spinal Cord Med. 1999 Summer;22(2):119-24
references.pmid: 10826269
references.citation: Brain Res Bull. 1999 Aug;49(6):377-91
references.pmid: 10483914
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3024-9
references.pmid: 11867737
references.citation: J Neurosci. 2008 Apr 9;28(15):3887-96
references.pmid: 18400887
references.citation: J Neurosci. 1999 Jun 1;19(11):4370-87
references.pmid: 10341240
references.citation: Brain. 2002 Jan;125(Pt 1):14-21
references.pmid: 11834589
references.citation: Neuroscience. 1997 Mar;77(2):553-62
references.pmid: 9472411
references.citation: Nat Biotechnol. 2009 Aug;27(8):743-5
references.pmid: 19590502
references.citation: J Neurosci. 1999 Oct 1;19(19):8182-98
references.pmid: 10493720
references.citation: J Neurosci Res. 2007 Jan;85(1):47-57
references.pmid: 17075895
references.citation: Exp Neurol. 2007 Aug;206(2):257-68
references.pmid: 17585905
references.citation: Gene Ther. 2002 Feb;9(4):245-55
references.pmid: 11896463
references.citation: Brain. 2010 Feb;133(Pt 2):433-47
references.pmid: 20085927
references.citation: J Neurosci. 2001 Dec 1;21(23):9334-44
references.pmid: 11717367
references.citation: Neurol Res. 2006 Jul;28(5):474-81
references.pmid: 16808875
references.citation: J Neurosci Methods. 1994 Jul;53(1):55-63
references.pmid: 7990513
references.citation: Mol Cell Neurosci. 2004 Nov;27(3):322-31
references.pmid: 15519246
references.citation: Neurochem Int. 2007 Jul-Sep;51(2-4):68-73
references.pmid: 17544171
references.citation: Surg Neurol. 2001 May;55(5):249-54; discussion 254-5
references.pmid: 11516457
references.citation: Spinal Cord. 2007 Mar;45(3):190-205
references.pmid: 17179973
references.citation: J Neurosci. 2006 Mar 29;26(13):3377-89
references.pmid: 16571744
references.citation: Brain. 2000 Aug;123 ( Pt 8):1543-4
references.pmid: 10908185
references.citation: J Neurosci. 2008 Dec 17;28(51):13876-88
references.pmid: 19091977
references.citation: Brain. 2006 Dec;129(Pt 12):3249-69
references.pmid: 17071951
references.citation: Brain Pathol. 2006 Apr;16(2):99-109
references.pmid: 16768749
references.citation: Exp Neurol. 2004 Dec;190(2):289-310
references.pmid: 15530870
references.citation: Exp Neurol. 2003 Nov;184(1):97-113
references.pmid: 14637084
references.citation: J Neurotrauma. 2003 Jan;20(1):1-16
references.pmid: 12614584
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):146-56
references.pmid: 14735117
references.citation: Diabetes. 1995 Dec;44(12):1392-8
references.pmid: 7589844
references.citation: Brain Res. 2000 Aug 25;874(2):87-106
references.pmid: 10960593
references.citation: Exp Neurol. 2003 Jun;181(2):115-29
references.pmid: 12781986
references.citation: PLoS One. 2009 Jun 11;4(6):e5871
references.pmid: 19517014
references.citation: J Neurosci Res. 2006 Dec;84(8):1669-81
references.pmid: 17044031
references.citation: Exp Neurol. 2007 Aug;206(2):296-307
references.pmid: 17599835
references.citation: J Neurotrauma. 2010 Feb;27(2):411-21
references.pmid: 19831737
references.citation: Nature. 1997 Dec 18-25;390(6661):680-3
references.pmid: 9414159
references.citation: Exp Neurol. 2006 Oct;201(2):281-92
references.pmid: 16904107
references.citation: J Neurotrauma. 2005 Jan;22(1):157-71
references.pmid: 15665610
references.citation: Eur J Neurosci. 2004 Feb;19(3):577-89
references.pmid: 14984408
references.citation: PLoS Med. 2007 Feb;4(2):e39
references.pmid: 17298165
references.citation: J Neurotrauma. 2006 May;23(5):635-59
references.pmid: 16689667
references.citation: Eur J Neurosci. 2003 Aug;18(4):743-51
references.pmid: 12925000
references.citation: J Neurotrauma. 2004 Apr;21(4):429-40
references.pmid: 15115592
references.citation: Eur J Neurosci. 2004 Nov;20(9):2401-14
references.pmid: 15525281
references.citation: Nat Neurosci. 2005 Mar;8(3):346-53
references.pmid: 15711542
references.citation: J Neurosci. 2005 Nov 2;25(44):10064-73
references.pmid: 16267213
references.citation: J Neurotrauma. 2007 May;24(5):835-45
references.pmid: 17518538
references.citation: Neurosurgery. 2005 Nov;57(5):1014-25; discussion 1014-25
references.pmid: 16284571
references.citation: Cell Transplant. 2008;17(7):735-51
references.pmid: 19044201
references.citation: Neurosurgery. 2005;56(1):163-71; discussion 171
references.pmid: 15617599
references.citation: J Neurotrauma. 2001 Feb;18(2):187-201
references.pmid: 11229711
references.citation: Eur J Neurosci. 2007 Apr;25(7):1931-9
references.pmid: 17439482
references.citation: Exp Neurol. 2002 Dec;178(2):150-64
references.pmid: 12504875
references.citation: Spine J. 2004 Jan-Feb;4(1):16-26
references.pmid: 14749190
references.citation: Exp Neurol. 2004 Oct;189(2):231-40
references.pmid: 15380475
references.citation: Semin Cell Dev Biol. 2003 Jun;14(3):191-8
references.pmid: 12948354
references.citation: Exp Neurol. 2001 Jan;167(1):48-58
references.pmid: 11161592