title: An in vivo characterization of trophic factor production following neural precursor cell or bone marrow stromal cell transplantation for spinal cord injury.
abstract: Cellular transplantation strategies for repairing the injured spinal cord have shown consistent benefit in preclinical models, and human clinical trials have begun. Interactions between transplanted cells and host tissue remain poorly understood. Trophic factor secretion is postulated a primary or supplementary mechanism of action for many transplanted cells, however, there is little direct evidence to support trophin production by transplanted cells in situ. In the present study, trophic factor expression was characterized in uninjured, injured-untreated, injured-treated with transplanted cells, and corresponding control tissue from the adult rat spinal cord. Candidate trophic factors were identified in a literature search, and primers were designed for these genes. We examined in vivo trophin expression in 3 paradigms involving transplantation of either brain or spinal cord-derived neural precursor cells (NPCs) or bone marrow stromal cells (BMSCs). Injury without further treatment led to a significant elevation of nerve growth factor (NGF), leukemia inhibitory factor (LIF), insulin-like growth factor-1 (IGF-1), and transforming growth factor-β1 (TGF-β1), and lower expression of vascular endothelial growth factor isoform A (VEGF-A) and platelet-derived growth factor-A (PDGF-A). Transplantation of NPCs led to modest changes in trophin expression, and the co-administration of intrathecal trophins resulted in significant elevation of the neurotrophins, glial-derived neurotrophic factor (GDNF), LIF, and basic fibroblast growth factor (bFGF). BMSCs transplantation upregulated NGF, LIF, and IGF-1. NPCs isolated after transplantation into the injured spinal cord expressed the neurotrophins, ciliary neurotrophic factor (CNTF), epidermal growth factor (EGF), and bFGF at higher levels than host cord. These data show that trophin expression in the spinal cord is influenced by injury and cell transplantation, particularly when combined with intrathecal trophin infusion. Trophins may contribute to the benefits associated with cell-based repair strategies for spinal cord injury.
authors.affiliation: Division of Genetics and Development, Krembil Neuroscience Center, Toronto Western Research Institute, University Health Network, Toronto, Canada.
authors.forename: Gregory W J
authors.initials: GW
authors.lastname: Hawryluk
authors.forename: Andrea
authors.initials: A
authors.lastname: Mothe
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Shelly
authors.initials: S
authors.lastname: Wang
authors.forename: Charles
authors.initials: C
authors.lastname: Tator
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D002574:Cervical Vertebrae / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000628:therapy*; D013904:Thoracic Vertebrae / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D009414:Nerve Growth Factors; D042461:Vascular Endothelial Growth Factor A; C485184:enhanced green fluorescent protein; C467498:vascular endothelial growth factor A, rat; D049452:Green Fluorescent Proteins
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8774-9
references.pmid: 15161978
references.citation: J Comp Neurol. 2004 Nov 29;480(1):101-14
references.pmid: 15514921
references.citation: J Neurosci Res. 2004 Sep 1;77(5):662-9
references.pmid: 15352212
references.citation: Exp Neurol. 2001 Jun;169(2):407-15
references.pmid: 11358454
references.citation: Cell Transplant. 2006;15(8-9):675-87
references.pmid: 17269439
references.citation: Neurosci Lett. 1995 Nov 10;200(1):45-8
references.pmid: 8584263
references.citation: Neurosci Lett. 2006 Dec 27;410(3):222-7
references.pmid: 17055159
references.citation: Exp Neurol. 2004 Nov;190(1):17-31
references.pmid: 15473977
references.citation: Exp Neurol. 1997 Apr;144(2):273-86
references.pmid: 9168829
references.citation: Exp Neurol. 2003 Nov;184(1):313-25
references.pmid: 14637102
references.citation: Brain Res. 2005 Aug 9;1052(2):147-55
references.pmid: 16005441
references.citation: J Chem Neuroanat. 2008 Dec;36(3-4):138-43
references.pmid: 18692128
references.citation: Exp Neurol. 1997 Jun;145(2 Pt 1):592-6
references.pmid: 9217096
references.citation: J Neurosci. 2001 May 15;21(10):3457-75
references.pmid: 11331375
references.citation: J Neurosci Methods. 2010 Aug 30;191(2):201-7
references.pmid: 20600315
references.citation: Exp Neurol. 1996 Oct;141(2):225-39
references.pmid: 8812156
references.citation: Brain Res. 1988 Sep 20;460(2):253-9
references.pmid: 3224261
references.citation: Stem Cells. 2007 Aug;25(8):2066-73
references.pmid: 17464087
references.citation: J Neurosci Res. 2002 Jun 15;68(6):647-54
references.pmid: 12111826
references.citation: Glia. 1994 Oct;12(2):87-98
references.pmid: 7532622
references.citation: Nature. 1992 Dec 24-31;360(6406):753-5
references.pmid: 1281520
references.citation: Biochem Biophys Res Commun. 2001 Aug 31;286(4):779-85
references.pmid: 11520065
references.citation: J Comp Neurol. 2004 Aug 2;475(4):590-603
references.pmid: 15236239
references.citation: J Neuropathol Exp Neurol. 2005 Jan;64(1):37-45
references.pmid: 15715083
references.citation: Neurosci Lett. 1996 Jan 19;203(2):97-100
references.pmid: 8834102
references.citation: J Cereb Blood Flow Metab. 1993 May;13(3):521-5
references.pmid: 8097519
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3024-9
references.pmid: 11867737
references.citation: Spinal Cord. 2011 Sep;49(9):967-73
references.pmid: 21606931
references.citation: J Neurosci Res. 2008 May 15;86(7):1538-47
references.pmid: 18214991
references.citation: Acta Neuropathol. 2003 Jul;106(1):29-36
references.pmid: 12774239
references.citation: J Neurosci. 2000 May 15;20(10):RC77
references.pmid: 10783401
references.citation: J Neuropathol Exp Neurol. 2006 Sep;65(9):914-29
references.pmid: 16957585
references.citation: Nature. 2000 Jan 20;403(6767):312-6
references.pmid: 10659850
references.citation: Stem Cells Dev. 2012 Feb 10;21(3):432-47
references.pmid: 22013972
references.citation: J Neurosci Res. 2003 Nov 15;74(4):552-61
references.pmid: 14598299
references.citation: Mol Med. 1995 Nov;1(7):732-43
references.pmid: 8612196
references.citation: J Neurotrauma. 2011 Aug;28(8):1611-82
references.pmid: 20146557
references.citation: Science. 1982 Aug 27;217(4562):860-1
references.pmid: 7100931
references.citation: Microsc Res Tech. 2001 Sep 1;54(5):317-24
references.pmid: 11514988
references.citation: Eur J Neurosci. 1996 Jun;8(6):1167-75
references.pmid: 8752586
references.citation: J Neurosci Res. 1999 Apr 1;56(1):1-7
references.pmid: 10213469
references.citation: Eur J Neurosci. 1990 Jan;2(1):69-76
references.pmid: 12106104
references.citation: J Cell Biol. 1990 Oct;111(4):1701-11
references.pmid: 2211833
references.citation: J Neurosci Res. 2005 Aug 15;81(4):457-68
references.pmid: 15968644
references.citation: Curr Biol. 1996 Jun 1;6(6):686-94
references.pmid: 8793295
references.citation: Nat Biotechnol. 2010 Oct;28(10):989-90
references.pmid: 20944564
references.citation: Neurosci Lett. 1998 Jun 12;249(1):1-4
references.pmid: 9672374
references.citation: Neuroreport. 2003 Jan 20;14(1):39-42
references.pmid: 12544827
references.citation: Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1113-29
references.pmid: 16633897
references.citation: Neurosci Lett. 2008 Aug 29;441(3):261-6
references.pmid: 18585435
references.citation: J Comp Neurol. 1994 Apr 1;342(1):45-56
references.pmid: 7515907
references.citation: Science. 2002 Nov 8;298(5596):1184-6
references.pmid: 12424359
references.citation: J Neurotrauma. 2000 Mar;17(3):203-18
references.pmid: 10757326
references.citation: Neurosci Lett. 2006 Jul 10;402(1-2):51-6
references.pmid: 16713677
references.citation: J Neurotrauma. 2006 Mar-Apr;23(3-4):438-52
references.pmid: 16629628
references.citation: Eur J Neurosci. 1998 Feb;10(2):798-802
references.pmid: 9749747
references.citation: J Neurotrauma. 2006 Mar-Apr;23(3-4):479-95
references.pmid: 16629631
references.citation: J Neurosci. 2006 Mar 29;26(13):3377-89
references.pmid: 16571744
references.citation: Exp Neurol. 2008 Sep;213(1):176-90
references.pmid: 18586031
references.citation: Exp Neurol. 2004 Jul;188(1):115-27
references.pmid: 15191808
references.citation: J Thorac Cardiovasc Surg. 2001 Jul;122(1):136-43
references.pmid: 11436046
references.citation: Neuropeptides. 2007 Jun;41(3):135-43
references.pmid: 17459471
references.citation: Glia. 2005 Mar;49(4):555-66
references.pmid: 15578728
references.citation: J Neurosci. 1995 Feb;15(2):1044-56
references.pmid: 7869082
references.citation: Brain Res. 2005 Feb 21;1035(1):73-85
references.pmid: 15713279
references.citation: Cell Transplant. 1996 Mar-Apr;5(2):191-204
references.pmid: 8689031
references.citation: J Neurosci Res. 2003 Sep 15;73(6):778-86
references.pmid: 12949903
references.citation: J Neurosurg Spine. 2008 Dec;9(6):600-10
references.pmid: 19035756
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14661-8
references.pmid: 11717413
references.citation: J Neurosci Res. 1995 Feb 15;40(3):306-17
references.pmid: 7745624
references.citation: Ann N Y Acad Sci. 2005 May;1049:146-60
references.pmid: 15965114
references.citation: Surg Neurol. 1978 Jul;10(1):38-43
references.pmid: 684604
references.citation: J Neurosci. 1997 Jul 15;17(14):5560-72
references.pmid: 9204937
references.citation: Exp Neurol. 2006 Mar;198(1):54-64
references.pmid: 16336965
references.citation: Glia. 2005 Jul;51(1):73-9
references.pmid: 15779090
references.citation: Cytotherapy. 2006;8(4):315-7
references.pmid: 16923606
references.citation: J Neurosci Res. 2003 May 1;72(3):343-51
references.pmid: 12692901
references.citation: Exp Neurol. 2004 Aug;188(2):391-407
references.pmid: 15246839
references.citation: Brain Res Mol Brain Res. 1994 Mar;22(1-4):1-8
references.pmid: 8015371
references.citation: Exp Neurol. 2003 Jun;181(2):115-29
references.pmid: 12781986
references.citation: Curr Opin Biotechnol. 2009 Oct;20(5):552-62
references.pmid: 19836942
references.citation: Eur J Neurosci. 1997 Jul;9(7):1422-38
references.pmid: 9240400
references.citation: Brain Res. 2004 Jul 9;1013(2):174-81
references.pmid: 15193526
references.citation: Science. 1993 May 21;260(5111):1130-2
references.pmid: 8493557
references.citation: Nat Neurosci. 2006 Nov;9(11):1371-81
references.pmid: 17057708
references.citation: Exp Neurol. 2009 Jan;215(1):53-9
references.pmid: 18938163
references.citation: J Neurosci. 1998 Sep 15;18(18):7351-60
references.pmid: 9736655
references.citation: Exp Neurol. 1993 Oct;123(2):295-302
references.pmid: 8405292
references.citation: Nat Med. 2004 Jun;10(6):610-6
references.pmid: 15156204
references.citation: J Cell Biochem. 1991 Apr;45(4):319-26
references.pmid: 2045423
references.citation: J Neurotrauma. 2006 Aug;23(8):1254-60
references.pmid: 16928183
references.citation: Exp Neurol. 2004 Jun;187(2):266-78
references.pmid: 15144853
references.citation: Prog Brain Res. 2009;175:125-37
references.pmid: 19660652
references.citation: Stem Cells. 2010 Sep;28(9):1541-9
references.pmid: 20665739
references.citation: Stem Cells. 2006 Mar;24(3):748-62
references.pmid: 16166253
references.citation: Neuron. 2002 Oct 24;36(3):375-86
references.pmid: 12408842
references.citation: Stem Cells. 2010 Jan;28(1):152-63
references.pmid: 19877167
references.citation: J Neurotrauma. 2006 Jan;23(1):55-65
references.pmid: 16430372
references.citation: J Neurotrauma. 1995 Oct;12(5):853-70
references.pmid: 8594213
references.citation: Nat Neurosci. 2000 Jun;3(6):537-44
references.pmid: 10816308
references.citation: J Neurosci. 1999 May 1;19(9):3556-66
references.pmid: 10212315
references.citation: Neuroscience. 2008 Aug 26;155(3):760-70
references.pmid: 18588947
references.citation: Exp Neurol. 2003 Dec;184(2):912-22
references.pmid: 14769383
references.citation: Glia. 2001 Oct;36(1):48-57
references.pmid: 11571783
references.citation: Eur J Neurosci. 1996 Feb;8(2):291-9
references.pmid: 8714700
references.citation: Development. 1994 Jan;120(1):143-53
references.pmid: 8119123
references.citation: Neurobiol Dis. 2010 Feb;37(2):384-93
references.pmid: 19879362
references.citation: Methods Mol Biol. 1997;75:249-56
references.pmid: 9276274
references.citation: Neurobiol Dis. 2000 Dec;7(6 Pt B):574-85
references.pmid: 11114257
references.citation: J Neurosci. 1997 Dec 15;17(24):9583-95
references.pmid: 9391013
references.citation: Exp Neurol. 2005 Feb;191(2):344-60
references.pmid: 15649491
references.citation: J Neurotrauma. 2000 Dec;17(12):1219-31
references.pmid: 11186234
references.citation: J Neuropathol Exp Neurol. 2004 Jan;63(1):64-72
references.pmid: 14748562
references.citation: Neurobiol Dis. 2003 Jul;13(2):89-101
references.pmid: 12828933
references.citation: J Neurobiol. 1998 Sep 15;36(4):509-24
references.pmid: 9740023
references.citation: Acta Neuropathol. 2001 Sep;102(3):239-45
references.pmid: 11585248
references.citation: Spine J. 2004 Jan-Feb;4(1):16-26
references.pmid: 14749190
references.citation: Neuroreport. 2000 Sep 11;11(13):3001-5
references.pmid: 11006983
references.citation: PLoS One. 2010 Jul 29;5(7):e11852
references.pmid: 20686613
references.citation: Cell Stem Cell. 2008 Sep 11;3(3):230-2
references.pmid: 18786407
references.citation: J Neurosci Res. 1993 Dec 15;36(6):663-71
references.pmid: 8145295
references.citation: J Neurotrauma. 2002 Jun;19(6):777-85
references.pmid: 12165137
references.citation: Front Biosci. 2003 Sep 01;8:s1181-6
references.pmid: 12957860
references.citation: Prog Neurobiol. 1997 Jan;51(1):19-37
references.pmid: 9044427
references.citation: Stem Cells. 2011 Feb;29(2):169-78
references.pmid: 21732476
references.citation: J Neurotrauma. 2009 Dec;26(12):2313-22
references.pmid: 19645530
references.citation: Exp Neurol. 1998 Jul;152(1):74-87
references.pmid: 9682014
references.citation: Bone Marrow Transplant. 2007 Oct;40(7):609-19
references.pmid: 17603514