title: Localized delivery of brain-derived neurotrophic factor-expressing mesenchymal stem cells enhances functional recovery following cervical spinal cord injury.
abstract: Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are important in modulating neuroplasticity and promoting recovery after spinal cord injury. Intrathecal delivery of BDNF enhances functional recovery following unilateral spinal cord hemisection (SH) at C2, a well-established model of incomplete cervical spinal cord injury. We hypothesized that localized delivery of BDNF-expressing mesenchymal stem cells (BDNF-MSCs) would promote functional recovery of rhythmic diaphragm activity after SH. In adult rats, bilateral diaphragm electromyographic (EMG) activity was chronically monitored to determine evidence of complete SH at 3 days post-injury, and recovery of rhythmic ipsilateral diaphragm EMG activity over time post-SH. Wild-type, bone marrow-derived MSCs (WT-MSCs) or BDNF-MSCs (2×10(5) cells) were injected intraspinally at C2 at the time of injury. At 14 days post-SH, green fluorescent protein (GFP) immunoreactivity confirmed MSCs presence in the cervical spinal cord. Functional recovery in SH animals injected with WT-MSCs was not different from untreated SH controls (n=10; overall, 20% at 7 days and 30% at 14 days). In contrast, functional recovery was observed in 29% and 100% of SH animals injected with BDNF-MSCs at 7 days and 14 days post-SH, respectively (n=7). In BDNF-MSCs treated SH animals at 14 days, root-mean-squared EMG amplitude was 63±16% of the pre-SH value compared with 12±9% in the control/WT-MSCs group. We conclude that localized delivery of BDNF-expressing MSCs enhances functional recovery of diaphragm muscle activity following cervical spinal cord injury. MSCs can be used to facilitate localized delivery of trophic factors such as BDNF in order to promote neuroplasticity following spinal cord injury.
authors.affiliation: 1 Department of Physiology and Biomedical Engineering, Mayo Clinic , Rochester, Minnesota.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Gransee
authors.forename: Wen-Zhi
authors.initials: WZ
authors.lastname: Zhan
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Mantilla
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage*; D002574:Cervical Vertebrae; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D018613:Microscopy, Confocal; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000473:pathology*; D014161:Transduction, Genetic
chemical_list: D019208:Brain-Derived Neurotrophic Factor
keywords: diaphragm muscle; neuroplasticity; neurotrophin; respiration; spinal hemisection
references.citation: Science. 1995 Mar 17;267(5204):1658-62
references.pmid: 7886457
references.citation: J Neurosci. 2012 Jun 13;32(24):8208-18
references.pmid: 22699902
references.citation: Pain. 2002 Nov;100(1-2):171-81
references.pmid: 12435470
references.citation: Neuroreport. 2000 Sep 11;11(13):3001-5
references.pmid: 11006983
references.citation: J Neurochem. 2005 May;93(3):584-94
references.pmid: 15836617
references.citation: Cytotherapy. 2010 May;12(3):313-25
references.pmid: 20370348
references.citation: Exp Neurol. 2004 Nov;190(1):17-31
references.pmid: 15473977
references.citation: Respir Physiol Neurobiol. 2010 Aug 31;173(1):101-6
references.pmid: 20620243
references.citation: Arch Phys Med Rehabil. 2000 Jun;81(6):757-63
references.pmid: 10857520
references.citation: J Neurosci. 2001 May 15;21(10):3457-75
references.pmid: 11331375
references.citation: J Neurosci. 2009 Nov 25;29(47):14932-41
references.pmid: 19940189
references.citation: Muscle Nerve. 2004 Mar;29(3):381-6
references.pmid: 14981737
references.citation: Regen Med. 2010 Nov;5(6):933-46
references.pmid: 21082892
references.citation: Exp Neurol. 2013 Sep;247:101-9
references.pmid: 23583688
references.citation: J Neurotrauma. 2006 Jul;23(7):1137-46
references.pmid: 16866626
references.citation: Prog Brain Res. 2014;209:309-29
references.pmid: 24746055
references.citation: Exp Neurol. 1997 Jan;143(1):70-81
references.pmid: 9000447
references.citation: Conf Proc IEEE Eng Med Biol Soc. 2006;2006:1204-7
references.pmid: 17946030
references.citation: J Neurotrauma. 2011 Sep;28(9):1951-61
references.pmid: 20822464
references.citation: Neurosci Lett. 2006 May 1;398(1-2):129-34
references.pmid: 16423458
references.citation: Respir Care. 2006 Aug;51(8):853-68;discussion 869-70
references.pmid: 16867197
references.citation: Tissue Eng Part A. 2009 Oct;15(10):3049-59
references.pmid: 19335061
references.citation: Cell. 2006 Aug 25;126(4):663-76
references.pmid: 16904174
references.citation: Biochimie. 2013 Dec;95(12):2257-70
references.pmid: 23994163
references.citation: Respir Physiol Neurobiol. 2011 Jul 31;177(2):176-82
references.pmid: 21414423
references.citation: Cell Transplant. 2005;14(10):775-86
references.pmid: 16454352
references.citation: Exp Neurol. 2012 Dec;238(2):254-64
references.pmid: 22982152
references.citation: J Appl Physiol (1985). 2013 Feb;114(3):380-6
references.pmid: 23195635
references.citation: J Neurotrauma. 2004 Mar;21(3):329-37
references.pmid: 15115607
references.citation: J Appl Physiol (1985). 1995 Nov;79(5):1640-9
references.pmid: 8594024
references.citation: Brain Res. 2010 Nov 4;1359:33-43
references.pmid: 20732313
references.citation: Neuroscience. 2007 Apr 25;146(1):178-89
references.pmid: 17346898
references.citation: Exp Neurol. 1991 Jan;111(1):135-9
references.pmid: 1984430
references.citation: PLoS One. 2013 May 28;8(5):e64755
references.pmid: 23724091
references.citation: Exp Neurol. 2000 Oct;165(2):327-41
references.pmid: 10993692
references.citation: J Neurophysiol. 1988 Mar;59(3):1055-66
references.pmid: 3367195
references.citation: Neurosci Lett. 2006 Jul 10;402(1-2):51-6
references.pmid: 16713677
references.citation: Neurology. 1999 Apr 22;52(7):1427-33
references.pmid: 10227630
references.citation: Int J Mol Sci. 2014 Jun 25;15(7):11275-93
references.pmid: 24968269
references.citation: J Comp Neurol. 2010 Oct 15;518(20):4213-25
references.pmid: 20878784
references.citation: J Comp Neurol. 2000 Dec 25;428(4):671-80
references.pmid: 11077420
references.citation: Science. 2002 Aug 23;297(5585):1299
references.pmid: 12193778
references.citation: J Neurosurg Spine. 2008 Dec;9(6):600-10
references.pmid: 19035756
references.citation: Electroencephalogr Clin Neurophysiol. 1982 Apr;53(4):459-62
references.pmid: 6175508
references.citation: J Hematother Stem Cell Res. 2001 Feb;10(1):125-40
references.pmid: 11276366
references.citation: Mol Ther. 2004 Feb;9(2):189-97
references.pmid: 14759803
references.citation: Exp Neurol. 2006 Mar;198(1):54-64
references.pmid: 16336965
references.citation: Cytotherapy. 2006;8(4):315-7
references.pmid: 16923606
references.citation: Nature. 2005 Dec 15;438(7070):1017-21
references.pmid: 16355225
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Jun;1(3):201-6
references.pmid: 11464953
references.citation: J Neurosci Res. 2003 May 1;72(3):343-51
references.pmid: 12692901
references.citation: J Appl Physiol (1985). 2003 Feb;94(2):795-810
references.pmid: 12531916
references.citation: Exp Neurol. 1997 Dec;148(2):475-94
references.pmid: 9417827
references.citation: J Appl Physiol (1985). 1989 Jun;66(6):2539-45
references.pmid: 2745316
references.citation: J Appl Physiol (1985). 1997 Apr;82(4):1145-53
references.pmid: 9104851
references.citation: J Neurocytol. 1984 Feb;13(1):85-109
references.pmid: 6707715
references.citation: J Neurosci. 1998 Oct 15;18(20):8436-43
references.pmid: 9763486
references.citation: Neurology. 2002 Aug 27;59(4):514-23
references.pmid: 12196642
references.citation: Respir Physiol Neurobiol. 2011 Oct 15;179(1):57-63
references.pmid: 21763470
references.citation: Anat Embryol (Berl). 2000 Aug;202(2):159-77
references.pmid: 10985434
references.citation: J Appl Physiol (1985). 2001 Jun;90(6):2466-75
references.pmid: 11356815
references.citation: Muscle Nerve. 1999 Mar;22(3):307-19
references.pmid: 10086891
references.citation: Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11282-6
references.pmid: 1333605
references.citation: Brain Res. 2010 Jul 9;1343:226-35
references.pmid: 20470759
references.citation: J Appl Physiol (1985). 2000 Aug;89(2):563-72
references.pmid: 10926639
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12704-9
references.pmid: 20615974
references.citation: J Neurosci. 2003 Mar 15;23(6):2494-501
references.pmid: 12657710
references.citation: J Neurosci. 2005 Mar 16;25(11):2925-32
references.pmid: 15772352
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16825-30
references.pmid: 21949375
references.citation: J Neurotrauma. 2006 May;23(5):617-34
references.pmid: 16689666
references.citation: J Comp Neurol. 2002 Oct 21;452(3):255-63
references.pmid: 12353221
references.citation: J Neurosci Methods. 2009 Sep 15;182(2):244-9
references.pmid: 19559048
references.citation: Eur J Neurosci. 2012 Jan;35(2):221-32
references.pmid: 22211901
references.citation: Neurobiol Dis. 2000 Dec;7(6 Pt B):574-85
references.pmid: 11114257
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 Jun;6(2):100-3
references.pmid: 16036433
references.citation: Exp Neurol. 2005 Feb;191(2):344-60
references.pmid: 15649491
references.citation: J Neuropathol Exp Neurol. 2004 Jan;63(1):64-72
references.pmid: 14748562
references.citation: Exp Neurol. 2012 Mar;234(1):191-9
references.pmid: 22227062
references.citation: J Comp Neurol. 1990 Dec 22;302(4):707-14
references.pmid: 1707065
references.citation: Neuroscience. 2005;136(1):161-9
references.pmid: 16229956
references.citation: Stem Cells. 2012 Jun;30(6):1163-73
references.pmid: 22419556
references.citation: Annu Int Conf IEEE Eng Med Biol Soc. 2009;2009:404-7
references.pmid: 19965125
references.citation: Respir Physiol Neurobiol. 2009 Nov 30;169(2):218-25
references.pmid: 19703592
references.citation: Brain Res. 2007 May 7;1148:96-104
references.pmid: 17379194
references.citation: Bone Marrow Transplant. 2007 Oct;40(7):609-19
references.pmid: 17603514