title: Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain.
abstract: Stem cell transplantation promises new hope for the treatment of stroke although significant questions remain about how the grafted cells elicit their effects. One hypothesis is that transplanted stem cells enhance endogenous repair mechanisms activated after cerebral ischaemia. Recognizing that bilateral reorganization of surviving circuits is associated with recovery after stroke, we investigated the ability of transplanted human neural progenitor cells to enhance this structural plasticity. Our results show the first evidence that human neural progenitor cell treatment can significantly increase dendritic plasticity in both the ipsi- and contralesional cortex and this coincides with stem cell-induced functional recovery. Moreover, stem cell-grafted rats demonstrated increased corticocortical, corticostriatal, corticothalamic and corticospinal axonal rewiring from the contralesional side; with the transcallosal and corticospinal axonal sprouting correlating with functional recovery. Furthermore, we demonstrate that axonal transport, which is critical for both proper axonal function and axonal sprouting, is inhibited by stroke and that this is rescued by the stem cell treatment, thus identifying another novel potential mechanism of action of transplanted cells. Finally, we established in vitro co-culture assays in which these stem cells mimicked the effects observed in vivo. Through immunodepletion studies, we identified vascular endothelial growth factor, thrombospondins 1 and 2, and slit as mediators partially responsible for stem cell-induced effects on dendritic sprouting, axonal plasticity and axonal transport in vitro. Thus, we postulate that human neural progenitor cells aid recovery after stroke through secretion of factors that enhance brain repair and plasticity.
authors: Department of Neurosurgery, Stanford Stroke Centre, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305-5487, USA.
authors: Robert H
authors: RH
authors: Andres
authors: Nobutaka
authors: N
authors: Horie
authors: William
authors: W
authors: Slikker
authors: Hadar
authors: H
authors: Keren-Gill
authors: Ke
authors: K
authors: Zhan
authors: Guohua
authors: G
authors: Sun
authors: Nathan C
authors: NC
authors: Manley
authors: Marta P
authors: MP
authors: Pereira
authors: Lamiya A
authors: LA
authors: Sheikh
authors: Erin L
authors: EL
authors: McMillan
authors: Bruce T
authors: BT
authors: Schaar
authors: Clive N
authors: CN
authors: Svendsen
authors: Tonya M
authors: TM
authors: Bliss
authors: Gary K
authors: GK
authors: Steinberg
references: J Trauma. 1997 Apr;42(4):659-64
references: 9137254
references: Neuroscience. 2003;122(2):563-71
references: 14614920
references: Stroke. 1997 Jun;28(6):1225-31; discussion 1231-2
references: 9183356
references: Stem Cells. 2011 Feb;29(2):274-85
references: 21732485
references: Brain Res. 2000 Jul 21;871(2):288-302
references: 10899295
references: J Neurosurg. 2005 Jul;103(1):38-45
references: 16121971
references: Nat Rev Neurosci. 2008 Mar;9(3):206-21
references: 18270515
references: J Neurochem. 2003 Jul;86(1):179-95
references: 12807438
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):9031-6
references: 12084941
references: J Neurosci. 2009 Aug 12;29(32):10081-6
references: 19675241
references: Neurobiol Dis. 2001 Oct;8(5):910-22
references: 11592858
references: Brain Res. 2002 Jan 4;924(1):63-70
references: 11743996
references: J Neurosci Methods. 1998 Dec 1;85(2):141-52
references: 9874150
references: Neuroscience. 2007 Apr 25;146(1):31-40
references: 17320299
references: PLoS One. 2008 Jun 25;3(6):e2470
references: 18575624
references: Nat Rev Neurosci. 2005 Nov;6(11):889-98
references: 16224497
references: Neuropharmacology. 2000 Mar 3;39(5):777-87
references: 10699444
references: Ann Neurol. 2005 Jun;57(6):874-82
references: 15929052
references: Nat Neurosci. 2005 Jan;8(1):85-92
references: 15568021
references: Stroke. 1986 May-Jun;17(3):472-6
references: 3715945
references: Exp Neurol. 2005 Jun;193(2):291-311
references: 15869933
references: Eur J Neurosci. 2003 Oct;18(7):1950-62
references: 14622227
references: Brain Res. 1992 May 22;581(1):156-60
references: 1498666
references: J Comp Neurol. 1991 Apr 8;306(2):307-19
references: 1711057
references: J Clin Invest. 2004 Aug;114(3):330-8
references: 15286799
references: Ann Neurol. 1999 Jun;45(6):778-86
references: 10360770
references: J Neurochem. 2005 Oct;95(1):33-45
references: 16045451
references: Neuron. 2005 Apr 21;46(2):173-9
references: 15848797
references: Neurobiol Dis. 2010 Feb;37(2):259-66
references: 19931616
references: Stroke. 1989 Sep;20(9):1226-35
references: 2475923
references: Stroke. 2007 Oct;38(10):2833-40
references: 17717315
references: Stem Cells Dev. 2005 Dec;14(6):722-33
references: 16433627
references: J Neurosci. 2003 Jan 15;23(2):510-7
references: 12533611
references: J Neurosci. 1994 Apr;14(4):2140-52
references: 8158262
references: Neuron. 2001 Nov 8;32(3):389-401
references: 11709151
references: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14638-43
references: 18794523
references: Stroke. 2003 Jan;34(1):177-86
references: 12511771
references: J Neurosci. 2002 Sep 1;22(17):7471-7
references: 12196569
references: J Neurosci. 2007 Jul 4;27(27):7208-21
references: 17611274
references: J Neurosci. 1995 Jul;15(7 Pt 2):5372-8
references: 7623159
references: Nat Rev Neurosci. 2009 Dec;10(12):861-72
references: 19888284
references: J Cereb Blood Flow Metab. 2000 May;20(5):765-71
references: 10826526
references: Nat Neurosci. 2007 Feb;10(2):206-14
references: 17206140
references: Stroke. 2011 Mar;42(3):740-4
references: 21307396
references: Stroke. 2010 Mar;41(3):516-23
references: 20075340
references: Neuroscientist. 2006 Dec;12(6):489-99
references: 17079515
references: Eur J Neurosci. 2009 Feb;29(3):562-74
references: 19175403
references: Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11839-44
references: 15280535
references: Cerebrovasc Dis. 2005;20(2):101-7
references: 15976503
references: Nat Methods. 2005 Aug;2(8):599-605
references: 16094385
references: J Cereb Blood Flow Metab. 2008 Oct;28(10):1722-32
references: 18594557
references: Dev Biol. 1992 Apr;150(2):256-65
references: 1551474
references: J Cereb Blood Flow Metab. 2011 Jan;31(1):235-42
references: 20531461
references: Stroke. 2008 Sep;39(9):2571-7
references: 18617661
references: J Neurosci. 2001 Jul 15;21(14):5272-80
references: 11438602
references: Stem Cells. 2006 Nov;24(11):2504-13
references: 16840550
references: J Anat. 1968 Mar;102(Pt 3):363-74
references: 5656134
references: Stroke. 2008 Apr;39(4):1380-8
references: 18309162
references: J Neurosci Res. 2008 Mar;86(4):873-82
references: 17975825
references: Stroke. 2001 Nov;32(11):2682-8
references: 11692034
references: Nat Neurosci. 2010 Dec;13(12):1496-504
references: 21057507
references: Nat Rev Drug Discov. 2004 May;3(5):391-400
references: 15136787
references: Nat Med. 2002 Sep;8(9):963-70
references: 12161747
references: Neuron. 2006 Jul 6;51(1):29-42
references: 16815330
references: J Neurosci. 2003 Dec 3;23(35):11036-44
references: 14657160
references: Proc Natl Acad Sci U S A. 1990 Feb;87(4):1561-5
references: 1689489
references: Circ Res. 2003 Apr 4;92(6):692-9
references: 12609969
references: Neurobiol Dis. 2010 Feb;37(2):275-83
references: 19822211