Interactions between endothelial and neural stem cells are believed to play a critical role in the kinetics of neural stem cells in the central nervous system. Here we demonstrate that endothelial progenitor cells promote the repair of injured spinal cord through the induction of Notch-dependent astrogliosis and vascular regulation. The transplantation of Jagged1+/+ endothelial progenitor cells, but not Jagged1−/− endothelial progenitor cells, increased the number of reactive astrocytes during the acute phase, and improved functional recovery following spinal cord injury. Expression of the Notch effector Hes5 was upregulated in the injured spinal cord after Jagged1+/+ endothelial progenitor cell transplantation. Furthermore, we found that the Notch ligand Delta-like-1 was highly expressed in Jagged1−/− endothelial progenitor cells. Transplantation of Delta-like-1, as well as Jagged1-overexpressing 3T3 cells, revealed that only Jagged1-overexpressing 3T3 stromal cells enhanced astrogliosis following spinal cord injury. In addition, Jagged1+/+ endothelial progenitor cells exhibited not only dramatic pro-angiogenic effects, but also morphologically abnormal vessel stabilization, compared with Jagged1−/−endothelial progenitor cells in injured spinal cord. Thus, transplanted endothelial progenitor cells promote astrogliosis, vascular regulation, and spinal cord regeneration through activation of Jagged1-Notch signaling.
Get full access to this article
View all access options for this article.
References
1.
AsaharaT., MuroharaT., SullivanA., SilverM., van der ZeeR., LiT., WitzenbichlerB., SchattemanG., IsnerJ.M.1997. Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275:964–967.
BarrettC.P., DonatiE.J., GuthL.1984. Differences between adult and neonatal rats in their astroglial response to spinal injury. Exp. Neurol., 84:374–385.
4.
BassoD.M., FisherL.C., AndersonA.J., JakemanL.B., McTigueD.M., PopovichP.G.2006. Basso mouse scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J. Neurotrauma, 23:635–659.
5.
BiernaskieJ., SparlingJ.S., LiuJ., ShannonC.P., PlemelJ.R., XieY., MillerF.D., TetzlaffW.2007. Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury. J. Neurosci., 27:9545–9559.
BrookerR., HozumiK., LewisJ.2006. Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development, 133:1277–1286.
8.
BushT.G., PuvanachandraN., HornerC.H., PolitoA., OstenfeldT., SvendsenC.N., MuckeL., JohnsonM.H., SofroniewM.V.1999. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron, 23:297–308.
9.
FaulknerJ.R., HerrmannJ.E., WooM.J., TanseyK.E., DoanN.B., SofroniewM.V.2004. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci., 24:2143–2155.
10.
GhalyR.F., StoneJ.L., AldreteJ.A., LevyW.J.1990. Effects of incremental ketamine hydrochloride doses on motor evoked potentials (MEPs) following transcranial magnetic stimulation: a primate study. J. Neurosurg. Anesthesiol., 2:79–85.
HellstromM., PhngL.K., HofmannJ.J., WallgardE., CoultasL., LindblomP., AlvaJ., NilssonA.K., KarlssonL., GaianoN., YoonK., RossantJ., Iruela-ArispeM.L., KalenM., GerhardtH., BetsholtzC.2007. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature, 445:776–780.
13.
HighF.A., LuM.M., PearW.S., LoomesK.M., KaestnerK.H., EpsteinJ.A.2008. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc. Natl. Acad. Sci. USA, 105:1955–1959.
14.
HojoM., OhtsukaT., HashimotoN., GradwohlG., GuillemotF., KageyamaR.2000. Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development, 127:2515–2522.
15.
HornK.P., BuschS.A., HawthorneA.L., van RooijenN., SilverJ.2008. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J. Neurosci., 28:9330–9341.
16.
HornerP.J., PowerA.E., KempermannG., KuhnH.G., PalmerT.D., WinklerJ., ThalL.J., GageF.H.2000. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J. Neurosci., 20:2218–2228.
17.
HungK.S., TsaiS.H., LeeT.C., LinJ.W., ChangC.K., ChiuW.T.2007. Gene transfer of insulin-like growth factor-I providing neuroprotection after spinal cord injury in rats. J. Neurosurg. Spine, 6:35–46.
18.
IiM., NishimuraH., IwakuraA., WeckerA., EatonE., AsaharaT., LosordoD.W.2005. Endothelial progenitor cells are rapidly recruited to myocardium and mediate protective effect of ischemic preconditioning via “imported” nitric oxide synthase activity. Circulation, 111:1114–1120.
19.
IshibashiM., MoriyoshiK., SasaiY., ShiotaK., NakanishiS., KageyamaR.1994. Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J., 13:1799–1805.
20.
IsnerJ.M., AsaharaT.1999. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J. Clin. Invest., 103:1231–1236.
21.
JohanssonC.B., MommaS., ClarkeD.L., RislingM., LendahlU., FrisenJ.1999. Identification of a neural stem cell in the adult mammalian central nervous system. Cell, 96:25–34.
22.
KameiN., KwonS.M., AlevC., IshikawaM., YokoyamaA., NakanishiK., YamadaK., HoriiM., NishimuraH., TakakiS., KawamotoA., IiM., AkimaruH., TanakaN., NishikawaS., OchiM., AsaharaT.2010. Lnk deletion reinforces the function of bone marrow progenitors in promoting neovascularization and astrogliosis following spinal cord injury. Stem Cells, 28:365–375.
23.
KanekoS., IwanamiA., NakamuraM., KishinoA., KikuchiK., ShibataS., OkanoH.J., IkegamiT., MoriyaA., KonishiO., NakayamaC., KumagaiK., KimuraT., SatoY., GoshimaY., TaniguchiM., ItoM., HeZ., ToyamaY., OkanoH.2006. A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord. Nat. Med., 12:1380–1389.
KrebsL.T., XueY., NortonC.R., ShutterJ.R., MaguireM., SundbergJ.P., GallahanD., ClossonV., KitajewskiJ., CallahanR., SmithG.H., StarkK.L., GridleyT.2000. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev., 14:1343–1352.
26.
KrumJ.M., ManiN., RosensteinJ.M.2002. Angiogenic and astroglial responses to vascular endothelial growth factor administration in adult rat brain. Neuroscience, 110:589–604.
27.
KwonS.M., EguchiM., WadaM., IwamiY., HozumiK., IwaguroH., MasudaH., KawamotoA., AsaharaT.2008. Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization. Circulation, 118:157–165.
28.
LivakK.J., SchmittgenT.D.2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 25:402–408.
29.
LongbrakeE.E., LaiW., AnkenyD.P., PopovichP.G.2007. Characterization and modeling of monocyte-derived macrophages after spinal cord injury. J. Neurochem., 102:1083–1094.
MenetV., PrietoM., PrivatA., Gimenez y RibottaM.2003. Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes. Proc .Natl. Acad. Sci. USA, 100:8999–9004.
32.
NishioY., KodaM., KamadaT., SomeyaY., KadotaR., MannojiC., MiyashitaT., OkadaS., OkawaA., MoriyaH., YamazakiM.2007. Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice. J. Neuropathol. Exp. Neurol., 66:724–731.
33.
OhabJ.J., FlemingS., BleschA., CarmichaelS.T.2006. A neurovascular niche for neurogenesis after stroke. J. Neurosci., 26:13007–13016.
34.
OhoriY., YamamotoS., NagaoM., SugimoriM., YamamotoN., NakamuraK., NakafukuM.2006. Growth factor treatment and genetic manipulation stimulate neurogenesis and oligodendrogenesis by endogenous neural progenitors in the injured adult spinal cord. J. Neurosci., 26:11948–11960.
35.
OhtsukaT., IshibashiM., GradwohlG., NakanishiS., GuillemotF., KageyamaR.1999. Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J., 18:2196–2207.
36.
OhtsukaT., SakamotoM., GuillemotF., KageyamaR.2001. Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain. J. Biol. Chem., 276:30467–30474.
37.
OkadaS., NakamuraM., KatohH., MiyaoT., ShimazakiT., IshiiK., YamaneJ., YoshimuraA., IwamotoY., ToyamaY., OkanoH.2006. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat. Med., 12:829–834.
38.
OkanoH., SakaguchiM., OhkiK., SuzukiN., SawamotoK.2007. Regeneration of the central nervous system using endogenous repair mechanisms. J. Neurochem., 102:1459–1465.
39.
RehmanJ., LiJ., OrschellC.M., MarchK.L.2003. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation, 107:1164–1169.
40.
RutzS., MordmullerB., SakanoS., ScheffoldA.2005. Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur. J. Immunol., 35:2443–2451.
41.
SasaiY., KageyamaR., TagawaY., ShigemotoR., NakanishiS.1992. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev., 6:2620–2634.
ShenQ., WangY., KokovayE., LinG., ChuangS.M., GoderieS.K., RoysamB., TempleS.2008. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell, 3:289–300.
44.
TakamiT., OudegaM., BatesM.L., WoodP.M., KleitmanN., BungeM.B.2002. Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J. Neurosci., 22:6670–6681.
45.
TavazoieM., Van der VekenL., Silva-VargasV., LouissaintM., ColonnaL., ZaidiB., Garcia-VerdugoJ.M., DoetschF.2008. A specialized vascular niche for adult neural stem cells. Cell Stem Cell, 3:279–288.
46.
UrbichC., AicherA., HeeschenC., DernbachE., HofmannW.K., ZeiherA.M., DimmelerS.2005. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J. Mol. Cell Cardiol., 39:733–742.
YamamotoS., NagaoM., SugimoriM., KosakoH., NakatomiH., YamamotoN., TakebayashiH., NabeshimaY., KitamuraT., WeinmasterG., NakamuraK., NakafukuM.2001. Transcription factor expression and Notch-dependent regulation of neural progenitors in the adult rat spinal cord. J. Neurosci., 21:9814–9823.
49.
YoonK., GaianoN.2005. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat. Neurosci., 8:709–715.
ZhangJ., WangB., XiaoZ., ZhaoY., ChenB., HanJ., GaoY., DingW., ZhangH., DaiJ.2008. Olfactory ensheathing cells promote proliferation and inhibit neuronal differentiation of neural progenitor cells through activation of Notch signaling. Neuroscience, 153:406–413.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
