Intracerebroventricular Transplantation of Ex Vivo Expanded Endothelial Colony-Forming Cells Restores Blood–Brain Barrier Integrity and Promotes Angiogenesis of Mice with Traumatic Brain Injury
Restricted accessResearch articleFirst published online December, 2013
Intracerebroventricular Transplantation of Ex Vivo Expanded Endothelial Colony-Forming Cells Restores Blood–Brain Barrier Integrity and Promotes Angiogenesis of Mice with Traumatic Brain Injury
Endothelial progenitor cells (EPCs) play a key role in tissue repair and regeneration. Previous studies have shown a positive correlation between the number of circulating EPCs and clinical outcomes of patients with traumatic brain injury (TBI). A recent study has further shown that intravenous infusion of human umbilical cord blood-derived endothelial colony-forming cells (ECFCs) improves outcomes of mice subjected to experimental TBI. This follow-up study was designed to determine whether intracerebroventricular (i.c.v.) infusion of ECFCs, which may reduce systemic effects of these cells, could repair the blood–brain barrier (BBB) and promote angiogenesis of mice with TBI. Adult nude mice were exposed to fluid percussion injury and transplanted i.c.v. with ECFCs on day 1 post-TBI. These ECFCs were detected at the TBI zone 3 days after transplantation by SP-DiIC18(3) and fluorescence in situ hybridization. Mice with ECFCs transplant had reduced Evans blue extravasation and brain water content, increased expression of ZO-1 and claudin-5, and showed a higher expression of angiopoietin 1. Consistent with the previous report, mice with ECFCs transplant had also increased microvascular density. Modified neurological severity score and Morris water maze test indicated significant improvements in motor ability, spatial acquisition and reference memory in mice receiving ECFCs, compared to those receiving saline. These data demonstrate the beneficial effects of ECFC transplant on BBB integrity and angiogenesis in mice with TBI.
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References
1.
WernerC., and EngelhardK. (2007). Pathophysiology of traumatic brain injury. Br. J. Anaesth., 99, 4–9.
2.
MurasawaS., and AsaharaT. (2005). Endothelial progenitor cells for vasculogenesis. Physiology (Bethesda), 20, 36–42.
3.
NoguchiC.T., AsavaritikraiP., TengR., and JiaY. (2007). Role of erythropoietin in the brain. Crit. Rev. Oncol. Hematol., 64, 159–171.
4.
XiongY., MahmoodA., and ChoppM. (2010). Angiogenesis, neurogenesis and brain recovery of function following injury. Curr. Opin. Investig. Drugs, 11, 298–308.
5.
HaywardN.M., ImmonenR., TuunanenP.I., Ndode-EkaneX.E., GrohnO., and PitkanenA. (2010). Association of chronic vascular changes with functional outcome after traumatic brain injury in rats. J. Neurotrauma, 27, 2203–2219.
6.
AsaharaT., MuroharaT., SullivanA., SilverM., van der ZeeR., LiT., WitzenbichlerB., SchattemanG., and IsnerJ.M. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275, 964–967.
7.
TakahashiT., KalkaC., MasudaH., ChenD., SilverM., KearneyM., MagnerM., IsnerJ.M., and AsaharaT. (1999). Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med., 5, 434–438.
8.
WalterD.H., RittigK., BahlmannF.H., KirchmairR., SilverM., MurayamaT., NishimuraH., LosordoD.W., AsaharaT., and IsnerJ.M. (2002). Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation, 105, 3017–3024.
9.
GillM., DiasS., HattoriK., RiveraM.L., HicklinD., WitteL., GirardiL., YurtR., HimelH., and RafiiS. (2001). Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ. Res., 88, 167–174.
10.
LevE.I., KleimanN.S., BirnbaumY., HarrisD., KorblingM., and EstrovZ. (2005). Circulating endothelial progenitor cells and coronary collaterals in patients with non-ST segment elevation myocardial infarction. J. Vasc. Res., 42, 408–414.
11.
KhooC.P., PozzilliP., and AlisonM.R. (2008). Endothelial progenitor cells and their potential therapeutic applications. Regen. Med., 3, 863–876.
YoonY.S., LeeN., and ScadovaH. (2005). Myocardial regeneration with bone-marrow-derived stem cells. Biol. Cell, 97, 253–263.
14.
KawamotoA., TkebuchavaT., YamaguchiJ., NishimuraH., YoonY.S., MillikenC., UchidaS., MasuoO., IwaguroH., MaH., HanleyA., SilverM., KearneyM., LosordoD.W., IsnerJ.M., and AsaharaT. (2003). Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation, 107, 461–468.
15.
TaguchiA., SomaT., TanakaH., KandaT., NishimuraH., YoshikawaH., TsukamotoY., IsoH., FujimoriY., SternD.M., NaritomiH., and MatsuyamaT. (2004). Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J. Clin. Invest., 114, 330–338.
16.
ZhangZ.G., ZhangL., JiangQ., and ChoppM. (2002). Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ. Res., 90, 284–288.
17.
FanY., ShenF., FrenzelT., ZhuW., YeJ., LiuJ., ChenY., SuH., YoungW.L., and YangG.Y. (2010). Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann. Neurol., 67, 488–497.
18.
LiuL., LiuH., JiaoJ., BergeronA., DongJ.F., and ZhangJ. (2007). Changes in circulating human endothelial progenitor cells after brain injury. J. Neurotrauma, 24, 936–943.
19.
LiuL., WeiH., ChenF., WangJ., DongJ.F., and ZhangJ. (2011). Endothelial progenitor cells correlate with clinical outcome of traumatic brain injury. Crit. Care Med., 39, 1760–1765.
20.
ZhangY., LiY., WangS., HanZ., HuangX., LiS., ChenF., NiuR., DongJ.F., JiangR., and ZhangJ. (2013). Transplantation of expanded endothelial colony-forming cells improved outcomes of traumatic brain injury in a mouse model. J. Surg. Res.June11. doi: 10.1016/j.jss.2013.05.073. [Epub ahead of print]
21.
IngramD.A., MeadL.E., TanakaH., MeadeV., FenoglioA., MortellK., PollokK., FerkowiczM.J., GilleyD., and YoderM.C. (2004). Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood, 104, 2752–2760.
22.
BaudinB., BruneelA., BosselutN., and VaubourdolleM. (2007). A protocol for isolation and culture of human umbilical vein endothelial cells. Nat. Protoc., 2, 481–485.
23.
ZhaoJ., PatiS., RedellJ.B., ZhangM., MooreA.N., and DashP.K. (2012). Caffeic acid phenethyl ester protects blood-brain barrier integrity and reduces contusion volume in rodent models of traumatic brain injury. J. Neurotrauma, 29, 1209–1218.
24.
TayaK., MarmarouC.R., OkunoK., PrietoR., and MarmarouA. (2010). Effect of secondary insults upon aquaporin-4 water channels following experimental cortical contusion in rats. J. Neurotrauma, 27, 229–239.
25.
ElliottK.A., and JasperH. (1949). Measurement of experimentally induced brain swelling and shrinkage. Am. J. Physiol., 157, 122–129.
26.
LiS., WeiM., ZhouZ., WangB., ZhaoX., and ZhangJ. (2012). SDF-1alpha induces angiogenesis after traumatic brain injury. Brain Res., 1444, 76–86.
27.
ChenJ., SanbergP.R., LiY., WangL., LuM., WillingA.E., Sanchez-RamosJ., and ChoppM. (2001). Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke, 32, 2682–2688.
28.
LiZ., WangB., KanZ., ZhangB., YangZ., ChenJ., WangD., WeiH., ZhangJ.N., and JiangR. (2012). Progesterone increases circulating endothelial progenitor cells and induces neural regeneration after traumatic brain injury in aged rats. J. Neurotrauma, 29, 343–353.
29.
VorheesC.V., and WilliamsM.T. (2006). Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc., 1, 848–858.
30.
LinY., WeisdorfD.J., SoloveyA., and HebbelR.P. (2000). Origins of circulating endothelial cells and endothelial outgrowth from blood. J. Clin. Invest., 105, 71–77.
31.
JiaoH., WangZ., LiuY., WangP., and XueY. (2011). Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult. J. Mol. Neurosci., 44, 130–139.
32.
HansenT.M., MossA.J., and BrindleN.P. (2008). Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr. Neurovasc. Res., 5, 236–245.
33.
YoderM.C., MeadL.E., PraterD., KrierT.R., MrouehK.N., LiF., KrasichR., TemmC.J., PrchalJ.T., and IngramD.A. (2007). Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood, 109, 1801–1809.
34.
RichardsonM.R., and YoderM.C. (2011). Endothelial progenitor cells: quo vadis? J. Mol. Cell. Cardiol., 50, 266–272.
35.
Melero-MartinJ.M., KhanZ.A., PicardA., WuX., ParuchuriS., and BischoffJ. (2007). In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood, 109, 4761–4768.
36.
MukaiN., AkahoriT., KomakiM., LiQ., Kanayasu-ToyodaT., Ishii-WatabeA., KobayashiA., YamaguchiT., AbeM., AmagasaT., and MoritaI. (2008). A comparison of the tube forming potentials of early and late endothelial progenitor cells. Exp. Cell Res., 314, 430–440.
37.
JanzerR.C., and RaffM.C. (1987). Astrocytes induce blood-brain barrier properties in endothelial cells. Nature, 325, 253–257.
38.
ShearD.A., LuX.C., PedersenR., WeiG., ChenZ., DavisA., YaoC., DaveJ., and TortellaF.C. (2011). Severity profile of penetrating ballistic-like brain injury on neurofunctional outcome, blood-brain barrier permeability, and brain edema formation. J. Neurotrauma, 28, 2185–2195.
39.
UnterbergA.W., StoverJ., KressB., and KieningK.L. (2004). Edema and brain trauma. Neuroscience, 129, 1021–1029.
40.
ZhangZ.G., ZhangL., TsangW., Soltanian-ZadehH., MorrisD., ZhangR., GoussevA., PowersC., YeichT., and ChoppM. (2002). Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J. Cereb. Blood Flow Metab., 22, 379–392.
41.
PfaffD., FiedlerU., and AugustinH.G. (2006). Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking. J. Leukoc. Biol., 80, 719–726.
42.
SuriC., JonesP.F., PatanS., BartunkovaS., MaisonpierreP.C., DavisS., SatoT.N., and YancopoulosG.D. (1996). Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell, 87, 1171–1180.
43.
GreveM.W., and ZinkB.J. (2009). Pathophysiology of traumatic brain injury. Mt. Sinai J. Med., 76, 97–104.
44.
KhanM., ImY.B., ShunmugavelA., GilgA.G., DhindsaR.K., SinghA.K., and SinghI. (2009). Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact. J. Neuroinflammation, 6, 32.
45.
RehmanJ., LiJ., OrschellC.M., and MarchK.L. (2003). Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation, 107, 1164–1169.
46.
RouhlR.P., van OostenbruggeR.J., DamoiseauxJ., TervaertJ.W., and LodderJ. (2008). Endothelial progenitor cell research in stroke: a potential shift in pathophysiological and therapeutical concepts. Stroke, 39, 2158–2165.
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