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系統識別號 U0026-1508201200252800
論文名稱(中文) 人類臍帶靜脈內皮細胞對新生鼠腦部缺氧窒息的神經血管保護
論文名稱(英文) Effect of Human Umbilical Vein Endothelial Cells on Neurovascular Protection Against Hypoxic–Ischemia in Neonatal Rat Brain
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 100
學期 2
出版年 101
研究生(中文) 陳奕淇
研究生(英文) Yi-Chi Chen
學號 s96994057
學位類別 碩士
語文別 英文
論文頁數 89頁
口試委員 指導教授-黃朝慶
共同指導教授-吳佳慶
口試委員-江伯敏
口試委員-張瑛玿
中文關鍵字 缺氧窒息  神經血管單元  血腦屏障  人類臍帶靜脈內皮細胞  SDF-1/CXCR4 訊息傳遞路徑 
英文關鍵字 hypoxic-ischemia  neurovascular unit  blood-brain barrier  human umbilical vein endothelial cell  SDF-1/CXCR4 signaling 
學科別分類
中文摘要   缺氧窒息性腦傷是造成新生兒神經發育不健全及死亡的主要原因。近年來有學者認為,由神經元、血管內皮細胞、微膠細胞組成的神經血管單元是缺氧窒息性腦傷主要的目標。神經血管單元遭受缺氧窒息的刺激之下,容易誘發腦部神經及血管內皮細胞破壞,進而讓發育未成熟的大腦受到嚴重波及。若是針對神經和血管進行保護,對於缺氧窒息腦傷將會是非常有效的治療策略。而從新生兒臍帶純化出的人類臍帶靜脈內皮細胞具有新生且自體移植的優點,我們認為可以運用在治療新生兒缺氧窒息腦傷上。過去細胞治療的研究顯示,細胞會藉由SDF-1/CXCR4訊息傳遞路徑,通過血腦屏障而遷徙到腦部受傷的位置。因此,我們假設由周邊給予的人類臍帶靜脈內皮細胞,會藉由SDF-1/CXCR4 訊息傳遞路徑進入到腦部受傷的位置,進而提供了神經血管保護。
  我們在出生第七天的老鼠利用單側頸動脈結紮結合兩小時缺氧做為缺氧窒息腦傷的動物研究模式,在缺氧前後分別腹腔注射了第四代人類臍帶靜脈內皮細胞、第八代人類臍帶靜脈內皮細胞、細胞培養液、或生理食鹽水。以沒有缺氧窒息腦傷做為實驗控制組。並利用Neuro-2a和b.End3兩種細胞株建立體外缺氧缺糖細胞研究模式,在缺氧缺糖前將Neuro-2a和b.End3分別共同培養第四代人類臍帶靜脈內皮細胞。
  實驗結果顯示,缺氧窒息後腹腔注射的第四代人類臍帶靜脈內皮細胞進入到同側大腦皮質部位,並且相當靠近神經細胞及血管內皮細胞。相較於給予細胞培養液,注射第四代人類臍帶靜脈內皮細胞而非第八代人類臍帶靜脈內皮細胞的老鼠,在缺氧窒息後二十四小時的大腦皮質有較多的神經細胞以及較完整的血管內皮。藉由滲出的IgG較少檢測出給予第四代人類臍帶靜脈內皮細胞的組別有較完整的血腦屏障。在體外實驗當中,相較於第八代人類臍帶靜脈內皮細胞,第四代人類臍帶靜脈內皮細胞有著較高的細胞遷徙能力,此外,在腹腔注射細胞三小時後發現,給予第四代人類臍帶靜脈內皮細胞的老鼠血液當中也偵測較多綠色螢光細胞;且在出生後第十四天的老鼠,大腦皮質及紋狀體的體積損失有顯著下降。缺氧窒息後三小時,SDF-1分泌量在同側大腦皮質明顯增加;而抑制了SDF-1/CXCR4訊息傳遞路徑,明顯減少了由第四代人類臍帶靜脈內皮細胞提供的神經保護。神經細胞及血管內皮細胞在體外共同培養第四代人類臍帶靜脈內皮細胞後,皆獲得保護抵抗缺氧缺糖誘導的細胞死亡。
  總結,我們的研究指出,腹腔注射的第四代人類臍帶靜脈內皮細胞在缺氧窒息腦傷後會經由SDF-1/CXCR4訊息傳遞路徑進到腦部,保護神經血管單元,並提供長期的神經保護。使用人類臍帶靜脈內皮细胞的细胞療法,可能對於高危險新生兒缺氧窒息性損傷可以提供一個有效的治療策略。由人類臍帶靜脈內皮细胞共同調控的神經保護和血管保護機制可能類似藥物產生的神經血管保護,指出了對於高危險新生兒缺氧窒息性損傷用人類臍帶靜脈內皮细胞的细胞療法的優勢。
英文摘要 Hypoxic-ischemia (HI) is a major cause of neonatal mortality and neurological morbidity among survivors. The neurovascular unit, composed of neurons, microvessels and microglia, is considered a major target of HI injury. Neurons and vascular endothelial cells may respond equally to the HI insult, and agents that simultaneously act on neuronal and endothelial cell protection may provide a powerful therapeutic strategy against HI. Human umbilical vein endothelial cells (HUVEC) may have the potential for treatment in the high-risk neonates for HI encephalopathy because of its regenerative potential and autologous capability. Stromal cell-derived factor 1 (SDF-1)/ C-X-C chemokine receptor type 4 (CXCR4) signaling and transmigration via blood-brain barrier are the key issue for the cell migration into the injured brain area. In our study, we hypothesized that peripheral injection of HUVEC entered the brain via SDF-1/CXCR4 pathway after HI, protected against neurovascular damage, and provided neuroprotection in neonatal brain.
In vivo HI was induced by permanent ligation of unilateral carotid artery followed by 2-hours of hypoxia in postpartum day 7 Sprague-Dawley rat pups. Rat pups received intraperitoneal injections of HUVECs (1×105/per injection), conditioned medium or saline solution before and immediately after HI. The littermates were divided into five groups: control group, HUVEC-P4-treated group (Low passage), HUVEC-P8-treated group (High passage), condition medium-treated group, and normal saline-treated group. In vitro oxygen-glucose deprivation (OGD) was established on mouse neuroblastoma neuronal cells (Neuro-2a) and mouse immortalized cerebral vascular endothelial cells (b.End3). The Neuro-2a cells and b.End3 cells were then co-cultured, respectively, with HUVEC-P4 before OGD.
We found that intraperitoneally-injected HUVEC-P4 entered the ipsilateral cerebral cortex after HI and positioned closed to the neurons and microvessels. Compared with the condition medium-treated group, the HUVEC-P4 but not the HUVEC-P8 group showed significantly less neuronal loss and more preservation of microvessels in the cortex 24 hours after HI. BBB damage, determined by IgG extravasation, was also significantly reduced in the HUVEC-P4 but not the HUVEC-P8 group. Compared with HUVEC-P8, HUVEC-P4 had higher migratory properties, in addition, the HUVEC-P4-treated group had more GFP-positive cells in the circulation at 3 hours after injection than the HUVEC-P8-treated group. Seven days after injury, the HUVEC-P4 but not the HUVEC-P8 group had significantly decreased brain volume loss in the cortex and striatum compared with the condition medium or saline-treated group. SDF-1 was up-regulated in the ipsilateral cortex three hours after HI, and inhibiting the SDF-1/CXCR4 axis reduced the neuroprotective effect provided by HUVEC-P4. Co-culturing of HUVEC-P4 protected against OGD cell death in both neuronal cells and vascular endothelial cells.
In conclusion, our study indicates that peripherally-injected HUVEC-P4 enters the neonatal brain after HI via SDF-1/CXCR4 pathway, protects against neurovascular damage, and provides long-term neuroprotection. Cell therapy using HUVECs may provide a powerful therapeutic strategy in the treatment of high-risk neonates with HI injury. Elucidating the shared neuronal and vascular protective mechanism mediated by HUVEC may yield neurovascular protective drugs that mimic the beneficial effects of HUVEC for treating high-risk newborns with asphyxia.
論文目次 中文摘要 1
Abstract 3
Acknowledgement 6
Contents 8
Table Contents 9
Figure Contents 10
Abbreviation Index 11
Introduction 12
Materials and Methods 18
Results 30
Discussion 36
Tables 43
Figure Legends 49
Figures 55
References 73
Supplement Table 89
參考文獻 1. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol. 2004;207:3149-3154
2. Ferriero DM. Neonatal brain injury. N Engl J Med. 2004;351:1985-1995
3. Johnston MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol. 2011;10:372-382
4. Alvarez-Diaz A, Hilario E, de Cerio FG, Valls-i-Soler A, Alvarez-Diaz FJ. Hypoxic-ischemic injury in the immature brain--key vascular and cellular players. Neonatology. 2007;92:227-235
5. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361:1349-1358
6. Higgins RD, Shankaran S. Hypothermia: Novel approaches for premature infants. Early Hum Dev. 2011;87 Suppl 1:S17-18
7. Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, Gustafson KE, Leach TM, Green C, Bara R, Petrie Huitema CM, Ehrenkranz RA, Tyson JE, Das A, Hammond J, Peralta-Carcelen M, Evans PW, Heyne RJ, Wilson-Costello DE, Vaucher YE, Bauer CR, Dusick AM, Adams-Chapman I, Goldstein RF, Guillet R, Papile LA, Higgins RD. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012;366:2085-2092
8. Degos V, Loron G, Mantz J, Gressens P. Neuroprotective strategies for the neonatal brain. Anesth Analg. 2008;106:1670-1680
9. del Zoppo GJ. Stroke and neurovascular protection. N Engl J Med. 2006;354:553-555
10. Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: Molecular mechanisms and therapeutic implications. Neuron. 2011;71:406-424
11. Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature. 2005;436:193-200
12. Tam SJ, Watts RJ. Connecting vascular and nervous system development: Angiogenesis and the blood-brain barrier. Annu Rev Neurosci. 2010;33:379-408
13. Butler JM, Kobayashi H, Rafii S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer. 2010;10:138-146
14. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57:173-185
15. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362:329-344
16. Iadecola C. Neurovascular regulation in the normal brain and in alzheimer's disease. Nat Rev Neurosci. 2004;5:347-360
17. Lee HT, Chang YC, Tu YF, Huang CC. Vegf-a/vegfr-2 signaling leading to camp response element-binding protein phosphorylation is a shared pathway underlying the protective effect of preconditioning on neurons and endothelial cells. J Neurosci. 2009;29:4356-4368
18. Tu YF, Tsai YS, Wang LW, Wu HC, Huang CC, Ho CJ. Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through jnk hyperactivation. J Neuroinflammation. 2011;8:40
19. Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol. 2010;120:287-296
20. Hansen TM, Moss AJ, Brindle NP. Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr Neurovasc Res. 2008;5:236-245
21. James JM, Gewolb C, Bautch VL. Neurovascular development uses vegf-a signaling to regulate blood vessel ingression into the neural tube. Development. 2009;136:833-841
22. Li L, Xie T. Stem cell niche: Structure and function. Annu Rev Cell Dev Biol. 2005;21:605-631
23. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204-2213
24. Burns TC, Verfaillie CM, Low WC. Stem cells for ischemic brain injury: A critical review. J Comp Neurol. 2009;515:125-144
25. Haas S, Weidner N, Winkler J. Adult stem cell therapy in stroke. Curr Opin Neurol. 2005;18:59-64
26. Peterson DA. Umbilical cord blood cells and brain stroke injury: Bringing in fresh blood to address an old problem. J Clin Invest. 2004;114:312-314
27. Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R. Dopamine neurons derived from embryonic stem cells function in an animal model of parkinson's disease. Nature. 2002;418:50-56
28. Dunnett SB, Rosser AE. Cell therapy in huntington's disease. NeuroRx. 2004;1:394-405
29. Costa-Ferro ZS, Vitola AS, Pedroso MF, Cunha FB, Xavier LL, Machado DC, Soares MB, Ribeiro-dos-Santos R, DaCosta JC. Prevention of seizures and reorganization of hippocampal functions by transplantation of bone marrow cells in the acute phase of experimental epilepsy. Seizure. 2010;19:84-92
30. Koda M, Okada S, Nakayama T, Koshizuka S, Kamada T, Nishio Y, Someya Y, Yoshinaga K, Okawa A, Moriya H, Yamazaki M. Hematopoietic stem cell and marrow stromal cell for spinal cord injury in mice. Neuroreport. 2005;16:1763-1767
31. George AL, Bangalore-Prakash P, Rajoria S, Suriano R, Shanmugam A, Mittelman A, Tiwari RK. Endothelial progenitor cell biology in disease and tissue regeneration. J Hematol Oncol. 2011;4:24
32. Titomanlio L, Kavelaars A, Dalous J, Mani S, El Ghouzzi V, Heijnen C, Baud O, Gressens P. Stem cell therapy for neonatal brain injury: Perspectives and challenges. Ann Neurol. 2011;70:698-712
33. Ma J, Wang Y, Yang J, Yang M, Chang KA, Zhang L, Jiang F, Li Y, Zhang Z, Heo C, Suh YH. Treatment of hypoxic-ischemic encephalopathy in mouse by transplantation of embryonic stem cell-derived cells. Neurochem Int. 2007;51:57-65
34. Zheng T, Rossignol C, Leibovici A, Anderson KJ, Steindler DA, Weiss MD. Transplantation of multipotent astrocytic stem cells into a rat model of neonatal hypoxic-ischemic encephalopathy. Brain Res. 2006;1112:99-105
35. Brenneman M, Sharma S, Harting M, Strong R, Cox CS, Jr., Aronowski J, Grotta JC, Savitz SI. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. J Cereb Blood Flow Metab. 2010;30:140-149
36. Xia G, Hong X, Chen X, Lan F, Zhang G, Liao L. Intracerebral transplantation of mesenchymal stem cells derived from human umbilical cord blood alleviates hypoxic ischemic brain injury in rat neonates. J Perinat Med. 2010;38:215-221
37. Pimentel-Coelho PM, Mendez-Otero R. Cell therapy for neonatal hypoxic-ischemic encephalopathy. Stem Cells Dev. 2010;19:299-310
38. Sanberg PR, Willing AE, Garbuzova-Davis S, Saporta S, Liu G, Sanberg CD, Bickford PC, Klasko SK, El-Badri NS. Umbilical cord blood-derived stem cells and brain repair. Ann N Y Acad Sci. 2005;1049:67-83
39. Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, Hooper AT, Amano H, Avecilla ST, Heissig B, Hattori K, Zhang F, Hicklin DJ, Wu Y, Zhu Z, Dunn A, Salari H, Werb Z, Hackett NR, Crystal RG, Lyden D, Rafii S. Cytokine-mediated deployment of sdf-1 induces revascularization through recruitment of cxcr4+ hemangiocytes. Nat Med. 2006;12:557-567
40. Petit I, Jin D, Rafii S. The sdf-1-cxcr4 signaling pathway: A molecular hub modulating neo-angiogenesis. Trends Immunol. 2007;28:299-307
41. Shimizu S, Brown M, Sengupta R, Penfold ME, Meucci O. Cxcr7 protein expression in human adult brain and differentiated neurons. PLoS One. 2011;6:e20680
42. Liu KK, Dorovini-Zis K. Regulation of cxcl12 and cxcr4 expression by human brain endothelial cells and their role in cd4+ and cd8+ t cell adhesion and transendothelial migration. J Neuroimmunol. 2009;215:49-64
43. Young KC, Torres E, Hatzistergos KE, Hehre D, Suguihara C, Hare JM. Inhibition of the sdf-1/cxcr4 axis attenuates neonatal hypoxia-induced pulmonary hypertension. Circ Res. 2009;104:1293-1301
44. Penn MS. Importance of the sdf-1:Cxcr4 axis in myocardial repair. Circ Res. 2009;104:1133-1135
45. Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Hollt V, Schulz S. A dual role for the sdf-1/cxcr4 chemokine receptor system in adult brain: Isoform-selective regulation of sdf-1 expression modulates cxcr4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci. 2002;22:5865-5878
46. Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab. 2007;27:6-13
47. Miller JT, Bartley JH, Wimborne HJ, Walker AL, Hess DC, Hill WD, Carroll JE. The neuroblast and angioblast chemotaxic factor sdf-1 (cxcl12) expression is briefly up regulated by reactive astrocytes in brain following neonatal hypoxic-ischemic injury. BMC Neurosci. 2005;6:63
48. Baudin B, Bruneel A, Bosselut N, Vaubourdolle M. A protocol for isolation and culture of human umbilical vein endothelial cells. Nat Protoc. 2007;2:481-485
49. Cunningham R, Steplock D, Wang F, Huang H, E X, Shenolikar S, Weinman EJ. Defective parathyroid hormone regulation of nhe3 activity and phosphate adaptation in cultured nherf-1-/- renal proximal tubule cells. J Biol Chem. 2004;279:37815-37821
50. Sung ML, Wu CC, Chang HI, Yen CK, Chen HJ, Cheng JC, Chien S, Chen CN. Shear stress inhibits homocysteine-induced stromal cell-derived factor-1 expression in endothelial cells. Circ Res. 2009;105:755-763
51. Lee HT, Chang YC, Wang LY, Wang ST, Huang CC, Ho CJ. Camp response element-binding protein activation in ligation preconditioning in neonatal brain. Ann Neurol. 2004;56:611-623
52. Lin WY, Chang YC, Lee HT, Huang CC. Creb activation in the rapid, intermediate, and delayed ischemic preconditioning against hypoxic-ischemia in neonatal rat. J Neurochem. 2009;108:847-859
53. Paxinos G, Watson CR, Emson PC. Ache-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods. 1980;3:129-149
54. Lee HT, Chang YC, Tu YF, Huang CC. Creb activation mediates vegf-a's protection of neurons and cerebral vascular endothelial cells. J Neurochem. 2010;113:79-91
55. Tu YF, Lu PJ, Huang CC, Ho CJ, Chou YP. Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. Stroke. 2012;43:491-498
56. Lagger S, Meunier D, Mikula M, Brunmeir R, Schlederer M, Artaker M, Pusch O, Egger G, Hagelkruys A, Mikulits W, Weitzer G, Muellner EW, Susani M, Kenner L, Seiser C. Crucial function of histone deacetylase 1 for differentiation of teratomas in mice and humans. EMBO J. 2010;29:3992-4007
57. Sotlar K, Cerny-Reiterer S, Petat-Dutter K, Hessel H, Berezowska S, Mullauer L, Valent P, Horny HP. Aberrant expression of cd30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol. 2011;24:585-595
58. Bialas M, Okon K, Czopek J. Assessing microvessel density in gastric carcinoma: A comparison of three markers. Pol J Pathol. 2003;54:249-252
59. Lu C, Saless N, Hu D, Wang X, Xing Z, Hou H, Williams B, Swartz HM, Colnot C, Miclau T, Marcucio RS. Mechanical stability affects angiogenesis during early fracture healing. J Orthop Trauma. 2011;25:494-499
60. Bouras C, Kovari E, Herrmann FR, Rivara CB, Bailey TL, von Gunten A, Hof PR, Giannakopoulos P. Stereologic analysis of microvascular morphology in the elderly: Alzheimer disease pathology and cognitive status. J Neuropathol Exp Neurol. 2006;65:235-244
61. Wang LW, Chang YC, Lin CY, Hong JS, Huang CC. Low-dose lipopolysaccharide selectively sensitizes hypoxic ischemia-induced white matter injury in the immature brain. Pediatr Res. 2010;68:41-47
62. Zhao BC, Wang ZJ, Mao WZ, Ma HC, Han JG, Zhao B, Xu HM. Cxcr4/sdf-1 axis is involved in lymph node metastasis of gastric carcinoma. World J Gastroenterol. 2011;17:2389-2396
63. Dar A, Schajnovitz A, Lapid K, Kalinkovich A, Itkin T, Ludin A, Kao WM, Battista M, Tesio M, Kollet O, Cohen NN, Margalit R, Buss EC, Baleux F, Oishi S, Fujii N, Larochelle A, Dunbar CE, Broxmeyer HE, Frenette PS, Lapidot T. Rapid mobilization of hematopoietic progenitors by amd3100 and catecholamines is mediated by cxcr4-dependent sdf-1 release from bone marrow stromal cells. Leukemia. 2011;25:1286-1296
64. Banisadr G, Frederick TJ, Freitag C, Ren D, Jung H, Miller SD, Miller RJ. The role of cxcr4 signaling in the migration of transplanted oligodendrocyte progenitors into the cerebral white matter. Neurobiol Dis. 2011;44:19-27
65. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593-600
66. Fan Y, Shen F, Frenzel T, Zhu W, Ye J, Liu J, Chen Y, Su H, Young WL, Yang GY. Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol. 2010;67:488-497
67. Marrotte EJ, Chen DD, Hakim JS, Chen AF. Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J Clin Invest. 2010;120:4207-4219
68. Hung HS, Wu CC, Chien S, Hsu SH. The behavior of endothelial cells on polyurethane nanocomposites and the associated signaling pathways. Biomaterials. 2009;30:1502-1511
69. Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, Dimmeler S. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005;39:733-742
70. Kanaji N, Sato T, Nelson A, Wang X, Li Y, Kim M, Nakanishi M, Basma H, Michalski J, Farid M, Chandler M, Pease W, Patil A, Rennard SI, Liu X. Inflammatory cytokines regulate endothelial cell survival and tissue repair functions via nf-kappab signaling. J Inflamm Res. 2011;4:127-138
71. Cai G, Lian J, Shapiro SS, Beacham DA. Evaluation of endothelial cell migration with a novel in vitro assay system. Methods Cell Sci. 2000;22:107-114
72. Wu LQ, Ouyang XY, Liu Y, Peng SY, Wang L, Wang WJ. Inhibitory effects of sy0916, a platelet-activating factor receptor antagonist, on the angiogenesis of human umbilical vascular endothelial cells. J Asian Nat Prod Res. 2011;13:984-992
73. Li Q, Ford MC, Lavik EB, Madri JA. Modeling the neurovascular niche: Vegf- and bdnf-mediated cross-talk between neural stem cells and endothelial cells: An in vitro study. J Neurosci Res. 2006;84:1656-1668
74. Arien-Zakay H, Lecht S, Bercu MM, Tabakman R, Kohen R, Galski H, Nagler A, Lazarovici P. Neuroprotection by cord blood neural progenitors involves antioxidants, neurotrophic and angiogenic factors. Exp Neurol. 2009;216:83-94
75. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67-81
76. Lin HY, Wu CL, Huang CC. The akt-endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain. Stroke. 2010;41:1543-1551
77. Xing C, Hayakawa K, Lok J, Arai K, Lo EH. Injury and repair in the neurovascular unit. Neurol Res. 2012;34:325-330
78. Alfieri A, Srivastava S, Siow RC, Modo M, Fraser PA, Mann GE. Targeting the nrf2-keap1 antioxidant defence pathway for neurovascular protection in stroke. J Physiol. 2011;589:4125-4136
79. Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic stroke: A thrombo-inflammatory disease? J Physiol. 2011;589:4115-4123
80. Zlokovic BV. Neurovascular pathways to neurodegeneration in alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12:723-738
81. Daadi MM, Davis AS, Arac A, Li Z, Maag AL, Bhatnagar R, Jiang K, Sun G, Wu JC, Steinberg GK. Human neural stem cell grafts modify microglial response and enhance axonal sprouting in neonatal hypoxic-ischemic brain injury. Stroke. 2010;41:516-523
82. de Paula S, Vitola AS, Greggio S, de Paula D, Mello PB, Lubianca JM, Xavier LL, Fiori HH, Dacosta JC. Hemispheric brain injury and behavioral deficits induced by severe neonatal hypoxia-ischemia in rats are not attenuated by intravenous administration of human umbilical cord blood cells. Pediatr Res. 2009;65:631-635
83. Yasuhara T, Hara K, Maki M, Xu L, Yu G, Ali MM, Masuda T, Yu SJ, Bae EK, Hayashi T, Matsukawa N, Kaneko Y, Kuzmin-Nichols N, Ellovitch S, Cruz EL, Klasko SK, Sanberg CD, Sanberg PR, Borlongan CV. Mannitol facilitates neurotrophic factor up-regulation and behavioural recovery in neonatal hypoxic-ischaemic rats with human umbilical cord blood grafts. J Cell Mol Med. 2010;14:914-921
84. Meier C, Middelanis J, Wasielewski B, Neuhoff S, Roth-Haerer A, Gantert M, Dinse HR, Dermietzel R, Jensen A. Spastic paresis after perinatal brain damage in rats is reduced by human cord blood mononuclear cells. Pediatr Res. 2006;59:244-249
85. Pimentel-Coelho PM, Magalhaes ES, Lopes LM, deAzevedo LC, Santiago MF, Mendez-Otero R. Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: Functional outcome related to neuroprotection in the striatum. Stem Cells Dev. 2010;19:351-358
86. Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, Pittenger MF, van Zijl PC, Huang J, Bulte JW. Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke. 2008;39:1569-1574
87. Jenny B, Kanemitsu M, Tsupykov O, Potter G, Salmon P, Zgraggen E, Gascon E, Skibo G, Dayer AG, Kiss JZ. Fibroblast growth factor-2 overexpression in transplanted neural progenitors promotes perivascular cluster formation with a neurogenic potential. Stem Cells. 2009;27:1309-1317
88. van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010;24:387-393
89. Yasuhara T, Hara K, Maki M, Mays RW, Deans RJ, Hess DC, Carroll JE, Borlongan CV. Intravenous grafts recapitulate the neurorestoration afforded by intracerebrally delivered multipotent adult progenitor cells in neonatal hypoxic-ischemic rats. J Cereb Blood Flow Metab. 2008;28:1804-1810
90. Guzman R, Choi R, Gera A, De Los Angeles A, Andres RH, Steinberg GK. Intravascular cell replacement therapy for stroke. Neurosurg Focus. 2008;24:E15
91. Stem cell therapies as an emerging paradigm in stroke (steps): Bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009;40:510-515
92. Wang Y, Deng Y, Zhou GQ. Sdf-1alpha/cxcr4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res. 2008;1195:104-112
93. Rosenkranz K, Kumbruch S, Lebermann K, Marschner K, Jensen A, Dermietzel R, Meier C. The chemokine sdf-1/cxcl12 contributes to the 'homing' of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain. J Neurosci Res. 2010;88:1223-1233
94. Rosenkranz K, Kumbruch S, Tenbusch M, Marcus K, Marschner K, Dermietzel R, Meier C. Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. Cell Tissue Res. 2012;348:429-438
95. Borlongan CV, Hadman M, Sanberg CD, Sanberg PR. Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke. 2004;35:2385-2389
96. Boucherie C, Hermans E. Adult stem cell therapies for neurological disorders: Benefits beyond neuronal replacement? J Neurosci Res. 2009;87:1509-1521
97. Park KI, Himes BT, Stieg PE, Tessler A, Fischer I, Snyder EY. Neural stem cells may be uniquely suited for combined gene therapy and cell replacement: Evidence from engraftment of neurotrophin-3-expressing stem cells in hypoxic-ischemic brain injury. Exp Neurol. 2006;199:179-190
98. Muller FJ, Snyder EY, Loring JF. Gene therapy: Can neural stem cells deliver? Nat Rev Neurosci. 2006;7:75-84
99. Han BH, Holtzman DM. Bdnf protects the neonatal brain from hypoxic-ischemic injury in vivo via the erk pathway. J Neurosci. 2000;20:5775-5781
100. Lin S, Fan LW, Rhodes PG, Cai Z. Intranasal administration of igf-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol. 2009;217:361-370
101. Feng Y, Rhodes PG, Bhatt AJ. Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats. Pediatr Res. 2008;64:370-374
102. Nijboer CH, Heijnen CJ, Groenendaal F, van Bel F, Kavelaars A. Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappab inhibition in neonatal cerebral hypoxia-ischemia. Stroke. 2009;40:3362-3368
103. Wang M, Crisostomo PR, Herring C, Meldrum KK, Meldrum DR. Human progenitor cells from bone marrow or adipose tissue produce vegf, hgf, and igf-i in response to tnf by a p38 mapk-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2006;291:R880-884
104. Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J, Sidman RL, Walsh CA, Snyder EY, Khoury SJ. Directed migration of neural stem cells to sites of cns injury by the stromal cell-derived factor 1alpha/cxc chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101:18117-18122
105. Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino G. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature. 2005;436:266-271
106. Vendrame M, Gemma C, de Mesquita D, Collier L, Bickford PC, Sanberg CD, Sanberg PR, Pennypacker KR, Willing AE. Anti-inflammatory effects of human cord blood cells in a rat model of stroke. Stem Cells Dev. 2005;14:595-604
107. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100:13632-13637
108. Schwartz M. Macrophages and microglia in central nervous system injury: Are they helpful or harmful? J Cereb Blood Flow Metab. 2003;23:385-394
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