The inhibitory effect of mesenchymal stem cell on blood–brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6

Journal of Neuroinflammation

Chuanzhi Duan¹  Zequn Wang¹  Qinrui Fang¹  Hui Li¹  Wei Li¹  Guohui Zhu¹  Yanchao Liu²  Lingfeng Lai¹  Xuying He¹  Xin Zhang¹  Xifeng Li¹  Min Chen¹ 

[1] The National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China;Department of Neurosurgery, The First People’s Hospital of Foshan and Foshan Hospital of Sun Yat Sen University, Foshan 528000, Guangdong, China

关键词: Inducible nitric oxide synthase;    Nuclear factor-κB;    TNF-α stimulated gene/protein 6;    Peroxynitrite;    Blood–brain barrier;    Intracerebral hemorrhage;    Mesenchymal stem cell;   

Others  :  1227104
DOI  :  10.1186/s12974-015-0284-x

 received in 2015-02-10, accepted in 2015-03-17,  发布年份 2015

【 摘 要 】

Background

Mesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies. The therapeutic mechanisms are mainly to investigate proliferation, differentiation, and immunomodulation. However, few studies have used MSCs to treat blood–brain barrier (BBB) leakage after ICH. The influence of MSCs on the BBB and its related mechanisms were investigated when MSCs were transplanted into rat ICH model in this study.

Methods

Adult male Sprague–Dawley (SD) rats were randomly divided into sham-operated group, PBS-treated (ICH + PBS) group, and MSC-treated (ICH + MSC) group. ICH was induced by injection of IV collagenase into the rats’ brains. MSCs were transplanted intravenously into the rats 2 h after ICH induction in MSC-treated group. The following factors were compared: inflammation, apoptosis, behavioral changes, inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP-9), peroxynitrite (ONOO⁻), endothelial integrity, brain edema content, BBB leakage, TNF-α stimulated gene/protein 6 (TSG-6), and nuclear factor-κB (NF-κB) signaling pathway.

Results

In the ICH + MSC group, MSCs decreased the levels of proinflammatory cytokines and apoptosis, downregulated the density of microglia/macrophages and neutrophil infiltration at the ICH site, reduced the levels of iNOS and MMP-9, attenuated ONOO⁻ formation, and increased the levels of zonula occludens-1 (ZO-1) and claudin-5. MSCs also improved the degree of brain edema and BBB leakage. The protective effect of MSCs on the BBB in ICH rats was possibly invoked by increased expression of TSG-6, which may have suppressed activation of the NF-κB signaling pathway. The levels of iNOS and ONOO⁻, which played an important role in BBB disruption, decreased due to the inhibitory effects of TSG-6 on the NF-κB signaling pathway.

Conclusions

Our results demonstrated that intravenous transplantation of MSCs decreased the levels of ONOO⁻ and degree of BBB leakage and improved neurological recovery in a rat ICH model. This strategy may provide a new insight for future therapies that aim to prevent breakdown of the BBB in patients with ICH and eventually offer therapeutic options for ICH.

【 授权许可】

   
2015 Chen et al.; licensee BioMed Central.

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【 参考文献 】

• [1]Butcher K, Laidlaw J: Current intracerebral haemorrhage management. J Clin Neurosci 2003, 10:158-67.
• [2]Xi G, Keep RF, Hoff JT: Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 1998, 89:991-6.
• [3]Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT: Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood–brain barrier permeability in rats. J Neurosurg 1994, 81:93-102.
• [4]Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ: Structure and function of the blood–brain barrier. Neurobiol Dis 2010, 37:13-25.
• [5]Kim KS: Mechanisms of microbial traversal of the blood–brain barrier. Nat Rev Microbiol 2008, 6:625-34.
• [6]Chu H, Ding H, Tang Y, Dong Q: Erythropoietin protects against hemorrhagic blood–brain barrier disruption through the effects of aquaporin-4. Lab Invest 2014, 94:1042-53.
• [7]Wang T, Chen X, Wang Z, Zhang M, Meng H, Gao Y, et al.: Poloxamer-188 can attenuate blood–brain barrier damage to exert neuroprotective effect in mice intracerebral hemorrhage model. J Mol Neurosci 2014, 55:240-250.
• [8]Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 1990, 87:1620-4.
• [9]Ding R, Chen Y, Yang S, Deng X, Fu Z, Feng L, et al.: Blood–brain barrier disruption induced by hemoglobin in vivo: involvement of up-regulation of nitric oxide synthase and peroxynitrite formation. Brain Res 2014, 1571:25-38.
• [10]Marcus JS, Karackattu SL, Fleegal MA, Sumners C: Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk mitogen-activated protein kinase and NF-kappaB. Glia 2003, 41:152-60.
• [11]Candolfi M, Jaita G, Zaldivar V, Zarate S, Pisera D, Seilicovich A: Tumor necrosis factor-alpha-induced nitric oxide restrains the apoptotic response of anterior pituitary cells. Neuroendocrinology 2004, 80:83-91.
• [12]Chang CC, Wang YH, Chern CM, Liou KT, Hou YC, Peng YT, et al.: Prodigiosin inhibits gp91(phox) and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia. Toxicol Appl Pharmacol 2011, 257:137-47.
• [13]Qayyum I, Zubrow AB, Ashraf QM, Kubin J, Delivoria-Papadopoulos M, Mishra OP: Nitration as a mechanism of Na+, K + −ATPase modification during hypoxia in the cerebral cortex of the guinea pig fetus. Neurochem Res 2001, 26:1163-9.
• [14]Cassina A, Radi R: Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys 1996, 328:309-16.
• [15]Wang W, Sawicki G, Schulz R: Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res 2002, 53:165-74.
• [16]Suofu Y, Clark J, Broderick J, Wagner KR, Tomsick T, Sa Y, et al.: Peroxynitrite decomposition catalyst prevents matrix metalloproteinase activation and neurovascular injury after prolonged cerebral ischemia in rats. J Neurochem 2010, 115:1266-76.
• [17]Li J, Zhang L, Xin J, Jiang L, Li J, Zhang T, et al.: Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs. Hepatology 2012, 56:1044-52.
• [18]Shi LL, Liu FP, Wang DW: Transplantation of human umbilical cord blood mesenchymal stem cells improves survival rates in a rat model of acute hepatic necrosis. Am J Med Sci 2011, 342:212-7.
• [19]Liu L, Yu Y, Hou Y, Chai J, Duan H, Chu W, et al.: Human umbilical cord mesenchymal stem cells transplantation promotes cutaneous wound healing of severe burned rats. PLoS One 2014, 9:e88348.
• [20]Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P, et al.: Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation 2013, 10:106. BioMed Central Full Text
• [21]Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al.: Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009, 5:54-63.
• [22]Wu HJ, Yiu WH, Li RX, Wong DW, Leung JC, Chan LY, et al.: Mesenchymal stem cells modulatealbumin-induced renal tubular inflammation and fibrosis. PLoS One 2014, 9:e90883.
• [23]Oh JY, Roddy GW, Choi H, Lee RH, Ylostalo JH, Rosa RJ, et al.: Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. Proc Natl Acad Sci U S A 2010, 107:16875-80.
• [24]Liu Y, Zhang R, Yan K, Chen F, Huang W, Lv B, et al.: Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6. J Neuroinflammation 2014, 11:135. BioMed Central Full Text
• [25]Jung Y, Kim SH, Kim YH, Kim SH: The effects of dynamic and three-dimensional environments on chondrogenic differentiation of bone marrow stromal cells. Biomed Mater 2009, 4:55009.
• [26]Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M: Collagenase-induced intracerebral hemorrhage in rats. Stroke 1990, 21:801-7.
• [27]Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, et al.: Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res 2003, 12:255-70.
• [28]Ke K, Rui Y, Li L, Zheng H, Xu W, Tan X, et al.: Upregulation of EHD2 after intracerebral hemorrhage in adult rats. J Mol Neurosci 2014, 54:171-80.
• [29]Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al.: Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001, 32:1005-11.
• [30]Song EC, Chu K, Jeong SW, Jung KH, Kim SH, Kim M, et al.: Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke 2003, 34:2215-20.
• [31]Khan M, Sakakima H, Dhammu TS, Shunmugavel A, Im YB, Gilg AG, et al.: S-nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats. J Neuroinflammation 2011, 8:78. BioMed Central Full Text
• [32]Yang S, Chen Y, Deng X, Jiang W, Li B, Fu Z, et al.: Hemoglobin-induced nitric oxide synthase overexpression and nitric oxide production contribute to blood–brain barrier disruption in the rat. J Mol Neurosci 2013, 51:352-63.
• [33]Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP: Traumatic spinal cord injury induces nuclear factor-kappaB activation. J Neurosci 1998, 18:3251-60.
• [34]Genovese T, Mazzon E, Esposito E, Muia C, Di Paola R, Bramanti P, et al.: Beneficial effects of FeTSPP, a peroxynitrite decomposition catalyst, in a mouse model of spinal cord injury. Free Radic Biol Med 2007, 43:763-80.
• [35]Shlosberg D, Benifla M, Kaufer D, Friedman A: Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 2010, 6:393-403.
• [36]Muijsers RB, Folkerts G, Henricks PA, Sadeghi-Hashjin G, Nijkamp FP: Peroxynitrite: a two-faced metabolite of nitric oxide. Life Sci 1997, 60:1833-45.
• [37]Pacher P, Beckman JS, Liaudet L: Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007, 87:315-424.
• [38]Arima H, Wang JG, Huang Y, Heeley E, Skulina C, Parsons MW, et al.: Significance of perihematomal edema in acute intracerebral hemorrhage: the INTERACT trial. Neurology 2009, 73:1963-8.
• [39]Chen HY, Chen TY, Lee MY, Chen ST, Hsu YS, Kuo YL, et al.: Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood–brain barrier permeability after transient focal cerebral ischemia in mice. J Pineal Res 2006, 41:175-82.
• [40]Parathath SR, Parathath S, Tsirka SE: Nitric oxide mediates neurodegeneration and breakdown of the blood–brain barrier in tPA-dependent excitotoxic injury in mice. J Cell Sci 2006, 119:339-49.
• [41]Phares TW, Fabis MJ, Brimer CM, Kean RB, Hooper DC: A peroxynitrite-dependent pathway is responsible for blood–brain barrier permeability changes during a central nervous system inflammatory response: TNF-alpha is neither necessary nor sufficient. J Immunol 2007, 178:7334-43.
• [42]Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, et al.: Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J Cell Biol 2003, 161:653-60.
• [43]Zhang GS, Tian Y, Huang JY, Tao RR, Liao MH, Lu YM, et al.: The gamma-secretase blocker DAPT reduces the permeability of the blood–brain barrier by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia. CNS Neurosci Ther 2013, 19:53-60.
• [44]Anderson JM, Fanning AS, Lapierre L, Van Itallie CM: Zonula occludens (ZO)-1 and ZO-2: membrane-associated guanylate kinase homologues (MAGuKs) of the tight junction. Biochem Soc Trans 1995, 23:470-5.
• [45]Gursoy-Ozdemir Y, Can A, Dalkara T: Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 2004, 35:1449-53.
• [46]Wang J, Tsirka SE: Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 2005, 128:1622-33.
• [47]Wang J, Dore S: Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 2007, 27:894-908.
• [48]Seyfried D, Ding J, Han Y, Li Y, Chen J, Chopp M: Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. J Neurosurg 2006, 104:313-8.
• [49]Wang SP, Wang ZH, Peng DY, Li SM, Wang H, Wang XH: Therapeutic effect of mesenchymal stem cells in rats with intracerebral hemorrhage: reduced apoptosis and enhanced neuroprotection. Mol Med Rep 2012, 6:848-54.
• [50]Bao XJ, Liu FY, Lu S, Han Q, Feng M, Wei JJ, et al.: Transplantation of Flk-1+ human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and anti-inflammatory and angiogenesis effects in an intracerebral hemorrhage rat model. Int J Mol Med 2013, 31:1087-96.
• [51]Liao W, Zhong J, Yu J, Xie J, Liu Y, Du L, et al.: Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: implications of anti-inflammation and angiogenesis. Cell Physiol Biochem 2009, 24:307-16.
• [52]Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al.: Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009, 15:42-9.
• [53]Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D: Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004, 103:4619-21.
• [54]Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, Moretta L: Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 2008, 111:1327-33.
• [55]Aggarwal S, Pittenger MF: Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005, 105:1815-22.
• [56]Milner CM, Higman VA, Day AJ: TSG-6: a pluripotent inflammatory mediator? Biochem Soc Trans 2006, 34:446-50.
• [57]Getting SJ, Mahoney DJ, Cao T, Rugg MS, Fries E, Milner CM, et al.: The link module from human TSG-6 inhibits neutrophil migration in a hyaluronan- and inter-alpha -inhibitor-independent manner. J Biol Chem 2002, 277:51068-76.
• [58]Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ: Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood 2011, 118:330-8.
• [59]Zhao X, Zhang Y, Strong R, Zhang J, Grotta JC, Aronowski J: Distinct patterns of intracerebral hemorrhage-induced alterations in NF-kappaB subunit, iNOS, and COX-2 expression. J Neurochem 2007, 101:652-63.
• [60]Bowie A, O'Neill LA: Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 2000, 59:13-23.
• [61]Bredt DS: Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 1999, 31:577-96.
• [62]Ohtaki H, Funahashi H, Dohi K, Oguro T, Horai R, Asano M, et al.: Suppression of oxidative neuronal damage after transient middle cerebral artery occlusion in mice lacking interleukin-1. Neurosci Res 2003, 45:313-24.
• [63]Walford GA, Moussignac RL, Scribner AW, Loscalzo J, Leopold JA: Hypoxia potentiates nitric oxide-mediated apoptosis in endothelial cells via peroxynitrite-induced activation of mitochondria-dependent and -independent pathways. J Biol Chem 2004, 279:4425-32.
• [64]Yokoo H, Chiba S, Tomita K, Takashina M, Sagara H, Yagisita S, et al.: Neurodegenerative evidence in mice brains with cecal ligation and puncture-induced sepsis: preventive effect of the free radical scavenger edaravone. PLoS One 2012, 7:e51539.
• [65]Luth HJ, Munch G, Arendt T: Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation. Brain Res 2002, 953:135-43.
• [66]Murphy G, Willenbrock F, Crabbe T, O'Shea M, Ward R, Atkinson S, et al.: Regulation of matrix metalloproteinase activity. Ann N Y Acad Sci 1994, 732:31-41.