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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2013

Open Access 01-12-2013 | Research

Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury

Authors: Run Zhang, Yi Liu, Ke Yan, Lei Chen, Xiang-Rong Chen, Peng Li, Fan-Fan Chen, Xiao-Dan Jiang

Published in: Journal of Neuroinflammation | Issue 1/2013

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Abstract

Background

Previous studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model.

Methods/results

MSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-β1] in brain homogenates. The immunosuppression-related factors TNF-α stimulated gene/protein 6 (TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway.

Conclusions

The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI.
Literature
1.
2.
Helmy A, Carpenter KL, Menon DK, Pickard JD, Hutchinson PJ: The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab 2011, 31:658–670.CrossRefPubMed
3.
Correale J, Villa A: The neuroprotective role of inflammation in nervous system injuries. J Neurol 2004, 251:1304–1316.CrossRefPubMed
4.
Ziebell JM, Morganti-Kossmann MC: Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 2010, 7:22–30.CrossRefPubMedPubMedCentral
5.
Rhodes J: Peripheral immune cells in the pathology of traumatic brain injury? Curr Opin Crit Care 2011, 17:122–130.CrossRefPubMed
6.
Lucas SM, Rothwell NJ, Gibson RM: The role of inflammation in CNS injury and disease. Br J Pharmacol 2006,147(Suppl 1):S232-S240.PubMedPubMedCentral
7.
Helmy A, De Simoni MG, Guilfoyle MR, Carpenter KL, Hutchinson PJ: Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury. Prog Neurobiol 2011, 95:352–372.CrossRefPubMed
8.
d’Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA: Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation 2012, 9:31.PubMedPubMedCentral
9.
Morganti-Kossmann MC, Satgunaseelan L, Bye N, Kossmann T: Modulation of immune response by head injury. Injury 2007, 38:1392–1400.CrossRefPubMed
10.
Brait VH, Arumugam TV, Drummond GR, Sobey CG: Importance of T lymphocytes in brain injury, immunodeficiency, and recovery after cerebral ischemia. J Cereb Blood Flow Metab 2012, 32:598–611.CrossRefPubMedPubMedCentral
11.
12.
Winter CD, Pringle AK, Clough GF, Church MK: Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain 2004, 127:315–320.CrossRefPubMed
13.
Turrin NP, Rivest S: Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity. J Neurosci 2006, 26:143–151.CrossRefPubMed
14.
Biber K, Neumann H, Inoue K, Boddeke HW: Neuronal ‘on’ and ‘off’ signals control microglia. Trends Neurosci 2007, 30:596–602.CrossRefPubMed
15.
16.
Parr AM, Tator CH, Keating A: Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007, 40:609–619.CrossRefPubMed
17.
Chopp M, Li Y: Treatment of neural injury with marrow stromal cells. Lancet Neurol 2002, 1:92–100.CrossRefPubMed
18.
Si YL, Zhao YL, Hao HJ, Fu XB, Han WD: MSCs: Biological characteristics, clinical applications and their outstanding concerns. Ageing Res Rev 2011, 10:93–103.CrossRefPubMed
19.
Scuteri A, Miloso M, Foudah D, Orciani M, Cavaletti G, Tredici G: Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair? Curr Stem Cell Res Ther 2011, 6:82–92.CrossRefPubMed
20.
Meirelles Lda S, Fontes AM, Covas DT, Caplan AI: Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev 2009, 20:419–427.CrossRefPubMed
21.
Uccelli A, Moretta L, Pistoia V: Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008, 8:726–736.CrossRefPubMed
22.
Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G: How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 2012, 33:136–143.CrossRefPubMedPubMedCentral
23.
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM: Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002, 99:3838–3843.CrossRefPubMed
24.
Ooi YY, Ramasamy R, Rahmat Z, Subramaiam H, Tan SW, Abdullah M, Israf DA, Vidyadaran S: Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide. Int Immunopharmacol 2010, 10:1532–1540.CrossRefPubMed
25.
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, 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, 15:42–49.CrossRefPubMed
26.
Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F, Ottonello L, Pistoia V: Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 2008, 26:151–162.CrossRefPubMed
27.
Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, et al.: Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005, 106:1755–1761.CrossRefPubMed
28.
Gerdoni E, Gallo B, Casazza S, Musio S, Bonanni I, Pedemonte E, Mantegazza R, Frassoni F, Mancardi G, Pedotti R, Uccelli A: Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 2007, 61:219–227.CrossRefPubMed
29.
Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O: Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004, 363:1439–1441.CrossRefPubMed
30.
Stemberger S, Jamnig A, Stefanova N, Lepperdinger G, Reindl M, Wenning GK: Mesenchymal stem cells in a transgenic mouse model of multiple system atrophy: immunomodulation and neuroprotection. PLoS One 2011, 6:e19808.CrossRefPubMedPubMedCentral
31.
Ortiz LA, Dutreil M, Fattman C, Pandey AC, Torres G, Go K, Phinney DG: Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 2007, 104:11002–11007.CrossRefPubMedPubMedCentral
32.
Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA: Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007, 179:1855–1863.CrossRefPubMed
33.
Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ: 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.CrossRefPubMedPubMedCentral
34.
Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C: Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005, 289:F31-F42.CrossRefPubMed
35.
Sheikh AM, Nagai A, Wakabayashi K, Narantuya D, Kobayashi S, Yamaguchi S, Kim SU: Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-5. Neurobiol Dis 2011, 41:717–724.CrossRefPubMed
36.
Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS: Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells 2010, 28:329–343.PubMed
37.
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.CrossRefPubMed
38.
Lee ST, Chu K, Jung KH, Kim SJ, Kim DH, Kang KM, Hong NH, Kim JH, Ban JJ, Park HK, et al.: Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. Brain 2008, 131:616–629.CrossRefPubMed
39.
Aggarwal S, Pittenger MF: Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005, 105:1815–1822.CrossRefPubMed
40.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8:315–317.CrossRefPubMed
41.
Feeney DM, Boyeson MG, Linn RT, Murray HM, Dail WG: Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res 1981, 211:67–77.CrossRefPubMed
42.
Lu M, Chen J, Lu D, Yi L, Mahmood A, Chopp M: Global test statistics for treatment effect of stroke and traumatic brain injury in rats with administration of bone marrow stromal cells. J Neurosci Methods 2003, 128:183–190.CrossRefPubMed
43.
Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC: Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2−/− mice. J Cereb Blood Flow Metab 2010, 30:769–782.CrossRefPubMed
44.
Li M, Li F, Luo C, Shan Y, Zhang L, Qian Z, Zhu G, Lin J, Feng H: Immediate splenectomy decreases mortality and improves cognitive function of rats after severe traumatic brain injury. J Trauma 2011, 71:141–147.CrossRefPubMed
45.
Lau LT, Yu AC: Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma 2001, 18:351–359.CrossRefPubMed
46.
Konsman JP, Drukarch B, Van Dam AM: (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond) 2007, 112:1–25.CrossRef
47.
Cederberg D, Siesjo P: What has inflammation to do with traumatic brain injury? Childs Nerv Syst 2010, 26:221–226.CrossRefPubMed
48.
Kremlev SG, Palmer C: Interleukin-10 inhibits endotoxin-induced pro-inflammatory cytokines in microglial cell cultures. J Neuroimmunol 2005, 162:71–80.CrossRefPubMed
49.
Knoblach SM, Faden AI: Interleukin-10 improves outcome and alters proinflammatory cytokine expression after experimental traumatic brain injury. Exp Neurol 1998, 153:143–151.CrossRefPubMed
50.
Liu N, Chen R, Du H, Wang J, Zhang Y, Wen J: Expression of IL-10 and TNF-alpha in rats with cerebral infarction after transplantation with mesenchymal stem cells. Cell Mol Immunol 2009, 6:207–213.CrossRefPubMedPubMedCentral
51.
Du YY, Zhou SH, Zhou T, Su H, Pan HW, Du WH, Liu B, Liu QM: Immuno-inflammatory regulation effect of mesenchymal stem cell transplantation in a rat model of myocardial infarction. Cytotherapy 2008, 10:469–478.CrossRefPubMed
52.
Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV: Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 1999, 23:297–308.CrossRefPubMed
53.
Schafer S, Calas AG, Vergouts M, Hermans E: Immunomodulatory influence of bone marrow-derived mesenchymal stem cells on neuroinflammation in astrocyte cultures. J Neuroimmunol 2012, 249:40–48.CrossRefPubMed
54.
Semple BD, Bye N, Ziebell JM, Morganti-Kossmann MC: Deficiency of the chemokine receptor CXCR2 attenuates neutrophil infiltration and cortical damage following closed head injury. Neurobiol Dis 2010, 40:394–403.CrossRefPubMed
55.
Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, Morganti-Kossmann MC: Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol 2007, 204:220–233.CrossRefPubMed
56.
Rhodes JK, Sharkey J, Andrews PJ: The temporal expression, cellular localization, and inhibition of the chemokines MIP-2 and MCP-1 after traumatic brain injury in the rat. J Neurotrauma 2009, 26:507–525.CrossRefPubMed
57.
Rancan M, Otto VI, Hans VH, Gerlach I, Jork R, Trentz O, Kossmann T, Morganti-Kossmann MC: Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats. J Neurosci Res 2001, 63:438–446.CrossRefPubMed
58.
Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, Vogel SN: Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab 2003, 23:748–755.CrossRefPubMed
59.
Lumpkins K, Bochicchio GV, Zagol B, Ulloa K, Simard JM, Schaub S, Meyer W, Scalea T: Plasma levels of the beta chemokine regulated upon activation, normal T cell expressed, and secreted (RANTES) correlate with severe brain injury. J Trauma 2008, 64:358–361.CrossRefPubMed
60.
Gonzalez R, Glaser J, Liu MT, Lane TE, Keirstead HS: Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury. Exp Neurol 2003, 184:456–463.CrossRefPubMed
61.
Clausen F, Lorant T, Lewen A, Hillered L: T lymphocyte trafficking: a novel target for neuroprotection in traumatic brain injury. J Neurotrauma 2007, 24:1295–1307.CrossRefPubMed
62.
Prockop DJ, Oh JY: Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Ther 2012, 20:14–20.CrossRefPubMed
63.
Wisniewski HG, Vilcek J: TSG-6: an IL-1/TNF-inducible protein with anti-inflammatory activity. Cytokine Growth Factor Rev 1997, 8:143–156.CrossRefPubMed
64.
Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, Rosa RH Jr, Prockop DJ: Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6. Stem Cells 2011, 29:1572–1579.CrossRefPubMed
65.
Chen G, Shi J, Ding Y, Yin H, Hang C: Progesterone prevents traumatic brain injury-induced intestinal nuclear factor kappa B activation and proinflammatory cytokines expression in male rats. Mediators Inflamm 2007, 2007:93431.PubMedPubMedCentral
66.
Qu C, Mahmood A, Ning R, Xiong Y, Zhang L, Chen J, Jiang H, Chopp M: The treatment of traumatic brain injury with velcade. J Neurotrauma 2010, 27:1625–1634.CrossRefPubMedPubMedCentral
67.
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, 118:330–338.CrossRefPubMedPubMedCentral
68.
Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y: Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008, 2:141–150.CrossRefPubMed
69.
Koshinaga M, Katayama Y, Fukushima M, Oshima H, Suma T, Takahata T: Rapid and widespread microglial activation induced by traumatic brain injury in rat brain slices. J Neurotrauma 2000, 17:185–192.CrossRefPubMed
70.
Koshinaga M, Suma T, Fukushima M, Tsuboi I, Aizawa S, Katayama Y: Rapid microglial activation induced by traumatic brain injury is independent of blood brain barrier disruption. Histol Histopathol 2007, 22:129–135.PubMed
71.
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA: Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells 2006, 24:2582–2591.CrossRefPubMed
72.
Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, Abramsky O, Karussis D: Neuroprotection and immunomodulation with mesenchymal stem cells in chronic experimental autoimmune encephalomyelitis. Arch Neurol 2008, 65:753–761.CrossRefPubMed
73.
Metadata
Title
Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury
Authors
Run Zhang
Yi Liu
Ke Yan
Lei Chen
Xiang-Rong Chen
Peng Li
Fan-Fan Chen
Xiao-Dan Jiang
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2013
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-10-106

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