Mesenchymal stem cells transplantation delays functional deteriorationby inhibiting neuroinflammation response in aged mice

Mesenchymal stem cells transplantation delays functional deteriorationby inhibiting neuroinflammation response in aged mice

This study investigated the effect of transplantation of bone marrow mesenchymal stem cells (BM-MSCs) on functional deterioration and neuroinflammatory response in aged C57BL/6J mice. Mice were divided into 3 groups: normal aged group, saline control group, and BM-MSCs treatment group. Saline and BM-MSCs were administrated by intraventricular injection into the right ventricle. Spatial Y-maze (SYM) test, novel objective recognition (NOR) test, and locomotor activity test were used to evaluate cognitive and locomotor ability at 7 and 42 days after transplantation. Microglia and astrocyte expression in the hippocampus CA1 region and dentate gyrus (DG) were evaluated by immunohistochemical method. Furthermore, the content of TNF-α, IL-1α, and IL-1β in the hippocampus and cortex were detected with ELISA. We found that BM-MSCs transplantation increased time in novel arm and percentage of alteration in SYM test, discrimination ratio and discrimination index in the NOR test, and traveled total distance and mean velocity in the locomotor activity test. It also inhibited microglia and astrocyte expression, and reduced the content of IL-1α and IL-1β in the hippocampus. Our results suggested that BM-MSCs transplantation could delay cognitive and locomotor function deterioration through inhibiting neuroinflammation response, which would provide a rationale for exploring the viability of using BM-MSCs transplantation in cognitive deficit diseases.

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  • Babcock AA, Ilkjaer L, Clausen BH, Villadsen B, Dissing-Olesen L, Bendixen AT, Lyck L, Lambertsen KL, Finsen B (2015). Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice. Brain Behav Immun 48: 86– 101.
  • Boehme M, Guenther M, Stahr A, Liebmann M, Jaenisch N, Witte OW, Frahm C (2014). Impact of indomethacin on neuroinflammation and hippocampal neurogenesis in aged mice. Neurosci Lett 572: 7–12.
  • Chang YK, Chen MH, Chiang YH, Chen YF, Ma WH, Tseng CY, Soong BW, Ho JH, Lee OK (2011). Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci 18: 54.
  • Cutuli D, De Bartolo P, Caporali P, Laricchiuta D, Foti F, Ronci M, Rossi C, Neri C, Spalletta G, Caltagirone C et al. (2014). n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice. Front Aging Neurosci 6: 220.
  • Ersahin M, Cevik O, Akakin D, Sener A, Ozbay L, Yegen BC, Sener G (2012). Montelukast inhibits caspase-3 activity and ameliorates oxidative damage in the spinal cord and urinary bladder of rats with spinal cord injury. Prostaglandins Other Lipid Mediat 99: 131–139.
  • Franco EC, Cardoso MM, Gouveia A, Pereira A, Gomes-Leal W (2012). Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia. Neurosci Res 73: 122–132.
  • Gebara E, Udry F, Sultan S, Toni N (2015). Taurine increases hippocampal neurogenesis in aging mice. Stem Cell Res 14: 369–379.
  • Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA (2006). The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 99: 1263–1272.
  • Hamby AM, Suh SW, Kauppinen TM, Swanson RA (2007). Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia reperfusion. Stroke 38: 632–636.
  • Han D, Wu C, Xiong Q, Zhou L, Tian Y (2014). Anti-inflammatory Mechanism of bone marrow mesenchymal stem cell transplantation in rat model of spinal cord injury. Cell Biochem Biophys [Epub ahead of print].
  • Henry CJ, Huang Y, Wynne AM, Godbout JP (2009). Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23: 309– 317.
  • Hu J, Yang Z, Wang J, Tang Y, Liu H, Zhang B, Chen H (2013). Infusion of Trx-1-overexpressing hucMSC prolongs the survival of acutely irradiated NOD/SCID mice by decreasing excessive inflammatory injury. PLoS One 8: e78227.
  • Huang ZL, Liu R, Bai XY, Zhao G, Song JK, Wu S, Du GH (2014). Protective effects of the novel adenosine derivative WS0701 in a mouse model of posttraumatic stress disorder. Acta Pharmacol Sin 35: 24–32.
  • Jenrow KA, Brown SL, Lapanowski K, Naei H, Kolozsvary A, Kim JH (2013). Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res 179: 549–556.
  • Kajitani K, Thorne M, Samson M, Robertson GS (2010). Nitric oxide synthase mediates the ability of darbepoetin alpha to improve the cognitive performance of STOP null mice. Neuropsychopharmacology 35: 1718–1728.
  • Kim BW, Koppula S, Kumar H, Park JY, Kim IW, More SV, Kim IS, Han SD, Kim SK, Yoon SH et al. (2015). alpha-Asarone attenuates microglia-mediated neuroinflammation by inhibiting NF kappa B activation and mitigates MPTP-induced behavioral deficits in a mouse model of Parkinson’s disease. Neuropharmacology 97: 46–57.
  • Kong H, Yin F, He F, Omran A, Li L, Wu T, Wang Y, Peng J (2015). The effect of miR-132, miR-146a, and miR-155 on MRP8/ TLR4-induced astrocyte-related inflammation. J Mol Neurosci 57: 28–37.
  • Kopen GC, Prockop DJ, Phinney DG (1999). Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 96: 10711–10716.
  • Lanzrein AS, Johnston CM, Perry VH, Jobst KA, King EM, Smith AD (1998). Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1- antichymotrypsin. Alzheimer Dis Assoc Disord 12: 215–227.
  • Liu Y, Zhang R, Yan K, Chen F, Huang W, Lv B, Sun C, Xu L, Li F, Jiang X (2014). Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6. J Neuroinflammation 11: 135–145.
  • Neumann J, Sauerzweig S, Ronicke R, Gunzer F, Dinkel K, Ullrich O, Gunzer M, Reymann KG (2008). Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci 28: 5965–5975.
  • Norden DM, Godbout JP (2013). Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39: 19–34.
  • Park SY, Kim MJ, Kim YJ, Lee YH, Bae D, Kim S, Na Y, Yoon HG (2015). Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-kappaB-mediated neuroinflammation induced by Abeta in a model of Alzheimer’s disease. Int J Mol Med 35: 1109–1118.
  • Pastor D, Viso-Leon MC, Jones J, Jaramillo-Merchan J, Toledo-Aral JJ, Moraleda JM, Martinez S (2012). Comparative effects between bone marrow and mesenchymal stem cell transplantation in GDNF expression and motor function recovery in a motorneuron degenerative mouse model. Stem Cell Rev 8: 445–458.
  • Rachmany L, Tweedie D, Rubovitch V, Yu QS, Li Y, Wang JY, Pick CG, Greig NH (2013). Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-alpha. PLoS One 8: e79837.
  • Saleem S, Tabassum S, Ahmed S, Perveen T, Haider S (2014). Senescence related alteration in hippocampal biogenic amines produces neuropsychological deficits in rats. Pak J Pharm Sci 27: 837–845.
  • Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H (2011). Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 34: 3–11.
  • Schmidt S, Gawlik V, Holter SM, Augustin R, Scheepers A, Behrens M, Wurst W, Gailus-Durner V, Fuchs H, Hrabe de Angelis M et al. (2008). Deletion of glucose transporter GLUT8 in mice increases locomotor activity. Behav Genet 38: 396–406.
  • Wahl F, Allix M, Plotkine M, Boulu RG (1992). Neurological and behavioral outcomes of focal cerebral ischemia in rats. Stroke 23: 267–272.
  • Wu SM, Zhang WX, Wang MH, Zhang HZ, Wu DG, Zhou ZJ, Xiong LH (2013). Proteomic analysis of the immunosuppressive effects of mesenchymal stem cells in a rat heart transplantation model. Adv Clin Exp Med 22: 785–794.
  • Yamawaki-Ogata A, Fu X, Hashizume R, Fujimoto KL, Araki Y, Oshima H, Narita Y, Usui A (2014). Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model. Eur J Cardiothorac Surg 45: e156–165.
  • Zhang Q, Wei EQ, Zhu CY, Zhang WP, Wang ML, Zhang SH, Yu YP, Chen Z (2006). Focal cerebral ischemia alters the spatio-temporal properties, but not the amount of activity in mice. Behav Brain Res 169: 66–74.
  • Zhang Y, Zhao D, Tian C, Li F, Li X, Zhang L, Yang H (2013). Stro-1-positive human mesenchymal stem cells prolong skin graft survival in mice. Transplant Proc 45: 726–729.
  • Zhou C, Zhang C, Chi S, Xu Y, Teng J, Wang H, Song Y, Zhao R (2009). Effects of human marrow stromal cells on activation of microglial cells and production of inflammatory factors induced by lipopolysaccharide. Brain Res 1269: 23–30.
  • Zhu LH, Bai X, Zhang N, Wang SY, Li W, Jiang L (2014). Improvement of human umbilical cord mesenchymal stem cell transplantation on glial cell and behavioral function in a neonatal model of periventricular white matter damage. Brain Res 1563: 13–21