Abstract
Here, we have investigated the synergistic effect of quercetin administration and transplantation of human umbilical cord mesenchymal stromal cells (HUMSCs) following middle cerebral artery occlusion in rat. Combining quercetin treatment with delayed transplantation of HUMSCs after local cerebral ischemia significantly (i) improved neurological functional recovery; (ii) reduced proinflammatory cytokines (interleukin(IL)-1β and IL-6), increased anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor-β1), and reduced ED-1 positive areas; (iii) inhibited cell apoptosis (caspase-3 expression); and (iv) improved the survival rate of HUMSCs in the injury site. Altogether, our results demonstrate that combined HUMSC transplantation and quercetin treatment is a potential strategy for reducing secondary damage and promoting functional recovery following cerebral ischemia.
Similar content being viewed by others
References
Anderson AJ (2002) Mechanisms and pathways of inflammatory responses in CNS trauma: spinal cord injury. J Spinal Cord Med 25(2):70–79 discussion 80
Bednar MM, Gross CE (1999) Antiplatelet therapy in acute cerebral ischemia. Stroke 30(4):887–893
Bosoi CR, Rose CF (2013) Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 28(2):175–178. doi:10.1007/s11011-012-9351-5
Bosoi CR, Yang X, Huynh J, Parent-Robitaille C, Jiang W, Tremblay M, Rose CF (2012) Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure. Free Radic Biol Med 52(7):1228–1235. doi:10.1016/j.freeradbiomed.2012.01.006
Chelluboina B, Klopfenstein JD, Pinson DM, Wang DZ, Veeravalli KK (2014) Stem cell treatment after cerebral ischemia regulates the gene expression of apoptotic molecules. Neurochem Res 39(8):1511–1521. doi:10.1007/s11064-014-1341-z
Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M (2001) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32(4):1005–1011
Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73(6):778–786. doi:10.1002/jnr.10691
Cheng Q, Zhang Z, Zhang S, Yang H, Zhang X, Pan J, Weng L, Sha D, Zhu M, Hu X, Xu Y (2015) Human umbilical cord mesenchymal stem cells protect against ischemic brain injury in mouse by regulating peripheral immunoinflammation. Brain Res 1594:293–304. doi:10.1016/j.brainres.2014.10.065
Cho JY, Kim IS, Jang YH, Kim AR, Lee SR (2006) Protective effect of quercetin, a natural flavonoid against neuronal damage after transient global cerebral ischemia. Neurosci Lett 404(3):330–335. doi:10.1016/j.neulet.2006.06.010
Dok-Go H, Lee KH, Kim HJ, Lee EH, Lee J, Song YS, Lee YH, Jin C, Lee YS, Cho J (2003) Neuroprotective effects of antioxidative flavonoids, quercetin, (+)-dihydroquercetin and quercetin 3-methyl ether, isolated from Opuntia ficus-indica var. saboten. Brain Res 965(1–2):130–136
Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8(4):355–369. doi:10.1016/S1474-4422(09)70025-0
Geng CK, Cao HH, Ying X, Zhang HT, Yu HL (2015) The effects of hyperbaric oxygen on macrophage polarization after rat spinal cord injury. Brain Res 1606:68–76. doi:10.1016/j.brainres.2015.01.029
Karimi-Abdolrezaee S, Eftekharpour E (2012) Stem cells and spinal cord injury repair. Adv Exp Med Biol 760:53–73
Kinaci MK, Erkasap N, Kucuk A, Koken T, Tosun M (2012) Effects of quercetin on apoptosis, NF-kappaB and NOS gene expression in renal ischemia/reperfusion injury. Exp Ther Med 3(2):249–254. doi:10.3892/etm.2011.382
Koh SH, Kim KS, Choi MR, Jung KH, Park KS, Chai YG, Roh W, Hwang SJ, Ko HJ, Huh YM, Kim HT, Kim SH (2008) Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res 1229:233–248. doi:10.1016/j.brainres.2008.06.087
Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ (2009) 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 5(1):54–63. doi:10.1016/j.stem.2009.05.003
Lee JK, Kwak HJ, Piao MS, Jang JW, Kim SH, Kim HS (2011) Quercetin reduces the elevated matrix metalloproteinases-9 level and improves functional outcome after cerebral focal ischemia in rats. Acta Neurochir 153(6):1321–1329. doi:10.1007/s00701-010-0889-x discussion 1329
Lei X, Chao H, Zhang Z, Lv J, Li S, Wei H, Xue R, Li F, Li Z (2015) Neuroprotective effects of quercetin in a mouse model of brain ischemic/reperfusion injury via anti-apoptotic mechanisms based on the Akt pathway. Mol Med Rep 12(3):3688–3696. doi:10.3892/mmr.2015.3857
Leu S, Lin YC, Yuen CM, Yen CH, Kao YH, Sun CK, Yip HK (2010) Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats. J Transl Med 8:63. doi:10.1186/1479-5876-8-63
Liu N, Zhang Y, Fan L, Yuan M, Du H, Cheng R, Liu D, Lin F (2011) Effects of transplantation with bone marrow-derived mesenchymal stem cells modified by Survivin on experimental stroke in rats. J Transl Med 9:105. doi:10.1186/1479-5876-9-105
Liu X, Ye R, Yan T, Yu SP, Wei L, Xu G, Fan X, Jiang Y, Stetler RA, Liu G, Chen J (2014) Cell based therapies for ischemic stroke: from basic science to bedside. Prog Neurobiol 115:92–115. doi:10.1016/j.pneurobio.2013.11.007
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91
McCall J, Weidner N, Blesch A (2012) Neurotrophic factors in combinatorial approaches for spinal cord regeneration. Cell Tissue Res 349(1):27–37. doi:10.1007/s00441-012-1388-6
Schultke E, Griebel RW, Juurlink BH (2010) Quercetin attenuates inflammatory processes after spinal cord injury in an animal model. Spinal Cord 48(12):857–861. doi:10.1038/sc.2010.45
Simard JM, Geng Z, Woo SK, Ivanova S, Tosun C, Melnichenko L, Gerzanich V (2009) Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cerebr Blood Flow Metab 29(2):317–330. doi:10.1038/jcbfm.2008.120
Troyer DL, Weiss ML (2008) Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells 26(3):591–599. doi:10.1634/stemcells.2007-0439
Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC (2004) Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 22(7):1330–1337. doi:10.1634/stemcells.2004-0013
Yao RQ, Qi DS, Yu HL, Liu J, Yang LH, Wu XX (2012) Quercetin attenuates cell apoptosis in focal cerebral ischemia rat brain via activation of BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem Res 37(12):2777–2786. doi:10.1007/s11064-012-0871-5
Yuan YM, He C (2013) The glial scar in spinal cord injury and repair. Neurosci Bull 29(4):421–435. doi:10.1007/s12264-013-1358-3
Zhang L, Zhang HT, Hong SQ, Ma X, Jiang XD, Xu RX (2009) Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection. Neurochem Res 34(11):2030–2039. doi:10.1007/s11064-009-9992-x
Zhang HT, Fan J, Cai YQ, Zhao SJ, Xue S, Lin JH, Jiang XD, Xu RX (2010) Human Wharton’s jelly cells can be induced to differentiate into growth factor-secreting oligodendrocyte progenitor-like cells. Differentiation 79(1):15–20. doi:10.1016/j.diff.2009.09.002
Zhu Y, Guan YM, Huang HL, Wang QS (2014) Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits. Acta Pharmacol Sin 35(5):585–591. doi:10.1038/aps.2014.9
Acknowledgments
This work was supported by the President Foundation of Nanfang Hospital, Southern Medical University (2012B016) and the Natural Scientific Research funds of China (No. 81371345).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, LL., Zhang, HT., Cai, YQ. et al. Anti-inflammatory Effect of Mesenchymal Stromal Cell Transplantation and Quercetin Treatment in a Rat Model of Experimental Cerebral Ischemia. Cell Mol Neurobiol 36, 1023–1034 (2016). https://doi.org/10.1007/s10571-015-0291-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-015-0291-6