Journal of Shandong University (Health Sciences) ›› 2024, Vol. 62 ›› Issue (6): 1-8.doi: 10.6040/j.issn.1671-7554.0.2024.0265

• Preclinical Medicine •    

Effects of mesenchymal stem cells on ferroptosis in experimental autoimmune encephalomyelitis mice

LIU Haixia, HUANGFU Shasha, SANG Xiaoyu, CUI Dongqing, BI Jianzhong, WANG Ping   

  1. Department of Neurology, The Second Hospital of Shandong University, Jinan 250033, Shandong, China
  • Published:2024-07-15

Abstract: Objective To investigate the effects of mesenchymal stem cells(MSCs)treatment on ferroptosis and expressions of key regulatory proteins in experimental autoimmune encephalomyelitis(EAE)mice. Methods The body weights and symptom scores of mice were evaluated daily. To assess conditions of inflammation and myelination in spinal cord, the sections were respectively stained. The contents of reduced glutathione(GSH), malondialdehyde(MDA)and total superoxide dismutase(T-SOD)were tested to detect ferroptosis. The protein expressions of transferrin receptor 1(TFR1), acyl-CoA synthetase long-chain family 4(ACSL4), glutathione peroxidase 4(GPX4)and ferroptosis suppressor protein 1(FSP1)were detected with Western blotting. Results MSCs treatment alleviated weight loss and symptoms of EAE mice. Pathologically, MSCs improved infiltration of inflammatory cells and remyelination of mice. MSCs upregulated the contents of GSH in spinal cord and brain(P<0.01, P<0.05), as well as T-SOD in spinal cord(P<0.01), and downregulated MDA concentration in brain(P<0.05). Besides, MSCs reduced the protein expressions of TFR1(P<0.05, P<0.01)and ACSL4(P<0.05, P<0.001), increased the protein expressions of FSP1(both P<0.05)in spinal cord and brain. Also, the protein expression of GPX4 in brain was promoted after MSCs treatment(P<0.05). Conclusion MSCs play a therapeutic role in inhibiting ferroptosis in EAE mice by regulating iron metabolism, lipid metabolism and promoting reactive oxygen species clearance.

Key words: Multiple sclerosis, Experimental autoimmune encephalomyelitis, Mesenchymal stem cells, Ferroptosis, Iron metabolism

CLC Number: 

  • R741
[1] Kobelt G, Thompson A, Berg J, et al. New insights into the burden and costs of multiple sclerosis in Europe[J]. Mult Scler, 2017, 23(8): 1123-1136.
[2] Dangond F, Donnelly A, Hohlfeld R, et al. Facing the urgency of therapies for progressive MS-a Progressive MS Alliance proposal[J]. Nat Rev Neurol, 2021, 17(3): 185-192.
[3] Andrzejewska A, Dabrowska S, Lukomska B, et al. Mesenchymal stem cells for neurological disorders[J]. Adv Sci, 2021, 8(7): 2002944. doi:10.1002/advs.202002944.
[4] Jhelum P, Zandee S, Ryan F, et al. Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS[J]. Acta Neuropathol Commun, 2023, 11(1): 121. doi:10.1186/s40478-023-01617-7.
[5] Charabati M, Wheeler MA, Weiner HL, et al. Multiple sclerosis: neuroimmune crosstalk and therapeutic targeting[J]. Cell, 2023, 186(7): 1309-1327.
[6] Curko-Cofek B, Kezele TG, Marini c J, et al. Chronic iron overload induces gender-dependent changes in iron homeostasis, lipid peroxidation and clinical course of experimental autoimmune encephalomyelitis[J]. Neurotoxicology, 2016, 57: 1-12. doi:10.1016/j.neuro.2016.08.014.
[7] Grant SM, Wiesinger JA, Beard JL, et al. Iron-deficient mice fail to develop autoimmune encephalomyelitis[J]. J Nutr, 2003, 133(8): 2635-2638.
[8] Luoqian JY, Yang WY, Ding XL, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis[J]. Cell Mol Immunol, 2022, 19(8): 913-924.
[9] Duarte-Silva E, Meuth SG, Peixoto CA. The role of iron metabolism in the pathogenesis and treatment of multiple sclerosis[J]. Front Immunol, 2023, 14: 1137635. doi:10.3389/fimmu.2023.1137635.
[10] Jakimovski D, Bittner S, Zivadinov R, et al. Multiple sclerosis[J]. Lancet, 2024, 403(10422): 183-202.
[11] Lindsay SL, Molda AM, MacLellan LM, et al. Human olfactory mesenchymal stromal cell transplantation ameliorates experimental autoimmune encephalomyelitis revealing an inhibitory role for IL16 on myelination[J]. Acta Neuropathol Commun, 2022, 10(1): 12. doi:10.1186/s40478-022-01316-9.
[12] de Freitas CL, Polonio CM, Brandão WN, et al. Human fallopian tube-derived mesenchymal stem cells inhibit experimental autoimmune encephalomyelitis by suppressing Th1/Th17 activation and migration to central nervous system[J]. Stem Cell Rev Rep, 2022, 18(2): 609-625.
[13] Gavasso S, Kråkenes T, Olsen H, et al. The therapeutic mechanisms of mesenchymal stem cells in MS-a review focusing on neuroprotective properties[J]. Int J Mol Sci, 2024, 25(3): 1365. doi:10.3390/ijms25031365.
[14] Stockwell BR. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications[J]. Cell, 2022, 185(14): 2401-2421.
[15] Chen JJ, Galluzzi L. Fighting resilient cancers with iron[J]. Trends Cell Biol, 2018, 28(2): 77-78.
[16] 唐文诚, 何清, 李俊峰, 等. 川芎嗪通过抑制炎症反应和铁死亡减轻对乙酰氨基酚所致肝损伤[J]. 世界中医药, 2023, 18(24): 3512-3517. TANG Wencheng, HE Qing, LI Junfeng, et al. Ligustrazine alleviates acetaminophen-induced liver injury by inhibiting inflammatory response and ferroptosis[J]. World Chinese Medicine, 2023, 18(24): 3512-3517.
[17] Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575(7784): 693-698.
[18] Hu CL, Nydes M, Shanley KL, et al. Reduced expression of the ferroptosis inhibitor glutathione peroxidase-4 in multiple sclerosis and experimental autoimmune encephalomyelitis[J]. J Neurochem, 2019, 148(3): 426-439.
[19] Fan JY, Han YS, Sun HH, et al. Mesenchymal stem cell-derived exosomal microRNA-367-3p alleviates experimental autoimmune encephalomyelitis via inhibition of microglial ferroptosis by targeting EZH2[J]. Biomed Pharmacother, 2023, 162: 114593. doi:10.1016/j.biopha.2023.114593.
[20] 朱月新. 人脐带间充质干细胞通过激活Nrf2调控铁死亡改善2型糖尿病肾病的机制研究[D]. 长春: 吉林大学, 2023.
[21] Wang H, Sun Y, Xiao FJ, et al. Mesenchymal stem cells ameliorate DSS-induced experimental colitis by modulating the gut microbiota and MUC-1 pathway[J]. J Inflamm Res, 2023, 16: 2023-2039. doi:10.2147/JIR.S402592.
[22] Xu JF, Zhang MH, Liu F, et al. Mesenchymal stem cells alleviate post-resuscitation cardiac and cerebral injuries by inhibiting cell pyroptosis and ferroptosis in a swine model of cardiac arrest[J]. Front Pharmacol, 2021, 12: 793829. doi:10.3389/fphar.2021.793829.
[23] 姜懿洋, 刘帅, 张静涛, 等. 中医药通过诱导铁死亡治疗肺癌的研究进展[J]. 中医药学报, 2024, 52(3): 100-108. JIANG Yiyang, LIU Shuai, ZHANG Jingtao, et al. Progress in the treatment of lung cancer by iron death induced by traditional Chinese medicine[J]. Acta Chinese Medicine and Pharmacology, 2024, 52(3): 100-108.
[24] Sindrilaru A, Peters T, Wieschalka S, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice[J]. J Clin Invest, 2011, 121(3): 985-997.
[25] van San E, Debruyne AC, Veeckmans G, et al. Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression[J]. Cell Death Differ, 2023, 30(9): 2092-2103.
[26] 黄美玲. 内质网应激PERK信号通路对糖尿病肾病模型铁死亡的影响及胎盘间充质干细胞的干预机制研究[D]. 南昌: 南昌大学, 2023.
[27] Shao CL, Chen Y, Yang TY, et al. Mesenchymal stem cell derived exosomes suppress neuronal cell ferroptosis via lncGm36569/miR-5627-5p/FSP1 axis in acute spinal cord injury[J]. Stem Cell Rev Rep, 2022, 18(3): 1127-1142.
[28] Diggle CP. In vitro studies on the relationship between polyunsaturated fatty acids and cancer: tumour or tissue specific effects?[J]. Prog Lipid Res, 2002, 41(3): 240-253.
[29] Andrews NC, Schmidt PJ. Iron homeostasis[J]. Annu Rev Physiol, 2007, 69: 69-85. doi:10.1146/annurev.physiol.69.031905.164337.
[30] Feng HZ, Schorpp K, Jin J, et al. Transferrin receptor is a specific ferroptosis marker[J]. Cell Rep, 2020, 30(10): 3411-3423.
[31] 闫霖, 陆珏秀, 罗颖, 等. BM-MSCs来源外泌体介导铁死亡减轻大鼠心肌细胞系H9c2缺氧/复氧损伤[J]. 基础医学与临床, 2023, 43(5): 771-776. YAN Lin, LU Juexiu, LUO Ying, et al. Protective effect of BM-MSCs-derived exosome-mediated ferroptosis against anoxia-reoxygenation injury in rat cardiomyoblastl cell line H9c2[J]. Basic and Clinical Medicine, 2023, 43(5): 771-776.
[32] Zarruk JG, Berard JL, Passos dos Santos R, et al. Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation[J]. Neurobiol Dis, 2015, 81: 93-107. doi:10.1016/j.nbd.2015.02.001.
[33] Juurlink BH, Thorburne SK, Hertz L. Peroxide-scavenging deficit underlies oligodendrocyte susceptibility to oxidative stress[J]. Glia, 1998, 22(4): 371-378.
[34] Qin DQ, Li D, Wang CJ, et al. Ferroptosis and central nervous system demyelinating diseases[J]. J Neurochem, 2023, 165(6): 759-771.
[35] Li XY, Chu YJ, Ma R, et al. Ferroptosis as a mechanism of oligodendrocyte loss and demyelination in experimental autoimmune encephalomyelitis[J]. J Neuroimmunol, 2022, 373: 577995. doi:10.1016/j.jneuroim.2022.577995.
[1] SHEN Haitao, QIAO Yaqin, DONG Ping, LU Yan. Effects of programmed necrosis and ferroptosis regulated by toll-like receptor 4 on acetaminophen-induced liver injury [J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 1-8.
[2] SHEN Feifei, LI Dong, LIU Linghong, JU Xiuli. Umbilical cord mesenchymal stem cells sheets treated by small intestinal submucosa promote wound healing [J]. Journal of Shandong University (Health Sciences), 2024, 62(4): 68-77.
[3] WANG Cheng, ZHANG Shuhui, YAN Na, MENG Linlin, CHEN Liangzhi, LIU Qinghua. Mechanism of umbilical cord mesenchymal stem cells treating bleomycin-induced pulmonary interstitial fibrosis in mice [J]. Journal of Shandong University (Health Sciences), 2023, 61(10): 17-22.
[4] HOU Shaojin, WANG Yunfeng, CAO Lili, LIU Xuewu, ZHAO Xiuhe, WANG Shengjun. Comparison of cerebrospinal fluid detection in 53 patients with neuromyelitis optica spectrum disorder and 11 patients with multiple sclerosis [J]. Journal of Shandong University (Health Sciences), 2023, 61(1): 32-37.
[5] JIANG Hui, WEI Tian, LI Jianping, WANG Cong. Protective effects and molecular mechanism of puerarin on sorafenib-induced cardiotoxicity [J]. Journal of Shandong University (Health Sciences), 2022, 60(8): 14-22.
[6] FENG Baomin, WANG Zhou, XU Han, LI Jiacun, YU Qiaowen, XIU Jianjun. Clinical and imaging features of 19 cases of anti-myelin oligodendrocyte glycoprotein-IgG antibody associated disorders [J]. Journal of Shandong University (Health Sciences), 2022, 60(3): 45-50.
[7] ZHANG Gaorui, ZHANG Yuting, ZHAO Yuxuan, WANG Fangqing, YU Dexin. Value of MnFe2O4@CNS in the theragnostic of pancreatic cancer [J]. Journal of Shandong University (Health Sciences), 2021, 59(4): 48-55.
[8] JU Xiuli. Potential mechanism and research progress of mesenchymal stem cells in the treatment of 2019 novel coronavirus pneumonia [J]. Journal of Shandong University (Health Sciences), 2020, 58(3): 32-37.
[9] XU Yanyan, YAN Bei, WANG Rui, WANG Hongyan. Menstrual blood mesenchymal stem cells improve premature ovarian failure in mice via IGF-1 signaling [J]. Journal of Shandong University (Health Sciences), 2020, 58(2): 13-20.
[10] ZHAO Hongjian, ZHOU Jijun, SU Qingliang, ZHAO Shuo, LI Yuming. Correlation between human gastric cancer mesenchymal stem cells and tumor progression in SGC-7901 tumor-bearing mice [J]. Journal of Shandong University (Health Sciences), 2019, 57(9): 69-73.
[11] ZHANG Zhihui, LIU Yanguo, XIAO Fengqi, MA Daoxin, WANG Xiuwen. Effect of cisplatin on IL-6 expression in tumor mesenchymal stem cells and underlying mechanism of p38MAPK pathway [J]. Journal of Shandong University (Health Sciences), 2019, 57(3): 1-6.
[12] GUO Pei, LI Xiuhua, ZHANG Xiaotao, HE Tianqi, ZHU Meijia, TANG Jiyou, ZHAO Zhangning, MAO Fei. Clinical characteristics and influencing factors of sleep disorders in patients with Parkinsons disease [J]. Journal of Shandong University (Health Sciences), 2018, 56(4): 76-80.
[13] HUANG Ping, ZHANG Kun, LI Fang, HUANG Guobao, YAN Bing,XIAO Dongjie, WANG Yunshan, LIU Hua. Comparative study on biological characteristics of mesenchymal stem cells from human umbilical cord and adipose [J]. Journal of Shandong University (Health Sciences), 2018, 56(3): 72-78.
[14] LI Jingyuan, SONG Ling, LIN Song, SONG Hui. Effects of carbon monoxide releasing molecule-3 on the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(7): 31-37.
[15] DIAO Xiaojun, CHEN Chunfu, LI Congcong, ZHANG Yingbo, LI Yingying. Characteristics and prevalence of primary headaches in patients with multiple sclerosis [J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(4): 42-45.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
No Suggested Reading articles found!