Protective effect and mechanism of mesenchymal stem cell-derived extracellular vesicle on radiation-induced liver injury

Chen Chi; Xiao Jiaqi; Sui Xin; Zhang Yingcai

doi:10.3969/j.issn.1674-7445.2023.03.013

Volume 14 Issue 3

May 2023

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Chen Chi, Xiao Jiaqi, Sui Xin, et al. Protective effect and mechanism of mesenchymal stem cell-derived extracellular vesicle on radiation-induced liver injury[J]. ORGAN TRANSPLANTATION, 2023, 14(3): 411-419. doi: 10.3969/j.issn.1674-7445.2023.03.013

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Protective effect and mechanism of mesenchymal stem cell-derived extracellular vesicle on radiation-induced liver injury

doi: 10.3969/j.issn.1674-7445.2023.03.013

Department of Hepatic Surgery, Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China

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Corresponding author: Zhang Yingcai, Email: zhangyc3@mail.sysu.edu.cn
Received Date: 2023-02-14
Publish Date: 2023-05-15

Abstract

Abstract

Objective To evaluate the protective effect and the underlying mechanism of mesenchymal stem cell-derived extracellular vesicle (MSC-EV) on radiation-induced liver injury and liver cell line injury in mouse models. Methods C57BL/6 mice were randomly divided into the blank group, model group and MSC-EV treatment group (treatment group), with 9 mice in each group. AML12 cells were randomly divided into the control group, irradiation group and MSC-EV intervention group (intervention group). Animal and cell models with radiation-induced injury were established by one-time 15 Gy and 6 Gy X-ray irradiation, respectively. At 48 h after irradiation, liver tissues and serum samples of mice were collected and prepared for subsequent experiments. At 15 h post-irradiation, cell experiment was carried out. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and content of malondialdehyde (MDA) in liver tissues and cells were measured. The relative expression levels of interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β and CXC chemokine ligand (CXCL)10 messenger RNA (mRNA) were detected by real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). Liver tissues were prepared for hematoxylin-eosin (HE) staining to calculate liver pathological injury score. The apoptosis of liver tissues and cells was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and propidiumiodide (PI) staining, respectively. The expression levels of glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) proteins were detected by Western blot. The production level of reactive oxygen species (ROS) was detected by dihydroethidine (DHE) staining. The fluorescence intensity of mitochondrial permeability transition pore (mPTP) was determined. Results Compared with the blank group, serum levels of AST and ALT were up-regulated, and the relative expression levels of IL-1β, TGF-β and CXCL10 mRNA in the mouse liver tissues were up-regulated, and MDA content was increased, liver injury score was elevated, cell apoptosis rate was increased, intracellular ROS level was elevated, and the relative expression levels of GPX4 and FSP1 proteins in the mouse liver tissues were down-regulated in the model group, and the differences were statistically significant (all P<0.05). Compared with the model group, serum levels of AST and ALT were decreased, and the relative expression levels of IL-1β, TGF-β and CXCL10 mRNA in the liver tissues of mice were down-regulated, MDA content was declined, liver injury score was declined, cell apoptosis rate was decreased, intracellular ROS level was decreased, and the relative expression levels of GPX4 and FSP1 proteins in the liver tissues of mice were up-regulated in the treatment group, and the differences were statistically significant (all P<0.05). Compared with the control group, cell apoptosis rate was increased, intracellular ROS level was elevated, the fluorescence intensity of mPTP was weakened, the relative expression levels of IL-1β, TGF-β and IL-6 mRNA were up-regulated, MDA content was increased, and the relative expression levels of GPX4 and FSP1 proteins were down-regulated in the irradiation group, and the differences were statistically significant (all P<0.05). Compared with the irradiation group, cell apoptosis rate was declined, intracellular ROS level was decreased, the fluorescence intensity of mPTP was strengthened, the relative expression levels of IL-1β, TGF-β and IL-6 mRNA were down-regulated, MDA content was decreased and the relative expression levels of GPX4 and FSP1 proteins were up-regulated in the intervention group, and the differences were statistically significant (all P<0.05). Conclusions MSC-EV may effectively alleviate radiation-induced liver injury by reducing ferroptosis of liver cells, enhancing antioxidant level and decreasing the production of lipid peroxide, thereby effectively alleviating radiation-induced liver injury.
- Extracellular vesicle,
- Radiotherapy,
- Radiation-induced liver injury,
- Ferroptosis,
- Oxidative stress,
- Lipid peroxidation,
- Inflammation,
- Mitochondrial permeability transition pore

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References(40)

References

[1]	武兵兵, 张爱平, 赵信科, 等. 当归红芪超滤物对X射线引起人脐静脉内皮细胞损伤的保护作用及其机制[J]. 吉林大学学报(医学版), 2022, 48(5): 1139-1147. DOI: 10.13481/j.1671-587X.20220506. WU BB, ZHANG AP, ZHAO XK, et al. Protective effect of ultra-filtration extract from Angelica Sinensis Radix and Hedysari Radix on human umbilical vein endothelial cell injury induced by X-ray and its mechanism[J]. J Jilin Univ(Med Edit), 2022, 48(5): 1139-1147. DOI: 10.13481/j.1671-587X.20220506.
[2]	张丹, 孙静, 王佳, 等. 原发性肝细胞癌患者立体定向放射治疗所致的放射性肝损伤影响因素分析[J]. 中华肝脏病杂志, 2021, 29(6): 575-579. DOI: 10.3760/cma.j.cn501113-20200221-00058. ZHANG D, SUN J, WANG J, et al. Analysis of factors influencing radiation-induced liver injury caused by stereotactic radiotherapy in patients with primary hepatocellular carcinoma[J]. Chin J Hepatol, 2021, 29(6): 575-579. DOI: 10.3760/cma.j.cn501113-20200221-00058.
[3]	TAKEDA K, SAKAYAUCHI T, KUBOZONO M, et al. Palliative radiotherapy for gastric cancer bleeding: a multi-institutional retrospective study[J]. BMC Palliat Care, 2022, 21(1): 52. DOI: 10.1186/s12904-022-00943-2.
[4]	WANG H, LI X, PENG R, et al. Stereotactic ablative radiotherapy for colorectal cancer liver metastasis[J]. Semin Cancer Biol, 2021, 71: 21-32. DOI: 10.1016/j.semcancer.2020.06.018.
[5]	RÜCKERT M, FLOHR AS, HECHT M, et al. Radiotherapy and the immune system: more than just immune suppression[J]. Stem Cells, 2021, 39(9): 1155-1165. DOI: 10.1002/stem.3391.
[6]	KUNDISOVÁ I, JUAN ME, PLANAS JM. Simultaneous determination of phenolic compounds in plasma by LC-ESI-MS/MS and their bioavailability after the ingestion of table olives[J]. J Agric Food Chem, 2020, 68(37): 10213-10222. DOI: 10.1021/acs.jafc.0c04036.
[7]	LI YH, WU JX, HE Q, et al. Amelioration of radiation-induced liver damage by p-coumaric acid in mice[J]. Food Sci Biotechnol, 2022, 31(10): 1315-1323. DOI: 10.1007/s10068-022-01118-8.
[8]	HAN NK, JUNG MG, JEONG YJ, et al. Plasma fibrinogen-like 1 as a potential biomarker for radiation-induced liver injury[J]. Cells, 2019, 8(9): 1042. DOI: 10.3390/cells8091042.
[9]	ZHOU YJ, TANG Y, LIU SJ, et al. Radiation-induced liver disease: beyond DNA damage[J]. Cell Cycle, 2023, 22(5): 506-526. DOI: 10.1080/15384101.2022.2131163.
[10]	NIU H, ZHANG L, WANG B, et al. CircTUBD1 regulates radiation-induced liver fibrosis response via a circTUBD1/micro-203a-3p/Smad3 positive feedback loop[J]. J Clin Transl Hepatol, 2022, 10(4): 680-691. DOI: 10.14218/JCTH.2021.00511.
[11]	KOAY EJ, OWEN D, DAS P. Radiation-induced liver disease and modern radiotherapy[J]. Semin Radiat Oncol, 2018, 28(4): 321-331. DOI: 10.1016/j.semradonc.2018.06.007.
[12]	TAMARI Y, TAKATA T, TAKENO S, et al. Influence of boron neutron capture therapy on normal liver tissue[J]. Radiat Res, 2022, 198(4): 368-374. DOI: 10.1667/RADE-22-00018.1.
[13]	LEI G, MAO C, YAN Y, et al. Ferroptosis, radiotherapy, and combination therapeutic strategies[J]. Protein Cell, 2021, 12(11): 836-857. DOI: 10.1007/s13238-021-00841-y.
[14]	ZHOU H, ZHOU YL, MAO JA, et al. NCOA4-mediated ferritinophagy is involved in ionizing radiation-induced ferroptosis of intestinal epithelial cells[J]. Redox Biol, 2022, 55: 102413. DOI: 10.1016/j.redox.2022.102413.
[15]	LI L, WU D, DENG S, et al. NVP-AUY922 alleviates radiation-induced lung injury via inhibition of autophagy-dependent ferroptosis[J]. Cell Death Discov, 2022, 8(1): 86. DOI: 10.1038/s41420-022-00887-9.
[16]	FENG Z, QIN Y, HUO F, et al. NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury[J]. Biochim Biophys Acta Mol Basis Dis, 2022, 1868(1): 166287. DOI: 10.1016/j.bbadis.2021.166287.
[17]	NIE J, LIN B, ZHOU M, et al. Role of ferroptosis in hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2018, 144(12): 2329-2337. DOI: 10.1007/s00432-018-2740-3.
[18]	SHOJAIE L, IORGA A, DARA L. Cell death in liver diseases: a review[J]. Int J Mol Sci, 2020, 21(24): 9682. DOI: 10.3390/ijms21249682.
[19]	WU J, WANG Y, JIANG R, et al. Ferroptosis in liver disease: new insights into disease mechanisms[J]. Cell Death Discov, 2021, 7(1): 276. DOI: 10.1038/s41420-021-00660-4.
[20]	张先平, 王乾兴, 陈斌等. 当归多糖抑制氧化损伤延缓造血干细胞衰老[J]. 中国中药杂志, 2013, 38(03): 407-412. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY201303025.htm ZHANG XP, WANG QX, CHEN B, et al. Angelica sinensis polysaccharides delay aging of hematopoietic stem cells through inhibitting oxidative damge[J]. China J Chin Mater Med, 2013, 38(3): 407-412. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY201303025.htm
[21]	CHENG Y, ZHOU J, LI Q, et al. The effects of polysaccharides from the root of Angelica sinensis on tumor growth and iron metabolism in H22-bearing mice[J]. Food Funct, 2016, 7(2): 1033-1039. DOI: 10.1039/c5fo00855g.
[22]	ZHU W, ZHANG X, YU M, et al. Radiation-induced liver injury and hepatocyte senescence[J]. Cell Death Discov, 2021, 7(1): 244. DOI: 10.1038/s41420-021-00634-6.
[23]	ZHAO M, LIU S, WANG C, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate mitochondrial damage and inflammation by stabilizing mitochondrial DNA[J]. ACS Nano, 2021, 15(1): 1519-1538. DOI: 10.1021/acsnano.0c08947.
[24]	DONG L, WANG Y, ZHENG T, et al. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice[J]. Stem Cell Res Ther, 2021, 12(1): 4. DOI: 10.1186/s13287-020-02072-0.
[25]	MA J, SHI X, LI M, et al. MicroRNA-181a-2-3p shuttled by mesenchymal stem cell-secreted extracellular vesicles inhibits oxidative stress in Parkinson's disease by inhibiting EGR1 and NOX4[J]. Cell Death Discov, 2022, 8(1): 33. DOI: 10.1038/s41420-022-00823-x.
[26]	WEN S, DOONER M, PAPA E, et al. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a radiation injury bone marrow murine model[J]. Int J Mol Sci, 2019, 20(21): 5468. DOI: 10.3390/ijms20215468.
[27]	GE M, YAO W, YUAN D, et al. Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury[J]. Cell Death Dis, 2017, 8(6): e2841. DOI: 10.1038/cddis.2017.236.
[28]	DAMM R, PECH M, HAAG F, et al. TNF-α indicates radiation-induced liver injury after interstitial high dose-rate brachytherapy[J]. In Vivo, 2022, 36(5): 2265-2274. DOI: 10.21873/invivo.12955.
[29]	HUMPTON TJ, HOCK AK, KIOURTIS C, et al. A noninvasive iRFP713 p53 reporter reveals dynamic p53 activity in response to irradiation and liver regeneration in vivo[J]. Sci Signal, 2022, 15(720): eabd9099. DOI: 10.1126/scisignal.abd9099.
[30]	陆春怡, 高斐, 朱慧, 等. 富硒长双歧杆菌DD98对X射线所致放射性肝损伤小鼠的保护作用[J]. 现代食品科技, 2021, 37(6): 10-19. DOI: 10.13982/j.mfst.1673-9078.2021.6.0957. LU CY, GAO F, ZHU H, et al. Protective effects of selenium-enriched bifidobacterium longum DD98 on X-ray radiation-induced hepatic tissue injury in mice[J]. Mod Food Sci Technol, 2021, 37(6): 10-19. DOI: 10.13982/j.mfst.1673-9078.2021.6.0957.
[31]	LIU Q, LI W, QIN S. Therapeutic effect of phycocyanin on acute liver oxidative damage caused by X-ray[J]. Biomed Pharmacother, 2020, 130: 110553. DOI: 10.1016/j.biopha.2020.110553.
[32]	LI W, JIANG L, LU X, et al. Curcumin protects radiation-induced liver damage in rats through the NF-κB signaling pathway[J]. BMC Complement Med Ther, 2021, 21(1): 10. DOI: 10.1186/s12906-020-03182-1.
[33]	LI T, CAO Y, LI B, et al. The biological effects of radiation-induced liver damage and its natural protective medicine[J]. Prog Biophys Mol Biol, 2021, 167: 87-95. DOI: 10.1016/j.pbiomolbio.2021.06.012.
[34]	MELIN N, YARAHMADOV T, SANCHEZ-TALTAVULL D, et al. A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus[J]. JHEP Rep, 2022, 4(7): 100508. DOI: 10.1016/j.jhepr.2022.100508.
[35]	LEI X, HE N, ZHU L, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate radiation-induced lung injury via miRNA-214-3p[J]. Antioxid Redox Signal, 2021, 35(11): 849-862. DOI: 10.1089/ars.2019.7965.
[36]	刘洋, 孙岳, 杨安宁, 等. 铁死亡参与高脂饮食诱导的ApoE^-/-小鼠动脉粥样硬化及ox-LDL诱导的泡沫细胞形成过程[J]. 实用医学杂志, 2021, 37(5): 585-590. DOI: 10.3969/j.issn.1006-5725.2021.05.006. LIU Y, SUN Y, YANG AN, et al. Involvement of ferroptosis in atherosclerosis induced by high-fat diet in ApoE^-/- mouse and formation of ox-LDL-induced foam cell[J]. J Pract Med, 2021, 37(5): 585-590. DOI: 10.3969/j.issn.1006-5725.2021.05.006.
[37]	JIANG X, STOCKWELL BR, CONRAD M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. DOI: 10.1038/s41580-020-00324-8.
[38]	刘思齐, 杨正飞. 铁死亡: 心肌缺血再灌注损伤分子机制和药物治疗研究新靶点[J]. 中山大学学报(医学科学版), 2022, 43(5): 712-719. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2022.0504. LIU SQ, YANG ZF. Ferroptosis: novel research targets of molecular mechanism and drug therapy for myocardial ischemia-reperfusion injury[J]. J Sun Yat-sen Univ(Med Sci), 2022, 43(5): 712-719. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2022.0504.
[39]	农复香, 蒋志雄, 李英豪, 等. 外泌体调控铁死亡在疾病诊断治疗中的应用与作用[J]. 中国组织工程研究, 2023, 27(15): 2443-2452. doi: 10.12307/2023.608 NONG FX, JIANG ZX, LI YH, et al. Application and role of exosome-regulated ferroptosis in disease diagnosis and treatment[J]. Chin J Tissue Eng Res, 2023, 27(15): 2443-2452. doi: 10.12307/2023.608
[40]	YE LF, CHAUDHARY KR, ZANDKARIMI F, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers[J]. ACS Chem Biol, 2020, 15(2): 469-484. DOI: 10.1021/acschembio.9b00939.

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Protective effect and mechanism of mesenchymal stem cell-derived extracellular vesicle on radiation-induced liver injury

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Protective effect and mechanism of mesenchymal stem cell-derived extracellular vesicle on radiation-induced liver injury

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