人脐带间充质干细胞来源的外泌体<italic style="font-style: italic">let-7a-5p</italic>通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡

李欣; 胡亚楠; 吴越廷; 杨作成; 刘洋; 刘瀚旻

doi:10.1631/jzus.B2300077

Your Location：

Home >

Browse articles >

人脐带间充质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡

Scan for full text

文章被引用时，请邮件提醒。

Submit

Research Article | Updated：2024-05-09

人脐带间充质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡
Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2024年25卷第5期页码：422-437
Affiliations：

1.Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
2.Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China
3.NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu 610041, China
4.The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu 610041, China
5.Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China
6.Department of Pediatrics, the Third Xiangya Hospital, Central South University, Changsha 410013, China
Funds：

the China Postdoctoral Science Foundation(2022M712252);the Natural Science Foundation of Sichuan Province, China(2023NSFSC1634)
DOI：10.1631/jzus.B2300077
中图分类号：
CSTR：
纸质出版日期： 2024-05-15 ，

收稿日期： 2023-02-07 ，

修回日期： 2023-06-29 ，

李欣,胡亚楠,吴越廷等.人脐带间充质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(05):422-437.

Xin LI, Yanan HU, Yueting WU, et al. Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis[J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2024,25(5):422-437.
李欣,胡亚楠,吴越廷等.人脐带间充质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(05):422-437. DOI： 10.1631/jzus.B2300077.

Xin LI, Yanan HU, Yueting WU, et al. Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis[J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2024,25(5):422-437. DOI： 10.1631/jzus.B2300077.

摘要

病毒性心肌炎（VMC）是儿童和青少年最常见的获得性心脏病之一。其发病机制尚不明确，且缺乏有效的治疗方法。本研究旨在探讨外泌体减轻柯萨奇病毒B3（CVB3）诱导的心肌细胞（CMCs）铁死亡的调控通路。我们用CVB3诱导小鼠VMC模型和细胞模型，使用心脏超声心动图、左室射血分数（LVEF）和左室短轴缩短率（LVFS）评价心功能。在CVB3诱导的VMC小鼠中，我们观察到小鼠心功能不全和铁死亡相关指标（谷胱甘肽过氧化酶4（GPX4）、谷胱甘肽（GSH）和丙二醛（MDA））的表达失调。然而，人脐带间充质干细胞来源的外泌体（hucMSCs-exo）可以恢复CVB3引起的改变。

Let-7a-5p

富集于hucMSCs-exo中，且hucMSCs-exo

let-7a-5p

mimic

对CVB3诱导的铁死亡的抑制作用高于hucMSCs-exo

mimic NC

。在VMC组中，

SMAD2

表达升高，而

ZFP36

表达降低。

Let-7a-5p

靶向

SMAD2

信使RNA（mRNA），且SMAD2蛋白与ZFP36蛋白直接相互作用。沉默

SMAD2

和过表达

ZFP36

均可抑制铁死亡相关指标的表达。同时，与oe-NC+

let-7a-5p

mimic组比较，oe-

SMAD2

let-7a-5p

mimic组中的GPX4、溶质载体家族7成员11（SLC7A11）和GSH水平降低，而MDA、活性氧（ROS）和Fe

水平升高。综上所述，这些数据表明铁死亡可以通过介导SMAD2的表达来调节。HucMSCs来源的exo-

let-7a-5p

可以通过介导SMAD2促进ZFP36的表达，进一步抑制CMCs的铁死亡，从而缓解CVB3诱导的VMC。

Abstract

Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However

its pathogenesis is still unclear

and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography

left ventricular ejection fraction (LVEF)

and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice

cardiac insufficiency was observed

as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4)

glutathione (GSH)

and malondialdehyde (MDA)). However

exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation.

Let-7a-5p

was enriched in hucMSCs-exo

and the inhibitory effect of hucMSCs-exo

let-7a-5p

mimic

on CVB3-induced ferroptosis was higher than that of hucMSCs-exo

mimic NC

(NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group

while the expression of zinc-finger protein 36 (ZFP36) decreased.

Let-7a-5p

was confirmed to interact with

SMAD2

messenger RNA (mRNA)

and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing

SMAD2

and overexpressing

ZFP36

inhibited the expression of ferroptosis-related indicators. Meanwhile

the levels of GPX4

solute carrier family 7

member 11 (SLC7A11)

and GSH were lower in the

SMAD2

overexpression plasmid (oe-

SMAD2

let-7a-5p

mimic group than in the oe-NC+

let-7a-5p

mimic group

while those of MDA

reactive oxygen species (ROS)

and Fe

increased. In conclusion

the

se data showed that ferroptosis could be regulated by mediating

SMAD2

expression. Exo-

let-7a-5p

derived from hucMSCs could mediate

SMAD2

to promote the expression of ZFP36

which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.

关键词

外泌体Let-7a-5pSMAD2柯萨奇病毒B3（CVB3）铁死亡

Keywords

ExosomeLet-7a-5pMothers against decapentaplegic homolog 2 (SMAD2)Coxsackievirus B3 (CVB3)Ferroptosis

references

Bao MH, Feng X, Zhang YW, et al., 2013. Let-7 in cardiovascular diseases, heart development and cardiovascular differentiation from stem cells. Int J Mol Sci, 14(11):23086-23102. https://doi.org/10.3390/ijms141123086https://doi.org/10.3390/ijms141123086

Camaschella C, Nai A, Silvestri L, 2020. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica, 105(2):260-272. https://doi.org/10.3324/haematol.2019.232124https://doi.org/10.3324/haematol.2019.232124

Chen B, Sang YT, Song XJ, et al., 2021. Exosomal miR-500a-5p derived from cancer-associated fibroblasts promotes breast cancer cell proliferation and metastasis through targeting USP28. Theranostics, 11(8):3932-3947. https://doi.org/10.7150/thno.53412https://doi.org/10.7150/thno.53412

Chen CY, Choong OK, Liu LW, et al., 2019. MicroRNA let-7-TGFBR3 signalling regulates cardiomyocyte apoptosis after infarction. EBioMedicine, 46:236-247. https://doi.org/10.1016/j.ebiom.2019.08.001https://doi.org/10.1016/j.ebiom.2019.08.001

Chen P, Xie YQ, Shen E, et al., 2011. Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-β1 signaling in coxsackievirus B3-induced cardiomyopathy. Eur J Pharmacol, 658(2-3):168-174. https://doi.org/10.1016/j.ejphar.2011.02.040https://doi.org/10.1016/j.ejphar.2011.02.040

Chen X, Comish PB, Tang DL, et al., 2021. Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol, 9:637162. https://doi.org/10.3389/fcell.2021.637162https://doi.org/10.3389/fcell.2021.637162

Dong LY, Wang Y, Zheng TT, et al., 2021. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Res Ther, 12:4. https://doi.org/10.1186/s13287-020-02072-0https://doi.org/10.1186/s13287-020-02072-0

el Andaloussi S, Mäger I, Breakefield XO, et al., 2013. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov, 12(5):347-357. https://doi.org/10.1038/nrd3978https://doi.org/10.1038/nrd3978

Garbo S, Maione R, Tripodi M, et al., 2022. Next RNA therapeutics: the mine of non-coding. Int J Mol Sci, 23(13):7471. https://doi.org/10.3390/ijms23137471https://doi.org/10.3390/ijms23137471

Gu XH, Li YC, Chen KX, et al., 2020. Exosomes derived from umbilical cord mesenchymal stem cells alleviate viral myocarditis through activating AMPK/mTOR-mediated autophagy flux pathway. J Cell Mol Med, 24(13):‍7515-7530. https://doi.org/10.1111/jcmm.15378https://doi.org/10.1111/jcmm.15378

Hu Y, Zhang Y, Ni CY, et al., 2020. Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism. Theranostics, 10(5):2293-2308. https://doi.org/10.7150/thno.39238https://doi.org/10.7150/thno.39238

Huber SA, 2016. Viral myocarditis and dilated cardiomyopathy: etiology and pathogenesis. Curr Pharm Des, 22(4):408-426. https://doi.org/10.2174/1381612822666151222160500https://doi.org/10.2174/1381612822666151222160500

Inamdar AA, Inamdar AC, 2016. Heart failure: diagnosis, management and utilization. J Clin Med, 5(7):62. https://doi.org/10.3390/jcm5070062https://doi.org/10.3390/jcm5070062

Jiang XJ, Stockwell BR, Conrad M, 2021. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol, 22(4):266-282. https://doi.org/10.1038/s41580-020-00324-8https://doi.org/10.1038/s41580-020-00324-8

Krützfeldt J, Rajewsky N, Braich R, et al., 2005. Silencing of microRNAs in vivo with ‘antagomirs’. Nature, 438(7068):685-689. https://doi.org/10.1038/nature04303https://doi.org/10.1038/nature04303

Li DP, Wang Y, Jin XR, et al., 2020. NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice. J Neuroinflammation, 17:126. https://doi.org/10.1186/s12974-020-01787-4https://doi.org/10.1186/s12974-020-01787-4

Li J, Xie YW, Li LW, et al., 2021. MicroRNA-30a modulates type I interferon responses to facilitate coxsackievirus B3 replication via targeting tripartite motif protein 25. Front Immunol, 11:603437. https://doi.org/10.3389/fimmu.2020.603437https://doi.org/10.3389/fimmu.2020.603437

Li JH, Tu JH, Gao H, et al., 2021. MicroRNA-425-3p inhibits myocardial inflammation and cardiomyocyte apoptosis in mice with viral myocarditis through targeting TGF-β1. Immun Inflamm Dis, 9(1):288-298. https://doi.org/10.1002/iid3.392https://doi.org/10.1002/iid3.392

Li KL, Yan GH, Huang HJ, et al., 2022. Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages. J Nanobiotechnol, 20:38. https://doi.org/10.1186/s12951-021-01236-1https://doi.org/10.1186/s12951-021-01236-1

Li MY, Li Y, Li SQ, et al., 2022. The nano delivery systems and applications of mRNA. Eur J Med Chem, 227:113910. https://doi.org/10.1016/j.ejmech.2021.113910https://doi.org/10.1016/j.ejmech.2021.113910

Li XX, Xiong L, Wen Y, et al., 2021. Comprehensive analysis of the tumor microenvironment and ferroptosis-related genes predict prognosis with ovarian cancer. Front Genet, 12:774400. https://doi.org/10.3389/fgene.2021.774400https://doi.org/10.3389/fgene.2021.774400

Liu C, Yan XJ, Zhang YJ, et al., 2022. Oral administration of turmeric-derived exosome-like nanovesicles with anti-inflammatory and pro-resolving bioactions for murine colitis therapy. J Nanobiotechnol, 20:206. https://doi.org/10.1186/s12951-022-01421-whttps://doi.org/10.1186/s12951-022-01421-w

Liu G, Ma JY, Hu G, et al., 2021. Identification and validation of a novel ferroptosis-related gene model for predicting the prognosis of gastric cancer patients. PLoS ONE, 16(7):e0254368. https://doi.org/10.1371/journal.pone.0254368https://doi.org/10.1371/journal.pone.0254368

Liu X, Zhang Y, Zhou SR, et al., 2022. Circular RNA: an emerging frontier in RNA therapeutic targets, RNA therapeutics, and mRNA vaccines. J Control Release, 348:84-94. https://doi.org/10.1016/j.jconrel.2022.05.043https://doi.org/10.1016/j.jconrel.2022.05.043

Mathieu M, Martin-Jaular L, Lavieu G, et al., 2019. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol, 21(1):9-17. https://doi.org/10.1038/s41556-018-0250-9https://doi.org/10.1038/s41556-018-0250-9

Murphy DE, de Jong OG, Brouwer M, et al., 2019. Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking. Exp Mol Med, 51(3):1-12. https://doi.org/10.1038/s12276-019-0223-5https://doi.org/10.1038/s12276-019-0223-5

Qiao C, Xu W, Zhu W, et al., 2008. Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol Int, 32(1):8-15. https://doi.org/10.1016/j.cellbi.2007.08.002https://doi.org/10.1016/j.cellbi.2007.08.002

Rodríguez-Graciani KM, Chapa-Dubocq XR, Ayala-Arroyo EJ, et al., 2022. Effects of ferroptosis on the metabolome in cardiac cells: the role of glutaminolysis. Antioxidants (Basel), 11(2):278. https://doi.org/10.3390/antiox11020278https://doi.org/10.3390/antiox11020278

Shao MY, Xu Q, Wu ZR, et al., 2020. Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p. Stem Cell Res Ther, 11:37. https://doi.org/10.1186/s13287-020-1550-0https://doi.org/10.1186/s13287-020-1550-0

Silva AKA, Morille M, Piffoux M, et al., 2021. Development of extracellular vesicle-based medicinal products: a position paper of the group “Extracellular Vesicle translatiOn to clinicaL perspectiVEs ‒ EVOLVE France”. Adv Drug Deliv Rev, 179:114001. https://doi.org/10.1016/j.addr.2021.114001https://doi.org/10.1016/j.addr.2021.114001

Sun LF, Zhu M, Feng W, et al., 2019. Exosomal miRNA let-7 from menstrual blood-derived endometrial stem cells alleviates pulmonary fibrosis through regulating mitochondrial DNA damage. Oxid Med Cell Longev, 2019:4506303. https://doi.org/10.1155/2019/4506303https://doi.org/10.1155/2019/4506303

Sun YT, Chen P, Zhai BT, et al., 2020. The emerging role of ferroptosis in inflammation. Biomed Pharmacother, 127:110108. https://doi.org/10.1016/j.biopha.2020.110108https://doi.org/10.1016/j.biopha.2020.110108

Thakur D, Taliaferro O, Atkinson M, et al., 2022. Inhibition of nuclear factor κB in the lungs protect bleomycin-induced lung fibrosis in mice. Mol Biol Rep, 49(5):3481-3490. https://doi.org/10.1007/s11033-022-07185-8https://doi.org/10.1007/s11033-022-07185-8

Ueta M, Nishigaki H, Komai S, et al., 2023. Positive regulation of innate immune response by miRNA-let-7a-5p. Front Genet, 13:1025539. https://doi.org/10.3389/fgene.2022.1025539https://doi.org/10.3389/fgene.2022.1025539

Velot É, Madry H, Venkatesan JK, et al., 2021. Is extracellular vesicle-based therapy the next answer for cartilage regeneration? Front Bioeng Biotechnol, 9:645039. https://doi.org/10.3389/fbioe.2021.645039https://doi.org/10.3389/fbioe.2021.645039

Wang GY, Yuan JT, Cai X, et al., 2020. HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice. Clin Transl Med, 10(2):e113. https://doi.org/10.1002/ctm2.113https://doi.org/10.1002/ctm2.113

Wu TT, Liu Y, Cao Y, et al., 2022. Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma. Adv Mater, 34(15):2110364. https://doi.org/10.1002/adma.202110364https://doi.org/10.1002/adma.202110364

Xia YZ, Shan GF, Yang H, et al., 2021. Cisatracurium regulates the CXCR4/let-7a-5p axis to inhibit colorectal cancer progression by suppressing TGF-β/SMAD2/3 signalling. Chem Biol Interact, 339:109424. https://doi.org/10.1016/J.CBI.2021.109424https://doi.org/10.1016/J.CBI.2021.109424

Yan C, Zhou QY, Wu J, et al., 2021. Csi-let-7a-5p delivered by extracellular vesicles from a liver fluke activates M1-like macrophages and exacerbates biliary injuries. Proc Natl Acad Sci USA, 118(46):e2102206118. https://doi.org/10.1073/pnas.2102206118https://doi.org/10.1073/pnas.2102206118

Yuan XQ, Li TF, Shi L, et al., 2021. Human umbilical cord mesenchymal stem cells deliver exogenous miR-26a-5p via exosomes to inhibit nucleus pulposus cell pyroptosis through METTL14/NLRP3. Mol Med, 27:91. https://doi.org/10.1186/s10020-021-00355-7https://doi.org/10.1186/s10020-021-00355-7

Zhu DS, Liu S, Huang K, et al., 2022. Intrapericardial exosome therapy dampens cardiac injury via activating Foxo3. Circ Res, 131(10):e135-e150. https://doi.org/10.1161/circresaha.122.321384https://doi.org/10.1161/circresaha.122.321384

Zhu JM, Liu B, Wang ZY, et al., 2019. Exosomes from nicotine-stimulated macrophages accelerate atherosclerosis through miR-21-3p/PTEN-mediated VSMC migration and proliferation. Theranostics, 9(23):6901-6919. https://doi.org/10.7150/thno.37357https://doi.org/10.7150/thno.37357

浏览量

Downloads

CSCD

工具集

关联资源

Transfer RNA-derived fragment tRF-23-Q99P9P9NDD promotes progression of gastric cancer by targeting ACADSB

Nrf2-mediated ferroptosis of spermatogenic cells involved in male reproductive toxicity induced by polystyrene nanoplastics in mice

Targeting ferroptosis and ferritinophagy: new targets for cardiovascular diseases

Promising roles of non-exosomal and exosomal non-coding RNAs in the regulatory mechanism and as diagnostic biomarkers in myocardial infarction

Novel perspective in transplantation therapy of mesenchymal stem cells: targeting the ferroptosis pathway

人脐带间充质干细胞来源的外泌体let-7a-5p通过SMAD2/ZFP36信号轴减轻柯萨奇病毒B3诱导的心肌细胞铁死亡

Exosomal let-7a-5p derived from human umbilical cord mesenchymal stem cells alleviates coxsackievirus B3-induced cardiomyocyte ferroptosis via the SMAD2/ZFP36 signal axis

DOI：10.1631/jzus.B2300077

摘要

Abstract

关键词

Keywords

references