Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg−1·d−1, ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.
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Dutta A, Gupta ML, Verma S. Podophyllotoxin and rutin in combination prevents oxidative stress mediated cell death and advances revival of mice gastrointestine following lethal radiation injury. Free Radic Res. 2018;52:103–17.
Carter CL, Hankey KG, Booth C, Tudor GL, Parker GA, Jones JW, et al. Characterizing the natural history of acute radiation syndrome of the gastrointestinal tract: combining high mass and spatial resolution using maldi-fticr-msi. Health Phys. 2019;116:454–72.
MacVittie TJ, Farese AM, Parker GA, Jackson W 3rd, Booth C, Tudor GL, et al. The gastrointestinal subsyndrome of the acute radiation syndrome in rhesus macaques: a systematic review of the lethal dose-response relationship with and without medical management. Health Phys. 2019;116:305–38.
Cao J, Li H, Yuan R, Dong Y, Wu J, Wang M, et al. Protective effects of new aryl sulfone derivatives against radiation-induced hematopoietic injury. J Radiat Res. 2020;61:388–98.
Xu G, Wu H, Zhang J, Li D, Wang Y, Wang Y, et al. Metformin ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radic Biol Med. 2015;87:15–25.
Chiba M, Uehara H, Niiyama I, Kuwata H, Monzen S. Changes in mirna expressions in the injured small intestine of mice following highdose radiation exposure. Mol Med Rep. 2020;21:2452–8.
Dong Y, Cheng Y, Hou Q, Wu J, Li D, Tian H. The protective effect of new compound xh-103 on radiation-induced gi syndrome. Oxid Med Cell Longev. 2018;2018:3920147.
Holler V, Buard V, Roque T, Squiban C, Benderitter M, Flamant S, et al. Early and late protective effect of bone marrow mononuclear cell transplantation on radiation-induced vascular dysfunction and skin lesions. Cell Transpl. 2019;28:116–28.
Lu L, Jiang M, Zhu C, He J, Fan S. Amelioration of whole abdominal irradiation-induced intestinal injury in mice with 3,3’-diindolylmethane (dim). Free Radic Biol Med. 2019;130:244–55.
Jabbour SK, Patel S, Herman JM, Wild A, Nagda SN, Altoos T, et al. Intensity-modulated radiation therapy for rectal carcinoma can reduce treatment breaks and emergency department visits. Int J Surg Oncol. 2012;2012:891067.
Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: Composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 2019;18:75.
Su X, Shen Y, Jin Y, Weintraub NL, Tang YL. Identification of critical molecular pathways involved in exosome-mediated improvement of cardiac function in a mouse model of muscular dystrophy. Acta Pharmacol Sin. 2020. https://doi.org/10.1038/s41401-020-0446-y.
Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal mir-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191.
Murdica V, Giacomini E, Makieva S, Zarovni N, Candiani M, Salonia A, et al. In vitro cultured human endometrial cells release extracellular vesicles that can be uptaken by spermatozoa. Sci Rep. 2020;10:8856.
Sun XH, Wang YT, Li GF, Zhang N, Fan L. Serum-derived three-circrna signature as a diagnostic biomarker for hepatocellular carcinoma. Cancer Cell Int. 2020;20:226.
Zhou X, Xie F, Wang L, Zhang L, Zhang S, Fang M, et al. The function and clinical application of extracellular vesicles in innate immune regulation. Cell Mol Immunol. 2020;17:323–34.
Rao Q, Zuo B, Lu Z, Gao X, You A, Wu C, et al. Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro. Hepatology. 2016;64:456–72.
Li SP, Lin ZX, Jiang XY, Yu XY. Exosomal cargo-loading and synthetic exosome-mimics as potential therapeutic tools. Acta Pharmacol Sin. 2018;39:542–51.
Jacques C, Tesfaye R, Lavaud M, Georges S, Baud’huin M, Lamoureux F, et al. Implication of the p53-related mir-34c, -125b, and -203 in the osteoblastic differentiation and the malignant transformation of bone sarcomas. Cells. 2020;9:810.
Endzelins E, Berger A, Melne V, Bajo-Santos C, Sobolevska K, Abols A, et al. Detection of circulating mirnas: Comparative analysis of extracellular vesicle-incorporated mirnas and cell-free mirnas in whole plasma of prostate cancer patients. BMC Cancer. 2017;17:730.
Malla B, Aebersold DM, Dal, Pra A. Protocol for serum exosomal mirnas analysis in prostate cancer patients treated with radiotherapy. J Transl Med. 2018;16:223.
Ferrao ML, Rocha MJ, Rocha E. Histological characterization of the maturation stages of the ovarian follicles of the goldfish carassius auratus (linnaeus, 1758). Anat Histol Embryol. 2020;49:749–62.
Wei S, Cheng F, Yu W. Pathological analysis on transurethral enucleation resection of the prostate-related prostate surgical capsule. Wideochir Inne Tech Maloinwazyjne. 2019;14:255–61.
Martin ML, Adileh M, Hsu KS, Hua G, Lee SG, Li C, et al. Organoids reveal that inherent radiosensitivity of small and large intestinal stem cells determines organ sensitivity. Cancer Res. 2020;80:1219–27.
Lee C, Choi C, Kang HS, Shin SW, Kim SY, Park HC, et al. Nod2 supports crypt survival and epithelial regeneration after radiation-induced injury. Int J Mol Sci. 2019;20:4297.
Ling Y, Suying F, Zhiliang L, Peiying J, Baoxi W, Lin L. Application of indirect immunofluorescence on the diagnosis of pemphigus. Acta Dermatovenerol Croat. 2019;27:142–5.
Russell JO, Lu WY, Okabe H, Abrams M, Oertel M, Poddar M, et al. Hepatocyte-specific beta-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology. 2019;69:742–59.
Kumar P, Nagarajan A, Uchil PD. Analysis of cell viability by the mtt assay. Cold Spring Harb Protoc. 2018;2018. https://doi.org/10.1101/pdb.prot095505.
Graziani F, Pinton P, Olleik H, Pujol A, Nicoletti C, Sicre M, et al. Deoxynivalenol inhibits the expression of trefoil factors (tff) by intestinal human and porcine goblet cells. Arch Toxicol. 2019;93:1039–49.
Levy A, Stedman A, Deutsch E, Donnadieu F, Virgin HW, Sansonetti PJ, et al. Innate immune receptor nod2 mediates lgr5(+) intestinal stem cell protection against ros cytotoxicity via mitophagy stimulation. Proc Natl Acad Sci USA. 2020;117:1994–2003.
Metcalfe C, Kljavin NM, Ybarra R, de Sauvage FJ. Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell. 2014;14:149–59.
Basak O, Beumer J, Wiebrands K, Seno H, van Oudenaarden A, Clevers H. Induced quiescence of lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell. 2017;20:177–90.e4.
Takakuwa A, Nakamura K, Kikuchi M, Sugimoto R, Ohira S, Yokoi Y, et al. Butyric acid and leucine induce alpha-defensin secretion from small intestinal paneth cells. Nutrients. 2019;11:2817. https://doi.org/10.3390/nu11112817.
Cheung R, Kelly J, Macleod RJ. Regulation of villin by wnt5a/ror2 signaling in human intestinal cells. Front Physiol. 2011;2:58.
Khan K, Tewari S, Awasthi NP, Mishra SP, Agarwal GR, Rastogi M, et al. Flow cytometric detection of gamma-h2ax to evaluate DNA damage by low dose diagnostic irradiation. Med Hypotheses. 2018;115:22–28.
Liu Q, Si T, Xu X, Liang F, Wang L, Pan S. Electromagnetic radiation at 900 mhz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats. Reprod Health. 2015;12:65.
Mizuta Y, Tokuda K, Guo J, Zhang S, Narahara S, Kawano T, et al. Sodium thiosulfate prevents doxorubicin-induced DNA damage and apoptosis in cardiomyocytes in mice. Life Sci. 2020;257:118074.
Wang L, Wulf GM. Not black or white but shades of gray: Homologous recombination deficiency as a continuous variable modulated by rnf168. Cancer Res. 2020;80:2720–1.
Zhu HF, Yan PW, Wang LJ, Liu YT, Wen J, Zhang Q, et al. Protective properties of huperzine a through activation nrf2/are-mediated transcriptional response in x-rays radiation-induced nih3t3 cells. J Cell Biochem. 2018;119:8359–67.
Zhou YQ, Liu DQ, Chen SP, Chen N, Sun J, Wang XM, et al. Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain. Acta Pharmacol Sin. 2020;41:1041–8.
Zhu B, Zhang L, Liang C, Liu B, Pan X, Wang Y, et al. Stem cell-derived exosomes prevent aging-induced cardiac dysfunction through a novel exosome/lncrna malat1/nf-kappab/tnf-alpha signaling pathway. Oxid Med Cell Longev. 2019;2019:9739258.
Wang Y, Jia L, Xie Y, Cai Z, Liu Z, Shen J, et al. Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development. Atherosclerosis. 2019;289:64–72.
Bhanja P, Saha S, Kabarriti R, Liu L, Roy-Chowdhury N, Roy-Chowdhury J, et al. Protective role of r-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS ONE. 2009;4:e8014.
Kong F, Wu CT, Geng P, Liu C, Xiao F, Wang LS, et al. Dental pulp stem cell-derived extracellular vesicles mitigate haematopoietic damage after radiation. Stem Cell Rev Rep. 2020. https://doi.org/10.1007/s12015-020-10020-x.
Chou DB, Frismantas V, Milton Y, David R, Pop-Damkov P, Ferguson D, et al. On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology. Nat Biomed Eng. 2020;4:394–406.
Zhao Z, Qu W, Wang K, Chen S, Zhang L, Wu D, et al. Bisphenol a inhibits mucin 2 secretion in intestinal goblet cells through mitochondrial dysfunction and oxidative stress. Biomed Pharmacother. 2019;111:901–8.
Venkateswaran K, Shrivastava A, Agrawala PK, Prasad AK, Devi SC, Manda K, et al. Mitigation of radiation-induced gastro-intestinal injury by the polyphenolic acetate 7, 8-diacetoxy-4-methylthiocoumarin in mice. Sci Rep. 2019;9:14134.
Li Q, Sun Y, Jarugumilli GK, Liu S, Dang K, Cotton JL, et al. Lats1/2 sustain intestinal stem cells and wnt activation through tead-dependent and independent transcription. Cell Stem Cell. 2020;26:675–92.e8.
Mundorf J, Donohoe CD, McClure CD, Southall TD, Uhlirova M. Ets21c governs tissue renewal, stress tolerance, and aging in the drosophila intestine. Cell Rep. 2019;27:3019–33.e5.
Setiawan J, Kotani T, Konno T, Saito Y, Murata Y, Noda T, et al. Regulation of small intestinal epithelial homeostasis by tsc2-mtorc1 signaling. Kobe J Med Sci. 2019;64:E200–E209.
Etemadi T, Momeni HR, Ghafarizadeh AA. Impact of silymarin on cadmium-induced apoptosis in human spermatozoa. Andrologia. 2020;52:e13795.
Zhu N, Liu R, He LX, Mao RX, Liu XR, Zhang T, et al. Radioprotective effect of walnut oligopeptides against gamma radiation-induced splenocyte apoptosis and intestinal injury in mice. Molecules. 2019;24:1582.
Liu Z, Liu H, Jiang J, Tan S, Yang Y, Zhan Y, et al. Pdgf-bb and bfgf ameliorate radiation-induced intestinal progenitor/stem cell apoptosis via akt/p53 signaling in mice. Am J Physiol Gastrointest Liver Physiol. 2014;307:G1033–43.
Ai TJ, Sun JY, Du LJ, Shi C, Li C, Sun XN, et al. Inhibition of neddylation by mln4924 improves neointimal hyperplasia and promotes apoptosis of vascular smooth muscle cells through p53 and p62. Cell Death Differ. 2018;25:319–29.
Yu G, Luo H, Zhang N, Wang Y, Li Y, Huang H, et al. Loss of p53 sensitizes cells to palmitic acid-induced apoptosis by reactive oxygen species accumulation. Int J Mol Sci. 2019;20:6268.
Penha RCC, Pellecchia S, Pacelli R, Pinto LFR, Fusco A. Ionizing radiation deregulates the microrna expression profile in differentiated thyroid cells. Thyroid. 2018;28:407–21.
Xiao AY, Maynard MR, Piett CG, Nagel ZD, Alexander JS, Kevil CG, et al. Sodium sulfide selectively induces oxidative stress, DNA damage, and mitochondrial dysfunction and radiosensitizes glioblastoma (gbm) cells. Redox Biol. 2019;26:101220.
Sharma D, De Falco L, Padavattan S, Rao C, Geifman-Shochat S, Liu CF, et al. Parp1 exhibits enhanced association and catalytic efficiency with gammah2a.X-nucleosome. Nat Commun. 2019;10:5751.
Lu M, Wang P, Qiao Y, Jiang C, Ge Y, Flickinger B, et al. Gsk3beta-mediated keap1-independent regulation of Nrf2 antioxidant response: a molecular rheostat of acute kidney injury to chronic kidney disease transition. Redox Biol. 2019;26:101275.
Resendez A, Tailor D, Graves E, Malhotra SV. Radiosensitization of head and neck squamous cell carcinoma (HNSCC) by a podophyllotoxin. ACS Med Chem Lett. 2019;10:1314–21.
Chaiprasongsuk A, Janjetovic Z, Kim TK, Jarrett SG, D’Orazio JA, Holick MF, et al. Protective effects of novel derivatives of vitamin d3 and lumisterol against uvb-induced damage in human keratinocytes involve activation of Nrf2 and p53 defense mechanisms. Redox Biol. 2019;24:101206.
Zhou Q, Huang SX, Zhang F, Li SJ, Liu C, Xi YY, et al. Micrornas: A novel potential biomarker for diagnosis and therapy in patients with non-small cell lung cancer. Cell Prolif. 2017;50:e12394.
Wang W, Hu L, Chang S, Ma L, Li X, Yang Z, et al. Total body irradiation-induced colon damage is prevented by nitrate-mediated suppression of oxidative stress and homeostasis of the gut microbiome. Nitric Oxide. 2020;102:1–11.
Li L, Zhang K, Zhang J, Zeng YN, Lai F, Li G, et al. Protective effect of polydatin on radiation-induced injury of intestinal epithelial and endothelial cells. Biosci Rep. 2018;38:BSR20180868.
Verginadis II, Kanade R, Bell B, Koduri S, Ben-Josef E, Koumenis C. A novel mouse model to study image-guided, radiation-induced intestinal injury and preclinical screening of radioprotectors. Cancer Res. 2017;77:908–17.
Lewicka M, Henrykowska G, Zawadzka M, Rutkowski M, Pacholski K, Buczynski A. Impact of electromagnetic radiation emitted by monitors on changes in the cellular membrane structure and protective antioxidant effect of vitamin A–in vitro study. Int J Occup Med Environ Health. 2017;30:695–703.
Zhang J, Han X, Zhao Y, Xue X, Fan S. Mouse serum protects against total body irradiation-induced hematopoietic system injury by improving the systemic environment after radiation. Free Radic Biol Med. 2019;131:382–92.
Tai S, Yang S, Tiew A, Wong YM, Ling SY, Tay YS, et al. Radiation exposure to allied health personnel handling blood specimens from patients receiving radioactive iodine-131 and recombinant human TSH (Thyrogen®) stimulation. J Radiol Prot. 2020. https://iopscience.iop.org/article/10.1088/1361-6498/ab9507.
This work was supported by grants from the National Natural Science Foundation of China (No. 81803046 and No. 81730086), the Natural Science Foundation of Tianjin City (19JCQNJC09700), and the CAMS Innovation Fund for Medical Sciences (2017-I2M-B&R-13).
The authors declare no competing interests.
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Li, H., Jiang, M., Zhao, Sy. et al. Exosomes are involved in total body irradiation-induced intestinal injury in mice. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00615-6
- total body irradiation
- radiation-induced intestinal injury
- DNA damage