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<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="research-article" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Russian Journal of Infection and Immunity</journal-id><journal-title-group><journal-title xml:lang="en">Russian Journal of Infection and Immunity</journal-title><trans-title-group xml:lang="ru"><trans-title>Инфекция и иммунитет</trans-title></trans-title-group></journal-title-group><issn publication-format="print">2220-7619</issn><issn publication-format="electronic">2313-7398</issn><publisher><publisher-name xml:lang="en">SPb RAACI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">1940</article-id><article-id pub-id-type="doi">10.15789/2220-7619-NPF-1940</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>ORIGINAL ARTICLES</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ СТАТЬИ</subject></subj-group><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title xml:lang="en">The non-protein fraction of embryonic stem cell secretome exerts antibacterial effects against antibiotic-resistant bacterial strains</article-title><trans-title-group xml:lang="ru"><trans-title>Небелковая фракция секретома эмбриональных стволовых клеток обладает антибактериальным эффектом, в том числе против антибиотикорезистентных штаммов бактерий</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><name-alternatives><name xml:lang="en"><surname>Kaigorodov</surname><given-names>Denis G.</given-names></name><name xml:lang="ru"><surname>Кайгородов</surname><given-names>Денис Григорьевич</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Director</p></bio><bio xml:lang="ru"><p>директор</p></bio><email>kaigorodov_denis@rambler.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name-alternatives><name xml:lang="en"><surname>Kaigorodova</surname><given-names>Alisa D.</given-names></name><name xml:lang="ru"><surname>Кайгородова</surname><given-names>Алиса Денисовна</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Student</p></bio><bio xml:lang="ru"><p>студентка</p></bio><email>kaigorodovaalisa@mail.ru</email><xref ref-type="aff" rid="aff2"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">LLC Institute for Scientific Research Biotechnologies “Mitokey”</institution></aff><aff><institution xml:lang="ru">ООО НИИ Биотехнологии «Митокей»</institution></aff></aff-alternatives><aff-alternatives id="aff2"><aff><institution xml:lang="en">Tyumen State Medical University</institution></aff><aff><institution xml:lang="ru">ФГБОУ ВО Тюменский государственный медицинский университет Минздрава России</institution></aff></aff-alternatives><pub-date date-type="preprint" iso-8601-date="2022-09-19" publication-format="electronic"><day>19</day><month>09</month><year>2022</year></pub-date><pub-date date-type="pub" iso-8601-date="2022-12-30" publication-format="electronic"><day>30</day><month>12</month><year>2022</year></pub-date><volume>12</volume><issue>6</issue><issue-title xml:lang="en"/><issue-title xml:lang="ru"/><fpage>1061</fpage><lpage>1068</lpage><history><date date-type="received" iso-8601-date="2022-05-04"><day>04</day><month>05</month><year>2022</year></date><date date-type="accepted" iso-8601-date="2022-06-19"><day>19</day><month>06</month><year>2022</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2022, Kaigorodov D.G., Kaigorodova A.D.</copyright-statement><copyright-statement xml:lang="ru">Copyright ©; 2022, Кайгородов Д.Г., Кайгородова А.Д.</copyright-statement><copyright-year>2022</copyright-year><copyright-holder xml:lang="en">Kaigorodov D.G., Kaigorodova A.D.</copyright-holder><copyright-holder xml:lang="ru">Кайгородов Д.Г., Кайгородова А.Д.</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/><license><ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/">https://creativecommons.org/licenses/by/4.0</ali:license_ref></license></permissions><self-uri xlink:href="https://iimmun.ru/iimm/article/view/1940">https://iimmun.ru/iimm/article/view/1940</self-uri><abstract xml:lang="en"><p>In recent years, it has been extremely evident to seek out for new antibacterial agents, because the burgeoning problem of antibiotic resistance and the toxicity of many antimicrobial compounds has forced scientists to turn attention to alternative approaches. Investigating stem cell secretomes, including the non-protein portion, to find new antimicrobials is a promising area in the field. We examined an effect of the non-protein portion within the embryonic stem cell secretome on various bacterial strains, including antibiotic-resistant members. The non-protein fraction of the stem cell secretome was obtained by preparative high-performance liquid chromatography. Bactericidal activity was tested against eight museum bacterial strains and 206 clinical strains by comparing the secretome-related effects on growth of bacterial cultures. The museum strains showed some dose-dependent effects at concentrations of 25–100 µg/ml. Some bactericidal activity was shown at a concentration of 100 µg/ml against the clinical strains of Gram-negative microorganisms of different species, but bacterial sensitivity to the secretome fraction varied, with growth stimulation being detected in some strains. Applying non-protein fraction of the stem cell secretome at higher concentrations of 100–1000 µg/ml showed no dose-dependent effect. The clinical strains of <italic>E. coli</italic> and <italic>P. aeruginosa</italic> were shown to have reduced bactericidal activity after 24-hour incubation. Thus, this study has shown that the non-protein fraction of the embryonic stem cell secretome exerts bactericidal effects against some bacterial strains. However, more detailed studies are needed to identify a mechanism of action and to determine the most effective dose as well as frequency of administration.</p></abstract><trans-abstract xml:lang="ru"><p>В последние годы чрезвычайно актуален поиск новых возможных антибактериальных препаратов, а проблема антибиотикорезистентности и токсичность химиопрепаратов заставляет ученых обращать внимание на альтернативные противомикробные средства. Изучение применения секретома стволовых клеток, в том числе его небелковой части, является перспективной областью современной науки. В нашем исследовании было изучено влияние небелковой части секретома эмбриональных стволовых клеток на различные штаммы микроорганизмов, в том числе антибиотикорезистентные. Небелковую часть секретома стволовых клеток получали при помощи препаративной высокоэффективной жидкостной хроматографии. Тестирование бактерицидной активности производилось в отношении 8 музейных штаммов бактерий и 206 клинических штаммов микроорганизмов методом сравнения влияния секретома на рост бактериальных культур. При первичном анализе было выявлено, что на музейных штаммах в концентрации 25–100 мкг/мл исследуемый секретом имеет некоторый дозозависимый эффект. При оценке бактерицидной активности в концентрации 100 мкг/мл в отношении клинических штаммов грамотрицательных микроорганизмов разной видовой принадлежности было показана различная чувствительность штаммов к секретому, причем у некоторых штаммов обнаружена стимуляция роста. Применение более высоких концентраций 100–1000 мкг/мл не выявило дозозависимого эффекта. При этом на клинических штаммах <italic>E. coli</italic> и <italic>P. aeruginosa</italic> было показано снижение бактерицидной активности через сутки инкубации. Таким образом, проведенное исследование показало, что небелковая фракция секретома эмбриональных стволовых клеток также обладает бактерицидным эффектом. Однако требуются более детальные исследования для выявления механизма действия и определения наиболее эффективной дозы и частоты применения.</p></trans-abstract><kwd-group xml:lang="en"><kwd>secretome</kwd><kwd>embryonic stem cells</kwd><kwd>antibacterial activity</kwd><kwd>antimicrobial properties</kwd><kwd>bactericidal effect</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>секретом</kwd><kwd>эмбриональные стволовые клетки</kwd><kwd>антибактериальная активность</kwd><kwd>противомикробные свойства</kwd><kwd>бактерицидный эффект</kwd></kwd-group><funding-group/></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Andersson D.I., Balaban N.Q., Baquero F., Courvalin P., Glaser P., Gophna U., Kishony R., Molin S., Tønjum T. Antibiotic resistance: turning evolutionary principles into clinical reality. FEMS Microbiol Rev., 2020, vol. 44, no. 2, pp. 171–188. doi: 10.1093/femsre/fuaa001</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Arango J.C., Puerta-Arias J.D., Pino-Tamayo P.A., Arboleda-Toro D., González Á. Bone marrow-derived mesenchymal stem cells transplantation alters the course of experimental paracoccidioidomycosis by exacerbating the chronic pulmonary inflammatory response. Med. Mycol., 2018, vol. 56, no. 7, pp. 884–895. doi: 10.1093/mmy/myx128</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Bahroudi M., Bakhshi B., Soudi S., Najar-Peerayeh S. Antibacterial and antibiofilm activity of bone marrow-derived human mesenchymal stem cells secretome against Vibrio cholerae. Microb. Pathog., 2020, vol. 139: 103867. doi: 10.1016/j.micpath.2019.103867</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>Bari E., Ferrarotti I., Saracino L., Perteghella S., Torre M.L., Corsico A.G. Mesenchymal stromal cell secretome for severe COVID-19 infections: premises for therapeutic use. Cells, 2020, vol. 9, no. 4: 924. doi: 10.3390/cells9040924</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Bukharin O.V., Brudastov Yu.A., Gritsenko V.A., Deriabin D.G. The role of bacterial ability to inactivate factors of natural anti-infective resistance in their resistance to bactericidal action (blood serum). Bull. Exp. Biol. Med., 1996, vol. 121, no. 2, pp. 174–176.</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Eleuteri S., Fierabracci A. Insights into the secretome of mesenchymal stem cells and its potential applications. Int. J. Mol. Sci., 2019, vol. 20, no. 18: 4597. doi: 10.3390/ijms20184597</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Fernandes-Cunha G.M., Na K.S., Putra I., Lee H.J., Hull S., Cheng Y.C., Blanco I.J., Eslani M., Djalilian A.R., Myung D. Corneal wound healing effects of mesenchymal stem cell secretome delivered within a viscoelastic gel carrier. Stem Cells Transl. Med., 2019, vol. 8, no. 5, pp. 478–489. doi: 10.1002/sctm.18-0178</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Gilany K., Masroor M.J., Minai-Tehrani A., Gilany K., Masroor M.J., Minai-Tehrani A., Mani-Varnosfaderani A., Arjmand B. Metabolic profiling of the mesenchymal stem cells’ secretome. In: Arjmand B. (eds) Genomics, proteomics, and metabolomics. stem cell biology and regenerative medicine. Humana, Cham., 2019, pp. 67–81. doi: 10.1007/978-3-030-27727-7_3</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>Gonzalez-Rey E., Anderson P., González M.A., Rico L., Büscher D., Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut, 2009, vol. 58, no. 7, pp. 929–939. doi: 10.1136/gut.2008.168534</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>Gwam C., Mohammed N., Ma X. Stem cell secretome, regeneration, and clinical translation: a narrative review. Ann. Transl. Med., 2021, vol. 9, no. 1: 70. doi: 10.21037/atm-20-5030</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>Johnson V., Webb T., Norman A., Coy J., Kurihara J., Regan D., Dow S. Activated mesenchymal stem cells interact with antibiotics and host innate immune responses to control chronic bacterial infections. Sci. Rep., 2017, vol. 7, no. 1: 9575. doi: 10.1038/s41598-017-08311-4</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>Khatri M., Richardson L.A., Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res. Ther., 2018, vol. 9, no. 1: 17. doi: 10.1186/s13287-018-0774-8</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>Krasnodembskaya A., Song Y., Fang X., Gupta N., Serikov V., Lee J.W., Matthay M.A. Antibacterial effect of human mesenchymal stem cells is mediated in part by secretion of the antimicrobial peptide LL-37. Stem Cells, 2010, vol. 28, no. 12, pp. 2229–2238. doi: 10.1002/stem.544</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>Legaki E., Roubelakis M.G., Theodoropoulos G.E., Lazaris A., Kollia A., Karamanolis G., Marinos E., Gazouli M. Therapeutic potential of secreted molecules derived from human amniotic fluid mesenchymal stem/stroma cells in a mice model of colitis. Stem Cell Rev. Rep., 2016, vol. 12, no. 5, pp. 604–612. doi: 10.1007/s12015-016-9677-1</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>Liesveld J.L., Sharma N., Aljitawi O.S. Stem cell homing: from physiology to therapeutics. Stem Cells, 2020, vol. 38, no. 10, pp. 1241–1253. doi: 10.1002/stem.3242</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Lobov A.A., Yudintceva N.M., Mittenberg A.G., Shabelnikov S.V., Mikhailova N.A., Malashicheva A.B., Khotin M.G. Proteomic profiling of the human fetal multipotent mesenchymal stromal cells secretome. Molecules, 2020, vol. 25, no. 22: 5283. doi: 10.3390/molecules25225283</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>Lopatkin A.J., Bening S.C., Manson A.L., Stokes J.M., Kohanski M.A., Badran A.H., Earl A.M., Cheney N.J., Yang J.H., Collins J.J. Clinically relevant mutations in core metabolic genes confer antibiotic resistance. Science, 2021, vol. 371, no. 6531: eaba0862. doi: 10.1126/science.aba0862</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>Madrigal M., Rao K.S., Riordan N.H. A review of the therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J. Transl. Med., 2014, vol. 12: 260. doi: 10.1186/s12967-014-0260-8</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Maguire G. Stem cell therapy without the cells. Commun. Integr. Biol., 2013, vol. 6, no. 6: 260.e26631. doi: 10.4161/cib.26631</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>Marchant J. When antibiotics turn toxic. Nature, 2018, vol. 555, no. 7697, pp. 431–433. doi: 10.1038/d41586-018-03267-5</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Marx C., Gardner S., Harman R.M., Van de Walle G.R. The mesenchymal stromal cell secretome impairs methicillin-resistant Staphylococcus aureus biofilms via cysteine protease activity in the equine model. Stem Cells Transl. Med., 2020, vol. 9, no. 7, pp. 746–757. doi: 10.1002/sctm.19-0333</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>Mita T., Furukawa-Hibi Y., Takeuchi H., Hattori H., Yamada K., Hibi H., Ueda M., Yamamoto A. Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease. Behav. Brain Res., 2015, vol. 293, pp. 189–197. doi: 10.1016/j.bbr.2015.07.043</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Moraes C.N., Maia L., de Oliveira E., de Paula Freitas Dell’Aqua C., Chapwanya A., da Cruz Landim-Alvarenga F., Oba E. Shotgun proteomic analysis of the secretome of bovine endometrial mesenchymal progenitor/stem cells challenged or not with bacterial lipopolysaccharide. Vet. Immunol. Immunopathol., 2017, vol. 187, pp. 42–47. doi: 10.1016/j.vetimm.2017.03.007</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Nakashima Y., Nahar S., Miyagi-Shiohira C., Kinjo T., Toyoda Z., Kobayashi N., Saitoh I., Watanabe M., Fujita J., Noguchi H. A liquid chromatography with tandem mass spectrometry-based proteomic analysis of the proteins secreted by human adipose-derived mesenchymal stem cells. Cell Transplant., 2018, vol. 27, no. 10, pp. 1469–1494. doi: 10.1177/0963689718795096</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Nakamura Y., Miyaki S., Ishitobi H., Matsuyama S., Nakasa T., Kamei N., Akimoto T., Higashi Y., Ochi M. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett., 2015, vol. 589, no. 11, pp. 1257–1265. doi: 10.1016/j.febslet.2015.03.031</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Park B.S., Kim W.S., Choi J.S., Kim H.K., Won J.H., Ohkubo F., Fukuoka H. Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. Biomed. Res., 2010, vol. 31, no. 1, pp. 27–34. doi: 10.2220/biomedres.31.27</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>Peng W., Chang M., Wu Y., Zhu W., Tong L., Zhang G., Wang Q., Liu J., Zhu X., Cheng T., Li Y., Chen X., Weng D., Liu S., Zhang H., Su Y., Zhou J., Li H., Song Y. Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6-p-STAT3-p63-JAG2 pathway. Stem Cell Res. Ther., 2021, vol. 12, no. 1: 216. doi: 10.1186/s13287-021-02276-y</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Qin Y., Wang L., Gao Z., Chen G., Zhang C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci. Rep., 2016, vol. 6: 21961. doi: 10.1038/srep21961</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Riduan S.N., Armugam A., Zhang Y. Antibiotic resistance mitigation: the development of alternative general strategies. J. Mater. Chem. B, 2020, vol. 8, no. 30, pp. 6317–6321. doi: 10.1039/D0TB01241F</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Russell K.A., Garbin L.C., Wong J.M., Koch T.G. Mesenchymal stromal cells as potential antimicrobial for veterinary use – a comprehensive review. Front. Microbiol., 2020, vol. 11: 606404. doi: 10.3389/fmicb.2020.606404</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>Saberpour M., Bakhshi B., Najar-Peerayeh S. Evaluation of the antimicrobial and antibiofilm effect of chitosan nanoparticles as carrier for supernatant of mesenchymal stem cells on multidrug-resistant Vibrio cholerae. Infect. Drug Resist., 2020, vol. 13, pp. 2251–2260. doi: 10.2147/IDR.S244990</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>Spekker K., Leineweber M., Degrandi D., Ince V., Brunder S., Schmidt S.K., Stuhlsatz S., Howard J.C., Schares G., Degistirici O., Meisel R., Sorg R.V., Seissler J., Hemphill A., Pfeffer K., Däubener W. Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondii and Neospora caninum: role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). Med. Microbiol. Immunol., 2013, vol. 202, no. 3, pp. 197–206. doi: 10.1007/s00430-012-0281-y</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>Tao H., Chen X., Wei A., Song X., Wang W., Liang L., Zhao Q., Han Z., Han Z., Wang X., Li Z. Comparison of teratoma formation between embryonic stem cells and parthenogenetic embryonic stem cells by molecular imaging. Stem Cells Int., 2018, vol. 2018: 7906531. doi: 10.1155/2018/7906531</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>Timmers L., Lim S.K., Arslan F., Armstrong J.S., Hoefer I.E., Doevendans P.A., Piek J.J., El Oakley R.M., Choo A., Lee C.N., Pasterkamp G., de Kleijn D.P. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res., 2007, vol. 1, no. 2, pp. 129–137. doi: 10.1016/j.scr.2008.02.002</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>Vizoso F.J., Eiro N., Cid S., Schneider J., Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int. J. Mol. Sci., 2017, vol. 18, no. 9: 1852. doi: 10.3390/ijms18091852</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>Xin H., Li Y., Cui Y., Yang J.J., Zhang Z.G., Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab., 2013, vol. 33, no. 11, pp. 1711–1715. doi: 10.1038/jcbfm.2013.152</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>Yagi H., Chen A.F., Hirsch D., Rothenberg A.C., Tan J., Alexander P.G., Tuan R.S. Antimicrobial activity of mesenchymal stem cells against Staphylococcus aureus. Stem Cell Res. Ther., 2020, vol. 11, no. 1: 293. doi: 10.1186/s13287-020-01807-3</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>Yang D., Chen Q., Hoover D.M., Staley P., Tucker K.D., Lubkowski J., Oppenheim J.J. Many chemokines including CCL20/MIP-3α display antimicrobial activity. J. Leukoc. Biol., 2003, vol. 74, no. 3, pp. 448–455. doi: 10.1189/jlb.0103024</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>Yang R., Liu Y., Kelk P., Qu C., Akiyama K., Chen C., Atsuta I., Chen W., Zhou Y., Shi S. A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect. Cell Res., 2013, vol. 23, no. 1, pp. 107–121. doi: 10.1038/cr.2012.179</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>Zullo J., Matsumoto K., Xavier S., Ratliff B., Goligorsky M.S. The cell secretome, a mediator of cell-to-cell communication. Prostaglandins Other Lipid Mediat., 2015, vol. 120, pp. 17–20. doi: 10.1016/j.prostaglandins.2015.03.012</mixed-citation></ref></ref-list></back></article>
