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<article article-type="research-article" dtd-version="1.3" 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" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">mimmun</journal-id><journal-title-group><journal-title xml:lang="ru">Медицинская иммунология</journal-title><trans-title-group xml:lang="en"><trans-title>Medical Immunology (Russia)</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">1563-0625</issn><issn pub-type="epub">2313-741X</issn><publisher><publisher-name>SPb RAACI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.15789/1563-0625-SEO-2283</article-id><article-id custom-type="elpub" pub-id-type="custom">mimmun-2426</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>МАТЕРИАЛЫ ФОРУМА "ДНИ ИММУНОЛОГИИ В СПБ" 2021</subject></subj-group></article-categories><title-group><article-title>СТИМУЛИРУЮЩЕЕ ВЛИЯНИЕ ВЫСОКИХ ДОЗ ГЕПАРИНА НА МИГРАЦИОННУЮ АКТИВНОСТЬ И СОХРАНЕНИЕ СТВОЛОВОСТИ МСК В ПРИСУТСТВИИ ОСТЕОЗАМЕЩАЮЩИХ МАТЕРИАЛОВ</article-title><trans-title-group xml:lang="en"><trans-title>STIMULATING EFFECT OF HIGH DOSE HEPARIN ON MIGRATION ACTIVITY AND MSC STEMNESS PRESERVATION IN THE PRESENCE OF BONE-SUBSTITUTING MATERIALS</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Норкин</surname><given-names>И. К.</given-names></name><name name-style="western" xml:lang="en"><surname>Norkin</surname><given-names>I. K.</given-names></name></name-alternatives><bio xml:lang="ru"><p>аспирант Центра иммунологии и клеточных биотехнологий, </p><p>236001, г. Калининград, ул. Гайдара, 6</p></bio><bio xml:lang="en"><p>Postgraduate Student, Center for Immunology and Cellular Biotechnology, </p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><email xlink:type="simple">norkin_igor@mail.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Юрова</surname><given-names>К. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Yurova</surname><given-names>K. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>к.м.н., научный сотрудник Центра иммунологии и клеточных биотехнологий,</p><p>г. Калининград</p></bio><bio xml:lang="en"><p>PhD (Medicine), Research Associate, Center for Immunology and Cellular Biotechnology,</p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Хазиахматова</surname><given-names>О. Г.</given-names></name><name name-style="western" xml:lang="en"><surname>Khaziakhmatova</surname><given-names>O. G.</given-names></name></name-alternatives><bio xml:lang="ru"><p>к.б.н., научный сотрудник Центра иммунологии и клеточных биотехнологий,</p><p>г. Калининград</p></bio><bio xml:lang="en"><p>PhD (Biology), Research Associate, Center for Immunology and Cellular Biotechnology,</p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Мелащенко</surname><given-names>Е. С.</given-names></name><name name-style="western" xml:lang="en"><surname>Melashchenko</surname><given-names>E. S.</given-names></name></name-alternatives><bio xml:lang="ru"><p>к.б.н., младший научный сотрудник Центра иммунологии и клеточных биотехнологий,</p><p>г. Калининград</p></bio><bio xml:lang="en"><p>PhD (Biology), Junior Research Associate, Center for Immunology and Cellular Biotechnology, </p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Малащенко</surname><given-names>В. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Malashchenko</surname><given-names>V. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p> к.б.н., инженер-лаборант Центра иммунологии и клеточных биотехнологий,</p><p>г. Калининград</p></bio><bio xml:lang="en"><p>PhD (Biology), Laboratory Engineer, Center for Immunology and Cellular Biotechnology,</p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Шунькин</surname><given-names>Е. О.</given-names></name><name name-style="western" xml:lang="en"><surname>Shunkin</surname><given-names>E. O.</given-names></name></name-alternatives><bio xml:lang="ru"><p>биолог Центра иммунологии и клеточных биотехнологий,</p><p>г. Калининград</p></bio><bio xml:lang="en"><p>Biologist, Center for Immunology and Cellular Biotechnology, </p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Хлусов</surname><given-names>И. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Khlusov</surname><given-names>I. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>д.м.н., cтарший научный сотрудник Центра иммунологии и клеточных биотехнологий, г. Калининград;</p><p>профессор кафедры морфологии и общей патологии,</p><p>г. Томск</p></bio><bio xml:lang="en"><p>PhD, MD (Medicine), Senior Research Associate, Center for Immunology and Cellular Biotechnology, 236001, Kaliningrad, Gaidar str., 6;</p><p>Professor, Department of Morphology and General Pathology, Tomsk</p></bio><xref ref-type="aff" rid="aff-2"/></contrib><contrib contrib-type="author" corresp="yes"><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Литвинова</surname><given-names>Л. С.</given-names></name><name name-style="western" xml:lang="en"><surname>Litvinova</surname><given-names>L. S.</given-names></name></name-alternatives><bio xml:lang="ru"><p>д.м.н., директор Центра иммунологии и клеточных биотехнологий,</p><p>г. Калининград</p></bio><bio xml:lang="en"><p>PhD, MD (Medicine), Director, Center for Immunology and Cellular Biotechnology, </p><p>236001, Kaliningrad, Gaidar str., 6</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>Научно-технологический парк «Фабрика» ФГАОУ ВО «Балтийский федеральный университет имени&#13;
Иммануила Канта»</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Science and Technology Park “Fabrika”, Immanuel Kant Baltic Federal University</institution><country>Russian Federation</country></aff></aff-alternatives><aff-alternatives id="aff-2"><aff xml:lang="ru"><institution>Научно-технологический парк «Фабрика» ФГАОУ ВО «Балтийский федеральный университет имени&#13;
Иммануила Канта»;&#13;
ФГБОУ ВО «Сибирский государственный медицинский университет»</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Science and Technology Park “Fabrika”, Immanuel Kant Baltic Federal University;&#13;
Siberian State Medical University</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2021</year></pub-date><pub-date pub-type="epub"><day>18</day><month>10</month><year>2021</year></pub-date><volume>23</volume><issue>4</issue><fpage>831</fpage><lpage>838</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Норкин И.К., Юрова К.А., Хазиахматова О.Г., Мелащенко Е.С., Малащенко В.В., Шунькин Е.О., Хлусов И.А., Литвинова Л.С., 2021</copyright-statement><copyright-year>2021</copyright-year><copyright-holder xml:lang="ru">Норкин И.К., Юрова К.А., Хазиахматова О.Г., Мелащенко Е.С., Малащенко В.В., Шунькин Е.О., Хлусов И.А., Литвинова Л.С.</copyright-holder><copyright-holder xml:lang="en">Norkin I.K., Yurova K.A., Khaziakhmatova O.G., Melashchenko E.S., Malashchenko V.V., Shunkin E.O., Khlusov I.A., Litvinova L.S.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://www.mimmun.ru/mimmun/article/view/2426">https://www.mimmun.ru/mimmun/article/view/2426</self-uri><abstract><p>Искусственные материалы, применяемые в регенеративной медицине, при имплантации индуцируют развитие воспалительной реакции, необходимой для эффективной регенерации поврежденной костной ткани. Контакт имплантата с тканями сопровождается осаждением белков крови и интерстициальной жидкости на его поверхности, что способствует активации системы комплемента, компонентов врожденного иммунитета и инициирует коагуляционный гемостаз, приводящий к образованию фибринового сгустка. На поверхности имплантата образуется внеклеточный матрикс на основе фибрина, коллагена и эластина, что обеспечивает основу для формирования тканевой структуры посредством адгезии стволовых клеток на формирующуюся костную мозоль до образования костного регенерата. Для предотвращения развития постоперационных патологических состояний, вызванных гиперкоагуляционным синдромом, используют терапевтические стратегии с применением антикоагулянтов (гепарин, варфарин). Однако их использование ограничивает нормальное образование сгустка фибрина in vivo. Это может привести к замедлению миграции мезенхимных стволовых клеток (МСК) и нарушить формирование костной мозоли, что ингибирует процессы остеоинтеграции имплантата и заживление кости. Целью исследования явилось изучение влияния гепарина в градиенте низких и высоких концентраций на миграционную активность и стволовость МСК человека в условиях культивирования in vitro. По результатам проточной цитометрии было выявлено, что высокие концентрации гепарина (130, 260 IU/ml) в 2D-модели культивирования способствуют увеличению количества клеток, экспрессирующих поверхностные маркеры CD73 и CD90, что свидетельствует о сохранении МСК высокого клоногенного потенциала. 3D-модель культивирования in vitro с добавлением гепарина и остеозамещающих имплантатов, несущих КФ покрытие с индексом шероховатости Ra = 2,6-4,9 мкм, способствовала сохранению «стволовости» МСК через экспрессию поверхностных маркеров CD73 и CD90. Согласно результатам, полученным с помощью системы xCELLigence, гепарин в поздние сроки (с 20-40 ч) повышает инвазию МСК через микропоры, симулирующие состояние стенки кровеносных сосудов. Однако в присутствии наночастиц ГАП, имитирующих процессы ремоделирования минерального костного матрикса и/или резорбции костного цемента, эффект гепарина был выражен в меньшей степени. Результаты могут быть использованы в области регенеративной медицины, связанной с введением МСК. Данные могут служить предпосылкой для разработки новых терапевтических стратегий для пациентов хирургического профиля с высоким риском развития послеоперационных тромбозов после проведения остеосинтеза. </p></abstract><trans-abstract xml:lang="en"><p>Synthetic materials used in regenerative medicine, upon implantation, induce the development of an inflammatory reaction necessary for the effective regeneration of damaged bone tissue. Implant contact with tissues is accompanied by the deposition of blood proteins and interstitial fluid on its surface, contributing to the activation of the complement system, components of innate immunity, initiating coagulation hemostasis, leading to the formation of a fibrin clot. An extracellular matrix based on fibrin, collagen and elastin forms on the implant’s surface, which provides the basis for the formation of tissue structure through the adhesion of stem cells to the forming bone callus before the formation of bone regenerate. To prevent the development of postoperative pathological conditions caused by hypercoagulable syndrome, therapeutic strategies are used to use anticoagulants (heparin, warfarin). However, their use limits the normal formation of a fibrin clot in vivo. This can slow down the migration of mesenchymal stem cells (MSC) and disrupt the formation of callus, inhibiting the processes of osseointegration of the implant and bone healing. The study’s goal was to study the effect of heparin in a gradient of low and high concentrations on the migration activity and stem capacity of human MSCs under in vitro cultivation conditions. According to the results of flow cytometry, it was revealed that high concentrations of heparin (130, 260 IU/ml) in a 2D cultivation model contribute to an increase in the number of cells expressing surface markers CD73 and CD90, which indicates that MSCs retain high clonogenic potential. A 3D model of in vitro cultivation with the addition of heparin and osteosubstituting implants bearing a CF coating with a roughness index of Ra = 2.6-4.9 μm contributed to preserving the “stemness” character of MSCs through the expression of surface markers CD73 and CD90. According to the results obtained using the xCELLigence system, heparin at a later time (from 20-40 hours) increases the invasion of MSCs through micropores that simulate the state of the blood vessel walls. However, in the presence of HAP nanoparticles that mimic the remodeling processes of the mineral bone matrix and/or resorption of bone cement, the effect of heparin was less pronounced. The results can be used in the field of regenerative medicine associated with the introduction of MSCs. The data can serve as a prerequisite for developing new therapeutic strategies for surgical patients with a high risk of postoperative thrombosis after osteosynthesis. </p></trans-abstract><kwd-group xml:lang="ru"><kwd>мезенхимальные стволовые клетки</kwd><kwd>гепарин</kwd><kwd>миграция</kwd><kwd>стволовость</kwd><kwd>имплантат</kwd><kwd>RTCA</kwd><kwd>in vitro</kwd></kwd-group><kwd-group xml:lang="en"><kwd>mesenchymal stem cells</kwd><kwd>heparin</kwd><kwd>migration</kwd><kwd>stemness</kwd><kwd>implant</kwd><kwd>RTCA</kwd><kwd>in vitro</kwd></kwd-group><funding-group><funding-statement xml:lang="en">The research was supported by the State assignment in the field of scientific activity (No. FZWM2020-0010 to Larisa Litvinova); State Support of Leading Scientific Schools of the Russian Federation (No. 2495.2020.7 to Larisa Litvinova).</funding-statement></funding-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Ali H., Al-Yatama M.K., Abu-Farha M., Behbehani K., Al Madhoun A. 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