ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2018-1-167-176ssmu-1127Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSЭффекты мезенхимальных стромальных клеток на дифференцировку макрофагов первого типа и их переключение в макрофаги второго типаEffects of mesenchymal stromal cells on monocyte differentiation to M1 phenotype and M1/M2 macrophage switchingШевелаЕ. Я.ShevelaE. Ya.

Шевела Екатерина Яковлевна, д-р мед. наук, вед. науч. сотрудник, лаборатория клеточной иммунотерапии.

630099, г. Новосибирск, ул. Ядринцевская, 14.

Shevela Ekaterina Ya., DM, Leading Researcher, Laboratory of Cellular Immunotherapy.

14, Yadrintsevskaya Str., Novosibirsk, 630099.

shevelak@mail.ruСахноЛ. В.SakhnoL. V.

Сахно Людмила Васильевна, канд. биол. наук, ст. науч. сотрудник, лаборатория клеточной иммунотерапии.

630099, г. Новосибирск, ул. Ядринцевская, 14.

Sakhno Ludmila V., PhD, Senior Researcher, Laboratory of Cellular Immunotherapy.

14, Yadrintsevskaya Str., Novosibirsk, 630099.

ТихоноваМ. А.TikhonovaM. A.

Тихонова Марина Александровна, канд. биол. наук, ст. науч. сотрудник, лаборатория клеточной иммунотерапии.

630099, г. Новосибирск, ул. Ядринцевская, 14.

Tikhonova Marina A., PhD, Senior Researcher, Laboratory of Cellular Immunotherapy.

14, Yadrintsevskaya Str., Novosibirsk, 630099.

БаторовЕ. В.BatorovE. V.

Баторов Егор Васильевич, канд. мед. наук, науч. сотрудник, лаборатория клеточной иммунотерапии.

630099, г. Новосибирск, ул. Ядринцевская, 14.

Batorov Egor V., PhD, Research fellow, Laboratory of Cellular Immunotherapy.

14, Yadrintsevskaya Str., Novosibirsk, 630099.

ОстанинА. А.OstaninA. A.

Останин Александр Анатольевич, д-р мед. наук, профессор, гл. науч. сотрудник, лаборатория клеточной иммунотерапии.

630099, г. Новосибирск, ул. Ядринцевская, 14.

Ostanin Aleksandr A., DM, Professor, Chief Researcher, Laboratory of Cellular Immunotherapy.

14, Yadrintsevskaya Str., Novosibirsk, 630099.

ЧерныхЕ. Р.ChernykhE. R.

Черных Елена Рэмовна, д-р мед. наук, профессор, член-корр. РАН, зав. лабораторией клеточной иммунотерапии.

630099, г. Новосибирск, ул. Ядринцевская, 14.

Chernykh Elena R., DM, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Cellular Immunotherapy.

14, Yadrintsevskaya Str., Novosibirsk, 630099.

Научно-исследовательский институт фундаментальной и клинической иммунологии (НИИФКИ).РоссияFederal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology (RIFCI) .Russian Federation201830032018171167176Copyright © Шевела Е.Я., Сахно Л.В., Тихонова М.А., Баторов Е.В., Останин А.А., Черных Е.Р., 20182018Шевела Е.Я., Сахно Л.В., Тихонова М.А., Баторов Е.В., Останин А.А., Черных Е.Р.Shevela E.Y., Sakhno L.V., Tikhonova M.A., Batorov E.V., Ostanin A.A., Chernykh E.R.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/1127

Известно, что мезенхимальные стромальные клетки (МСК) способны направлять и переключать дифференцировку непримированных макрофагов (Мф) или Мф I типа (М1) в направлении Мф II типа (М2).

Целью работы явилось исследование способности МСК индуцировать переключение М1 в М2 на основе сравнительного анализа эффектов МСК на поляризованные М1 и моноциты, стимулированные гранулоцитарно-макрофагальным колониестимулирующим фактором к М1-дифференцировке.

Материалы и методы

Материалы и методы. В условиях, блокирующих прямые межклеточные контакты (Transwell-система), МСК сокультивировали с моноцитами в течение 7 сут или с М1 в течение 48 ч. Характеристика генерированных таким образом Мф включала оценку экспрессии CD206, аллостимуляторной активности в смешанной культуре лимфоцитов и способности секретировать про- и противовоспалительные медиаторы.

Результаты

Результаты. Сокультивирование МСК и М1 приводило к появлению у них фенотипических (усиление экспрессии CD206) и функциональных (снижение аллостимуляторной активности) свойств М2. В то же время в результате сокультивирования МСК и моноцитов в М1-индуцирующей среде генерировались Мф с выраженной стимулирующей активностью в СКЛ, аналогичной таковой у М1 (3,45 и 3,4 расч. ед.; р = 0,46) и значимо превышающей аллостимуляторную активность М2 (3,45 vs 2,2 расч. ед.; р = 0,03). При этом МСК не влияли на уровень экспрессии CD206, а также на характер продукции про- (IL-1β, TNF-α, IL-6, IL-12) и противовоспалительных (IL1-ra, IL-4, IL-10) цитокинов, иммунорегуляторных цитокинов (IFN-γ, IL-17) и хемокинов (IP-10, MCP-1, MIP-1b, Rantes, Eotaxin).

Выводы

Выводы. Способность МСК индуцировать фенотип М2 зависит от стадии дифференцировки клеток моноцитарно-макрофагального ряда. В культурах поляризованных М1 МСК способствуют переключению М1 в М2. В то же время при культивировании МСК с моноцитами в М1-индуцирующей среде формируется популяция М1-подобных Мф, отличающихся высокой аллостимуляторной активностью и характерным для М1 спектром продуцируемых цитокинов и хемокинов.

Objective

Objective. Mesenchymal stromal cells (MSCs) promote the differentiation of unprimed macrophages (Mр) or classically activated M1 cells towards alternatively activated, M2 macrophages. The aim of the work was to study the ability of MSC to induce M1→M2 switching by comparing the MSC effects on polarized M1 macrophages and monocytes stimulated by granulocyte-macrophage colony-stimulating factor to M1 differentiation.

Material and мethods

Material and мethods. MSC were co-cultured with monocytes for 7 days or M1 macrophages for 48 hours in Transwell system to prevent direct cell-to-cell contacts. To characterize generated Mр, classical M2 marker CD206, allostimulatory activity in a mixed lymphocyte culture (MLC), and the ability to secrete pro-/antiinflammatory mediators were analyzed.

Results

Results. Co-cultivation of MSCs and M1 macrophages led to the appearance of phenotypic (increased expression of CD206) and functional (decrease in allostimulatory activity) features of M2 phenotype. When MSCs were cultured with monocytes in the M1-inducing medium, generated Mр elicited a pronounced stimulating activity in MLC similar to that of M1 (stimulation index 3.45 and 3.4, p = 0.46) and significantly higher than allostimulatory activity of M2 cells (3.45 vs 2.2, p = 0.03). In addition, MSCs did not influence the expression of CD206, as well as the production of pro- (IL-1β, TNF-α, IL-6, IL-12) and anti-inflammatory (IL1-ra, IL-4, IL-10) cytokines, immunoregulatory cytokines (IFN-γ, IL-17) and chemokines (IP-10, MCP-1, MIP-1b, Rantes, Eotaxin).

Conclusions

Conclusions: The ability of MSC to induce the M2 phenotype depends on the stage of differentiation of monocyte/macrophages. MSCs promote M1→M2 switching in cultures of polarized M1 macrophages. In contrast, when MSCs interacted with monocytes in M1-inducing medium, a population of M1-like macrophages is formed with high allostimulatory activity and typical for M1 spectrum of produced cytokines and chemokines.

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The authors declare that there are no conflicts of interest present.