Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук 1 , Федеральный исследовательский центр фундаментальной и трансляционной медицины Министерства науки и высшего образования РФ, Институт молекулярной патологии и патоморфологии 2 , АО Медицинский центр «Авиценна» 3 , г. Новосибирск, Российская Федерация Цель. Изучить результаты применения экстрацеллюлярных микровезикул мультипотентных мезенхимальных стромальных клеток костномозгового происхождения крысы (ЭМВ) для регенерации дефекта костной ткани кроликов, а также получить данные о сохранности ЭМВ в тканях после их введения. Материал и методы. В проксимальных мыщелках большеберцовой кости беспородных кроликов создавали дефект диаметром 2 мм и глубиной 4 мм. На левой конечности дефект заполняли физиологическим раствором, на правой конечности в дефект вводили 50 мкг ЭМВ. Результаты. К 12-м суткам в контроле у всех кроликов сохранялся дефект в костной ткани с формирующимися костными структурами и грубым толстым рубцом на границе с неповрежденными участками. После введения ЭМВ в большинстве случаев повреждение кости не было найдено, рубец был тонким, с упорядоченными структурами межклеточного матрикса. Спустя 12 суток после применения ЭМВ, меченных Vybrant ® CM-Dil, в надкостнице и рядом с ней, костном мозге, сосудах костной ткани были найдены единичные, очень мелкие, пылевидные объекты, флюоресцирующие красным цветом на фоне применения фильтра для родамина. Иногда был отмечен четкий красный оттенок включений в крупных клеточных элементах-макрофагах. К 21-му дню справа (опыт) в 4 случаях из 5 на месте дефекта костной ткани были найдены только структуры рубца, тогда как слева (контроль)-только в 2 наблюдениях из 5. Заключение. Предварительные результаты применения ЭМВ для регенерации дефекта костной ткани в эксперименте свидетельствуют о более быстром заживлении, увеличении частоты успешной регенерации поврежденной кости и формировании менее грубой костной мозоли. У кроликов ЭМВ присутствуют в тканях в месте применения не менее 12 суток. Часть введенных ЭМВ оказывается в макрофагах. Ключевые слова: костная ткань, регенерация костной ткани, экстрацеллюлярные микровезикулы, макрофаги, люминесцентная микроскопия Objective. To study the results of application extracellular microvesicles from rat multipotent mesenchymal stromal cells of the bone marrow origin (EMV) for the regeneration of rabbit bone defects, as well as to obtain data about the EMV preservation after their introduction into tissues. Methods. The bone defect (2 mm diameter and 4 mm depth) was created in the proximal condyles of the outbred rabbit tibia. On the left limb the bone defect was filled with saline, on the right-the 50 μ g EMV were introduced into defect. Results. By the 12 th day all control rabbits had retained a defect in the bone tissue with forming bone structures and hypertrophiс scar in the border with intact areas. In the most cases after the EMV introduction, no bone damage was found; the scar was thin with ordered structures of the interc...
When administered intravenously, extracellular vesicles derived from multipotent stromal cells (MSC EVs) immediately pass through the lungs along with the blood and regularly spread to all organs. When administered intraperitoneally, they are absorbed either into the blood or into the lymph and are quickly disseminated throughout the body. The possibility of generalized spread of MSC EVs to distant organs in case of local intratissular administration remains unexplored. However, it is impossible to exclude MSC EV influence on tissues distant from the injection site due to the active or passive migration of these injected nanoparticles through the vessels. The research is based on findings obtained when studying the samples of lungs, heart, spleen, and liver of outbred rabbits of both sexes weighing 3–4 kg at various times after the injection of EVs derived from MSCs of bone marrow origin and labeled by PKH26 into an artificially created defect of the proximal condyle of the tibia. MSC EVs were isolated by serial ultracentrifugation and characterized by transmission electron microscopy and flow cytometry. After the introduction of MSC EVs into the damaged proximal condyle of the tibia of rabbits, these MSC EVs can be found most frequently in the lungs, myocardium, liver, and spleen. MSC EVs enter all of these organs with the blood flow. The lungs contained the maximum number of labeled MSC EVs; moreover, they were often associated with detritus and were located in the lumen of the alveoli. In the capillary network of various organs except the myocardium, MSC EVs are adsorbed by paravasal phagocytes; in some cases, specifically labeled small dust-like objects can be detected throughout the entire experiment—up to ten days of observation. Therefore, we can conclude that the entire body, including distant organs, is effected both by antigenic detritus, which appeared in the bloodstream after extensive surgery, and MSC EVs introduced from the outside.
The scientific literature of recent years contains a lot of data about using multipotent stromal cells (MSCs) for urinary incontinence correction. Despite this, the ideal treatment method for urinary incontinence has not yet been created. The cell therapy results in patients and experimental animals with incontinence have shown promising results, but the procedures require further optimization, and more research is needed to focus on the clinical phase. The MSC use appears to be a feasible, safe, and effective method of treatment for patients with urinary incontinence. However, the best mode for application of cell technology is still under study. Most clinical investigations have been performed on only a few patients and during rather short follow-up periods, which, together with an incomplete knowledge of the mechanisms of MSC action, does not make it possible for their widespread implementation. The technical details regarding the MSC application remain to be identified in more rigorous preclinical and clinical trials.
Objective. To study the effect of exosomes of multipotent mesenchymal stromal cells (EMSCs) on soft tissues damaged during implantation of a metal screw into the bone. Methods. A defect (2 mm in diameter and 4 mm in depth) was created in the tibial proximal condyles of outbred rabbits. Metal screws were implanted into the defect by preliminary injection of saline (control, n=9 animals) or 19.2 μg of EMSCs per limb (experiment, n=10 rabbits). After 3, 7 and 10 days following the operation, the animals were taken out from the experiment; histological sections of soft tissues from the condyle surface, stained by hematoxylin and eosin were studied using light microscopy. Results. The use of water cooling in the process of introducing the metal implant into the tibial proximal condyle does not lead to complete removal of small bone fragments, which are subsequently either eliminated outward with wound discharge, or are destroyed and are subjected to lysis by macrophages. As a result of the EMSC effect on soft tissues near the site of damage, the activity of the postoperative inflammation reduces, leads to a slowdown in the resorption of hemorrhages, the elimination of fibrin clots, detritus and small bone fragments. Even on the 10<sup>th</sup> day after using EMSCs in the postoperative wound a structureless detritus with a small number of infiltrating cells was present, as well as a significant number of multinucleated macrophages with fused cytoplasm, non-viable lysed striated muscle symplasts and bone fragments with a low degree of degradation. Conclusion. Suppression of inflammation by EMSCs delays the clearance of the postoperative wound, promotes the prolongation of the repair process and the attachment of the granulomatous component to the inflammation. The using EMSCs in the process of intraosseous implantation may be recommended only to control the activity of the inflammatory process and only after maximum preliminary cleansing of the postoperative wound from detritus, including non-viable muscle tissue and bone fragments. What this paper adds It has been firstly shown that after the experimental use of exosome of multipotent mesenchymal stromal cells to influence the regeneration of surgical trauma of soft tissues after intraosseous implantation, it is possible to reduce the activity of the inflammatory reaction, which leads to a slowdown of resorption of hemorrhages, elimination of fibrin clots, detritus and small bone fragments and, accordingly, prolongation of cleansing damaged tissue and delayed repair.
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