Morphology of the Myocardium after Experimental Bone Tissue Trauma and the Use of Extracellular Vesicles Derived from Mesenchymal Multipotent Stromal Cells

The effect of extracellular vesicles (EVs) of various origins on the heart structures in the time of health and disease has been well studied. At the same time, data on the distribution of EVs throughout the body after introduction into the tissues and the possibility of the influence of these EVs on organs distant from the injection site are practically absent. It is also necessary to note a certain inconsistency in the results of various researchers: from articles on the direct absorption of EVs derived from mesenchymal multipotent stromal cells (MSC EVs) by cardiomyocytes to the data that the heart is inherently immune to drug delivery mediated by nanoparticles. In this regard, the morphological changes in the myocardium of outbred rabbits of both sexes weighing 3–4 kg were studied at various times after experimental trauma of the bone tissue in the proximal condyle of the tibia (PCT) and the use of MSC EVs. As a result of modeling the PCT defect, rabbits develop myocardial edema in the heart muscle by the 3rd day, their lymphatic vessels expand, and then, on the 7th day, the blood vessels become dilated. In the myocardium, the relative and absolute contents of neutrophils, erythrocytes, and macrophages increase, but the percentage of lymphocytes decreases. By day 10, almost all of these changes return to their initial values. The detected transformations of the myocardium are most likely due to the ingress of detritus with the blood flow from the PCT. The use of MSC EVs to influence the regeneration of damaged tissue of PCT promotes earlier dilatation of the blood vessels of the heart with pronounced diapedesis of erythrocytes or even hemorrhages, prolongation of edema, the formation of blood clots in vessels with obliteration of their lumen, sclerotic transformation of vascular walls and paravascular tissues. In the myocardium, the number density of neutrophils, the percentage of lymphocytes, and neutrophils become smaller, with a simultaneous increase in the relative numbers of erythrocytes and macrophages, and changes in the content of macrophages remained until the end of the observation—up to 10 days after the surgery. The discovered effect of MSC EVs is most likely associated with the suppression of the activity of the inflammatory process in the PCT area, which, in turn, was caused by a longer ingress of detritus with blood flow into the myocardium. The absence of statistically significant differences between changes in the myocardium of the left and right ventricles may indicate that both detritus from the surgical site and MSC EVs affect the heart spreading through the coronary artery system.

Neuroinflammatory penumbra in Parkinson’s disease

To date, the etiology and pathogenesis of Parkinson’s disease (PD) are not fully understood. In this publication, we present a critical review of the available international data on the involvement of inflammation processes in the etiopathogenesis of the disease in the context of our research results. The data obtained by us during modeling of parkinsonian syndrome of neuroinflammatory origin (lipopolysaccharide endotoxin was used) in laboratory rats (basic group, n = 21; control group, n = 7) indicate that intranasal administration of lipopolysaccharide in all three studied doses (1, 10 and 100 μg/kg/ml) seven days after the end of the experiment (21 injections) causes the same moderate morphological degenerative and inflammatory changes in the histostructure of the substantia nigra, extending to the striatum area (p > 0.05). This fact can be best explained by the all-or-none law. The staged, sequential transition of primary reversible (neuroinflammatory) pathomorphological changes to secondary irreversible (neurodegenerative) ones in PD, as well as secondary activation of microglia during neuronal degeneration, allows proposing the term “neuroinflammatory penumbra”, which will best help understand the pathogenesis of the disease and the development of therapies that change the course of Parkinson’s disease. Our data on the use of mesenchymal multipotent stromal cells in rats with neurotoxic (rotenone) parkinsonian syndrome (n = 10) and in PD individuals (n = 10) demonstrate a decrease in motor impairment, overall improvement of patients and an effect on laboratory parameters compared with control groups. We associate the early positive effect, observed already in the first week after the administration of mesenchymal multipotent stromal cells, with their paracrine action, including on the neuroinflammatory penumbra.

THE EFFECT OF MULTIAXIAL DEFORMATION ON THE DYNAMICS OF BIODEGRADATION AND CELL COLONIZATION OF ALLOY WE43

Introduction. The development of materials for bioresorbable implants is an urgent issue in medicine and materials science. Magnesium alloys are promising materials for this purpose. In particular, alloy WE43 (Mg-Y-Nd-Zr) has proven itself well in this field. However, the use of magnesium alloys is limited by a high degradation rate, which is often accompanied with nonuniform corrosion, which negatively affects the load bearing capacity of the product. In addition, the increased degradation rate usually seriously worsens the biocompatibility of magnesium alloys. Therefore, the study of the corrosion resistance of magnesium alloys, as well astheir biocompatibility, is an urgent task.Purpose of the study was to investigate the effect of multiaxial deformation (MAD), aimed at increasing the mechanical characteristics of the alloy WE43, on its biodegradation kinetics, as well as on cell colonization.Materials and methods. The alloy WE43 in two states – homogenized (WE43 hom) and strengthened by MAD (WE43 MAD) was investigated in this work. The kinetics of biodegradation was investigated on an xCELLigence RTCA Systems analyzer. A method for estimating the volume of hydrogen was used to study the process of gas formation, which was recorded using an automated digital microscope LionheartTM FX. The corrosive medium was a solution based on Dulbecco’s Modified Eagle’s Medium. A culture of mesenchymal multipotent stromal cells was used to study the colonization of the alloy surface by cells.Results. MAD of the alloy WE43 leads to a decrease in the biodegradation rate and the intensity of gas formation. The period of stabilization of biodegradation for the alloy after the MAD is 16 hours versus 3 hours for the alloy after homogenization. In this case, the volume of released hydrogen was 65.0 ± 4.4 mm3H2/mm3 alloy and 211.0 ± ± 21.1 mm3H2/mm3 alloy for the alloy after MAD and homogenization, respectively. MAD improves the biocompatibility of the alloy WE43, stimulating the colonization of mesenchymal multipotent stromal cells.Conclusion. MAD reduces biodegradation and improves the biocompatibility of the alloy WE43, which makes it a promising medical material, including for the purposes of oncoorthopedics

The possibility of using biomedical cell product in the treatment of chronic glomerulonephritis

The basic principles of rational treatment of glomerulonephritis are considered, based on etiology, clinical manifestations and pathomorphological variants of its different forms. Today it has been established that glomerulonephritis can be primary (the etiology is usually unknown) and secondary, when the disease occurs against the background of concomitant pathology (systemic lupus erythematosus, vasculitis, hepatitis, oncological diseases, chronic viral and bacterial infections). The participation of various pathological, genetic and systemic factors in the development of various forms of glomerulonephritis has been shown. The characteristic clinical picture of manifestations of different forms of the disease and the degree of involvement of different renal structures in them are described. Against the background of the severity of the course and prevalence of various forms of glomerulonephritis, it is especially important to develop therapeutic approaches aimed at the full restoration of kidney function and cure of patients. One of such approaches is the use of biomedical cell products based on allogenic mesenchymal multipotent stromal cells and hematopoietic stromal cells. A number of studies have confirmed that the best results can be achieved with the use of cell products in complex therapies with standard treatment methods (use of cytostatics and steroid anti-inflammatory drugs) and alternative drug approaches (combination of monoclonal antibodies and polyenzyme drugs). At the same time, the use of standard and alternative techniques does not lead to a complete recovery of patients, but only transfers the course of the disease from the exacerbation phase to remission. The relevance of further development of biomedical cell products of allogeneic mesenchymal multipotent bone marrow stromal cells is shown, verification of their safety and efficacy in preclinical and clinical studies.

Mesenchymal multipotent stromal cells and cancer safety: two sides of the same coin or a double-edged sword (review of foreign literature)

Knowledge about the mechanisms of action of mesenchymal multipotent stromal cells (MSC) has undergone a significant evolution since their discovery. From the first attempts to use the remarkable properties of MSC in restoring the functions of organs and tissues, the most important question arose – how safe their use would be? One of the aspects of safety of the use of such biomaterial is tumorogenicity and oncogenicity. Numerous studies have shown that the mechanisms by which MSC realize their regenerative potential can, in principle, have a stimulating effect on tumor cells. This review presents specific mechanisms that have a potentially pro-tumor effect, which include the homing of MSC to the tumor site, support for replicative and proliferative signaling of both cancer cells and cancer stem cells, angiogenesis, and effects on the epithelial-mesenchymal transition. Along with pro-tumor mechanisms, the mechanisms of possible antitumor action are also described – direct suppression of tumor growth, loading and transportation of chemotherapeutic agents, oncolytic viruses, genetic modifications for targeting cancer, delivery of “suicide genes” to the tumor. Also, in conclusion, a small review of the current clinical trials of MSC as antitumor agents for malignant neoplasms of various localization (gastrointestinal tract, lungs, ovaries) is given.

The acceleration of collagen biodegradation after adsorption of mesenchymal multipotent stromal cells in experiment

Background. The scientific literature contents clearly not enough data at interaction of collagen materials with a living organism and about influence of multipotent stromal cells (MSC) on this process. There are controversies about the collagen degradation and the development of foreign body reactions. However, without account these results, it is impossible to estimate the timeframes for complete lysis of such materials, to progress effective methods for the prevention and treatment of developing complications. Objective. To study the features of the collagen-based material degradation after implantation with adsorbed autologous mesenchymal MSC of bone marrow origin (AMMSCBMO) in the experiment. Design and methods. In different times the condition of tissues around the implanted collagen membrane with adsorbed AMMSCBMO was studied by method of light microscopy. Results. The number of vessels and cellular elements in the collagen material implanted without AMMSCBMO increases to 3 weeks and remains at this level until the end of the observation. A distinctive features of the use of collagen membrane with adsorbed AMMSCBMO are increased vascularization and cellular infiltration of the material in the first 2 weeks after surgery. This effect further leads to a more rapid degradation of all implanted collagen, including its more dense parts, but does not prevent the formation of multinuclear macrophages with fused cytoplasm. Conclusion. As a result of more significant vascularization and cellular infiltration caused by AMMSCBMO adsorbed on the surface of the collagen material, to the 4th week the entire implant is full destroyed and absorbed, and dense fibrous connective tissue is formed in its place. For the implantation into the body, one should choose the most homogeneous collagen materials, without areas of different density, as slowly degrading fragments can cause the development of granulomatous inflammation and the failure of the implantation procedure.