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Vol 12, No 2 (2017)

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Open Access Open Access
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Nikolay Grigorievich Khlopin: about life and scientific endeavors (devoted to the 120-th anniversary of birth)

Odintsova I.A., Gololobov V.G.


In 2017 we will celebrate the 120-th anniversary of the academician N.G. Khlopin's birth who was anoutstanding evolutionary histologist, the author of a basic concept of tissue divergent evolution, the father of a phylogenetic system of tissues. His endeavors were confirmed and further developed in normal morphology and pathomorphology, the concept of cambial reserve and tissue regeneration, when solving issues of transplantation, inflammatory epitheliza-tion, hematopoiesis (blood formation) and oncology. In his works N.G. Khlopin widely used a method of tissue culture in vitro, which in combination with a histological technique became fruitful in studying the histoblastic potency of normal and tumor tissues. N.G. Khlopin established a prominent scientific histologic school in Russia; its main achievements are described in this article. His concepts are fundamental and applied worldwide; they still have a great impact on the development of medical and biological sciences.
Genes & Cells. 2017;12(2):6-10
pages 6-10 views

Cellular models, genomic technologies and clinical practice: a synthesis of knowledge for the study of the mechanisms, diagnostics and treatment of Parkinson's disease

Kovalenko V.R., Khabarova E.A., Rzaev D.A., Medvedev S.P.


Nowadays we approached the turn, when the molecular genetics and the cell biology with its extensive baggage of methods and data, allow us to work with information about nucleotide sequences of whole genomes, to edit the nucleotide sequence of the genomes of laboratory animals and cultured human cells and also explore functions and interactions of genetic elements in health and in disease. The use of these instruments opens up huge possibilities for the study of severe human genetic abnormalities. In various laboratories around world an extensive work is carried out in this area by searching links between genetic elements and diseases, using the latest technology of genome editing and reprogramming somatic mature cells to a pluripotent stem condition. The most progressively developing area of research is the study of neurodegenerative diseases. In this review we discussed about possibilities and problems of using new techniques and instruments of cell biology, genetics and genomics in studying molecular and genetic basis of the pathogenesis of Parkinson's disease.
Genes & Cells. 2017;12(2):11-28
pages 11-28 views

The prospects of creating a pacemaker cardiac tissue using modern technologies

Bayramova S.A., Strelnikov A.G., Romanov A.B., Yakubov A.A., Losik D.V., Pavlova S.V., Agladze K.I., Pokushalov E.A.


At the present time there are a lot of implantable pacemakers, which are able to replace the function of physiological pacemakers (sinoatrial and atrioventricular nodes). These systems are currently imperfect and have a number of limitations. They require constant monitoring and maintenance due to limited battery life. There are risks of infection of pacemakers system, which may cause a pacemaker reimplantation. Implantable devices are often incompatible with other electric devices (metal detectors and magnets in MRI scanners, as well as power lines), which may affect the operation of pacemakers. Sometimes the electrodes can not be physiologically positioned, which may lead to heart failure and additional symptoms worsen the patient>s quality of life. This article is devoted to a review of methods for creating biological pacemakers, considering advantages and disadvantages of the available modern strategies for obtaining pacemaker tissue, which is based on the using of key modifier genes regulating the embryonic development of ventricular, atrial and pacemaker cardiomyocytes. Furthermore the technologies for creating induced patient specific pluripotent cells (IPSC) and the subsequent development of directional differentiation protocols in the cardial direction discover new approaches for the development of biological pacemakers. Also briefly described the prospects for using modern materials for the development of tissue engineering.
Genes & Cells. 2017;12(2):29-36
pages 29-36 views

Gingiva as a source of stromal cells with high differentiating and reparative potential

Zorin V.L., Zorina A.I., Eremin I.I., Deev R.V., Kopnin P.B., Volozhin G.A., Pulin A.A.


This review is focused on systematization of data describing several features of multipotent mesenchymal stromal cells. It also presents a detailed review of differentiation and reparation potential of human gingiva-derived stromal cells and opportunities of their therapeutic application in regenerative medicine.
Genes & Cells. 2017;12(2):37-51
pages 37-51 views

The modern strategies for working out of transplant tolerance by using blood and bone marrow cells

Onischenko N.A.


This review presents analysis of the modern state of transplant tolerance forming problem in recipient organism by using stem/ progenitory cells of bone marrow (BM) and differentiated immunoregulatory (tolerogenic) subsets of blood cells-regulatory B- and T-lymphocytes (Treg), and regulatory dendritic cells (DCreg). It is pointed out that protocols based on the using BM cells, permit to work out the tolerance state and now they are estimate at clinical kidney transplantation, during multicentre investigations. Protocols, based on the using of Treg and DCreg, do note gain the impression of reliable, although at the application of their cells the tolerogenic effect can be obtain. It was given supposition that at using BM cells the forming of steady transplant tolerance state is a result of successive entering of central (thymical induction of temporary mixed chimer-ism) and peripheral tolerance mechanisms. Treg and DCreg induce mechanisms only peripheral tolerance. Combined application of BM cells and Treg permits to increase the terms for maintaining of donor chimerism into all cell lines (incuding Tcells) and transplant tolerance in recipient organism.
Genes & Cells. 2017;12(2):52-61
pages 52-61 views

Somatic cells reprogramming and genome editing for stargardt disease modeling for investigation and treatment

Lebedin M.Y., Mayorova K.S., Maximov V.V., Bogomazova A.N., Lagarkova M.A., Kiselev S.L.


Degeneration of the retina occurs both in relation to age, and as a consequence of hereditary pathologies. A clinically similar pattern is often associated with different molecular pathways and gene mutations. The arsenal of therapeutic approaches for these patients is very limited. Modern advances in cellular reprogramming and genome editing make it possible to establish a model for the disease investigation and treatment. In this study we established induced pluripotent stem cells (iPSCs) from patients with a clinical diagnosis of Stargardt>s disease. Mutation in the peripherin 2 gene was found and it was shown that the mutation does not affect the efficiency of differentiation in the pigment epithelium of the retina. Using the CRISPR/Cas9 system the mutation was corrected in the patient's iPSCs. As a result, isogeneic iPSC lines with a corrected mutation have been generated for establishing of an in vitro model of the disease and potentially suitable for personalized therapy of Stargardt disease.
Genes & Cells. 2017;12(2):62-70
pages 62-70 views

Effects of autologous gingiva-derived cells with myogenic potential on regeneration of skeletal muscle

Korsakov I.N., Samchuk D.P., Pulin A.A., Mavlikeev M.O., Chernova O.N., Titova A.A., Deev R.V., Bozo I.Y., Zorin V.L., Eremin I.I., Denisova O.V., Karpukhina A.S., Gorodkov A.Y., Kotenko K.V., Kopnin P.B.


In our recent studies we found for the first time the ability of human multipotent mesenchymal stromal cells (MSCs) derived from alveolar gingiva (alveolar mucosa) to differentiate into myogenic direction. The aim of the present study was to evaluate the effects of autologous gingiva-derived MSCs with myogenic potential on the regeneration of muscular tissue after mechanical damage. The study was conducted on 11 male rabbits. Biopsy of alveolar gingiva was performed at each animal before experiment for autologous MSCs obtainment. Cultures of MSCs were induced in vitro into myogenic direction. To model the damage, the medial heads of the gastrocnemius muscles were intersected on both pelvic limbs of the rabbit. Injection of autologous MSCs was performed on the seventh day after injury into the damaged muscle of one of the extremities, while equal volume of saline (control) was injected into the muscle of the contralateral limb. The animals were sacrificed on 0, 21, and 35 days after the administration of cells. MSCs transplantation led to significant reduction of the area of muscle damage. Immunohistochemical analysis revealed earlier increase in the proportion of MyoD- and myogenin-positive cells, as well as decrease in the expression of Ki-67 in damaged tissue, in experimental group compared to the control. Autologous cells did not significantly affect the composition of muscle fibers. Significant decrease in the proportion of fibrous tissue was also observed in the experimental group. The results indicate the effectiveness of autologous alveolar gingiva-derived MSCs for treatment of mechanical damage of muscle tissue. Local administration of cells accelerated reparative regeneration and prevented fibrosis.
Genes & Cells. 2017;12(2):71-81
pages 71-81 views

Erythropoietin-mediated activation of functional properties of peripheral blood mononuclear cells in patients with chronic heart failure

Poveshchenko O.V., Bondarenko N.A., Kim I.I., Lykov A.P., Surovtseva M.A., Pokushalov E.A., Romanov A.B., Poveshchenko A.F., Konenkov V.I., Karaskov A.M.


Stem cell therapy of diseases of the cardiovascular system, such as myocardial infarction is a prospective method for the stimulation of ischemic tissue repair. The main mechanisms of stem and progenitor cells action is a paracrine. The purpose of the study was to assess the effects of erythropoietin on the functional activity of mononuclear cells (MNCs) in patients with chronic heart failure before and after enrichment of peripheral blood with stem and progenitor cells mobilized by granulocyte colony-stimulating factor (G-CSF). 48 patients with coronary heart disease participated in the study. MNCs from the separated blood were isolated by density gradient on Ficoll/verografin. The phenotype of endothelial progenitor cells was investigated using monoclonal antibodies to CD34, CD133, VEGFR2, CD31. The Change of MNCs proliferative potential in response to erythropoietin was evaluated by MTT-test. The cytokine production in conditioned media was studied using ELISA. The effectiveness of mobilized MNC intramyocardial administration was assessed at 6 and 12 months by detection of a change in functional class according to NYHA heart failure, volume ejection fraction of the left ventricle of the heart and a change in myocardial perfusion. We showed that the enrichment of peripheral blood by mobilization of stem and progenitor cells in patients with chronic heart failure led to activation of proliferative potential of MNCs and increased erythropoietin production, a cytokine with pro-angiogenic activity. MNC enriched with stem and progenitor cells being culturing with erythropoietin increased the levels of TNF-α, IL-10, IL-18, IL-8, G-CSF and VEGF, as compared with the basal level of production. Circulating endothelial progenitor cells with the phenotype CD34- /VEGFR2+ have a correlation with the level of erythropoietin production. Secretory erythropoietin level directly correlated with myocardial perfusion, left ventricular ejection fraction and heart failure class at 6 and 12 months follow-up. The findings suggest that erythropoietin improves functional properties of the MNC of patients with heart failure after mobilization with G-CSF.
Genes & Cells. 2017;12(2):82-87
pages 82-87 views

The effect of low-intensity electromagnetic irradiation with a frequency of 1 GHz on the content of the components of the M/TOLL signaling pathway and NF-kB in mononuclear cells of whole blood

Terekhov I.V., Nikiforov V.S., Bondar S.S., Bondar N.V., Voevodin A.A.


Signaling pathway IL1/TOLL and the nuclear transcription factor NF-KB plays a key role in the protection against pathogenic microorganisms, therefore, the violation of their functional activity under the influence of the chemical and physical nature (reactive oxygen species, endo and exotoxins, etc.) may adversely affect the course of pathological process. However, despite its important role in ensuring the resistance of the organism to infections and sanogenesis, the value of IL1/TOLL-signaling pathway in bacterial infection, including post-clinical phase, was studied insufficiently. Also not fully characterized the impact of low-intensity radiation close in frequency to those used in radio standards GSM, on the content of immunocompetent cells, particularly peripheral blood mononuclear cells (MNCs) of the components of signaling pathways and nuclear transcription factor NF-KB.The purpose of the study was to evaluate the influence of microwave radiation with a frequency of 1 GHz into the contents in the MNCs of healthy individuals and of patients with community-acquired pneumonia, components of the IL-1/TOLL-signaling pathways and nuclear transcription factor NF-KB.ELISA evaluated the contents in the MNC component of the nuclear transcription factor NF-KB, P38 protein kinases, TAK1, TRIM25 proteins, GADD45A and Bcl-xl, as well as the production of IL-4, IL-12, RANTES, cathelicidin and MMP-12 after exposure to low-intensity electromagnetic radiation with a frequency of 1 GHz on whole blood. Proved that subclinical phase in patients with community-acquired bacterial pneumonia (cap) reduces the content in the OLS components of NF-KB, in particular, P50, P65, p52, RelB, IKKα, IKKβ, and the level of IκВα phosphorylation. On the contrary, the level of C-Rel and IKKγ in the MNC of patients with VP greater than healthy individuals. These changes are accompanied by reduced production of cytokines IL-4, IL-12, RANTES and cathelicidin. The study found that low-intensity radiation of 1 GHz stimulates the increase in the MNC content of P65, IKKa, TAK1, TRIM25, and also contributes to the increased production of IL-4, IL-12 and LL37. In addition, microwaves have a stimulating effect on phosphorylation of the terminal kinase MARK/SAPK-signaling pathway - P38, which is most pronounced at the convalescent EP. Thus, in the post-clinical stage of community-acquired pneumonia is the inhibition of the functional activity of the IL1/TOLL-signaling pathways and nuclear transcription factor NF-KB, which is manifested by reduced production of MNCs cytokines that regulate the adaptive immune response (IL-4, IL-12). Effect on the cells of whole blood by microwaves with frequency of 1GHz is associated with activation of NF-KB, contributing to the increased production of IL-4, IL-12 and cathelicidin with the increase in MNK proteins GADD45A and TRIM25, which ensures the normalization of nonspecific resistance and immunological reactivity in patients with pneumonia.
Genes & Cells. 2017;12(2):90-96
pages 90-96 views

Capacity of bone marrow granylocyte and macrophage precursors in mice of different strains for in vitro colony formation under changed thymuline level in the organism and cell cultures

Labunets I.F., Rodnichenko A.E., Vasyliev R.G.


Thymiline/thymic serum factor is a highly active thymic hormone, which increases the ability of progenitors and mature T-lymphocytes to produce factors that affect hematopoiesis. The present experiments were undertaken to investigate the linear differences in the number and type of bone marrow colonies formed by the granulocyte and macrophage precursors under changed thymuline level in the organism and cell cultures. Young CBA/Ca (genotype H-2k) and FVB/N (genotype H-2q) male mice were the object of our research. In the intact, sham-operated and thymectomized mice, blood thymuline level, number of СD4+-, СD8+-Т-lymphocytes and progenitor cells for granulocyte-macrophage colonies were measured in the bone marrow. Also, changes of percent ratios of granulocytic, mixed and macrophagal blood-forming colonies under influence of thymuline in vitro and phagocytic activities of macrophages in the spleen were registered. The number of progenitor cells for granulocyte-macrophage colonies was found to be higher (p<0.05) in sham-operated versus intact mice of both strains. Thymectomy led to further increase of their number in СВА/Са mice and decrease in FVB/N mice. After thymectomy, СD4+-Т cells number decreased in СВА/Са mice whereas СD8+ Т cells in FVB/N mice. Blood thymuline level decreased after sham operation (p<0.05) only in СВА/Са mice. The activity of macrophages decreased essentially after thymectomy in СВА/Са mice and after sham operation in FVB/N mice. In sham-operated СВА/ Са mice, the ratio of blood-forming colonies was changed: the number of macrophagal colonies increased 5.8-fold compared to intact mice. This effect leveled in thymectomized mice. We observed a dose-dependent decrease in the number of macrophagal colonies under thymuline effect in vitro. In FVB/N mice the number of macrophagal colonies decreased significantly after thymectomy. However it increased under thymuline influence in vitro. Thus, the linear differences in capacity of bone marrow blood-forming cells to form colonies and be differentiated under conditions of changed functioning of the thymus can be largely linked with the specifics of its intra- and inter-systemic relationships.
Genes & Cells. 2017;12(2):97-103
pages 97-103 views

Ultrastructural features of intercellular contacts in pancreatic insulinomas

Gordienko E.N., Chekmareva I.A., Paklina O.V., Kriger A.G., Kaldarov A.R., Laricheva I.V.


Insulinomas are the most frequent functional pancreatic neuroendocrine tumors. To study the ultrastructural structure intercellular contacts of insulinomas G1-2. Material about tumors of 38 patients who had been in the surgical treatment from 2010 to 2015 was studied. Male to female ratio was 38:62 (10/28). The age range differed from 23 to 71 y.o. The average age was 48.2 years. All the patients had the symptoms of hyperinsulinism determined. In 39% (1 5/38) the MEN syndrome was revealed. All the tumors were clinically benign. The electron and histological study of the removed tumors was conducted. In 39,5% (15/38) the tumor was localized in the head, in 24% - in the tail, in 21% - in the body, and in 5% - in the isthmus. In two cases the lesion affected the body and the tail of the gland (5%), and in another two - it affected the whole gland (5%). Tumor nodule size ranged from 0.8 to 5.5 cm. The average size was 2.0 cm. G1 was present in 84%. G2 was present in six cases. The tumors were composed of monomorphic cells with a low nucleus-cytoplasmic ratio and abundant eosinophilic cytoplasm. Two main ß-cell phenotypes in different stages of functional activity were detected. The first type of cells was “the light cells», which were dominated by the processes of synthesis of granules. The second type was “the dark cells», in which the processes of hormone secretion outside the cell membrane were actively running. The two cell types were connected by the desmosomal junctions. In the area of contact of adjacent cells' cytomembrane the portions of the cytoplasmic fusion with the formation of cytoplasmic bridges were determined. This resulted in the formation of syncytium-like structures. These changes were more common between “the light cells”. Through the cytoplasmic bridges the metabolic processes of nutrients and secretory material occure. Perhaps, it is a condition for the release of granules synchronization processes in the bloodstream, which may explain the cause of hypoglycemic crises. Syncytium-like structure due to the large size cannot penetrate through the fenestrated capillary, eliminating the possibility of the formation of the secondary tumors. Moreover, their production makes it impossible to complete the next cell division. Progression of the tumor stops. The formation of syncytium-like structures may be one of the causes of a conservation of a benign potential in insulinoma.
Genes & Cells. 2017;12(2):104-109
pages 104-109 views

Distraction osteogenesis on microvascular bone flaps: histological analysis

Melikov E.A., Drobyshev A.Y., Volkov V.A., Yakimenko I.I., Klipa I.A., Shamrin S.V., Miterev A.A., Snigerev S.A., Redko N.A., Bondarev A.N.


Despite the high osteoinductive potential of vascularized autograft, being used to close significant jaw defects, the processes of osteoresorpton during remodeling in the oral cavity also affect them. The possibilities of distraction osteogenesis allow to restore the necessary volume of bone's tissue at one stage with minimal traumaticity and predictable result, however it's use on vascularized autografts causes a lot of controversy regarding its effectiveness. There has been held a clinical-experimental study of 60 people with jaw defects with various etiologic factors, which were divided into 2 groups: 1 group with defects without previously made osseous plastic, 2 group with defects partially restored by microvascular autografts. Both groups of patients underwent the method of distraction osteogenesis as pre-implantation preparation. At the stage of dental implantation, histological biopsies were taken from the area of the obtained regenerate, to study and visualize the processes during distraction osteogenesis of micro-vascular autografts. There have been received convincing results about the consistency of the distraction regenerate of both groups and have been revealed the high regenerative potential of microvascular autografts.
Genes & Cells. 2017;12(2):110-115
pages 110-115 views

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