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Vol 13, No 3 (2018)

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Morphologists of institute of experimental medicine and poets of Silver century

Dyban P.A.


The article highlights some aspects of the life of the morphologists of the Institute of Experimental Medicine, not related to their professional activities. Such different in their biography, career growth, the scientific contribution of morphologists (academicians N.G. Khlopin and V.G. Garshin, professor V.P. Mikhailov, D. Med. Sci. I.D. Starynkevich, Ph.D. M.G. Khizhnyak) united the general hobbies associated with art, and the brightness and uncommonness of their personalities and determined acquaintance with the poets of the Silver Age. Morphologists IEM contributed not only a significant contribution to the development of Russian histology, but their names were forever left in the biographies of the poets of the Silver Age.
Genes & Cells. 2018;13(3):9-13
pages 9-13 views

Esophageal organoids: possibility of creating and potential implications for tissue engineering

Gilazieva Z.E., Arkhipova S.S., Zhuravleva M.N.


Esophageal cancer, congenital anomalies, traumatic injuries and prolonged deformities of the esophagus often require radical surgical treatment followed by multi-stage organ reconstruction. Such operations are traumatic for the patient, and the use of the donor esophagus is associated with the need for prolonged immunosuppression. To replace a damaged tissue of the esophagus tissue-engineering structures can be applied. These tissue-engineering structures are based on the use of the association of differentiated or stem cells and natural or synthetic scaffolds, to create an artificial organ in vitro that can mimic an organ. Such formulations can be successfully used to study the development of organs, pathogenesis of diseases and preclinical studies of drugs as so-called "organoids”, and may also have a prospect for clinical use as tissue-engineered prototypes of the esophagus. This review describes the possibilities of using esophageal organoids, systematizes the literature data on studies on the creation of organoids and tissue-engineered prototypes and their effect on the experimental model in transplantation.
Genes & Cells. 2018;13(3):14-22
pages 14-22 views

Modern pathogenesis-based methods and development of new gene and cell-based methods for cystic fibrosis treatment

Smirnikhina S.A., Lavrov A.V.


Cystic fibrosis is a monogenic autosomal recessive disorder caused by mutations in CFTR gene. Until recent days, cystic fibrosis therapy was limited to symptomatic treatment of respiratory infections and malabsorption. In last years pathogenetic therapy of the disease received significant progress and premises for development of new methods of gene therapy came into sight. In the review, modern methods of cystic fibrosis treatment are considered, some of them are already used in the clinic (pathogenesis-based therapy with CFTR modulators), while the other part is only developing (gene therapy, including genome editing and cell therapy).
Genes & Cells. 2018;13(3):23-31
pages 23-31 views

Human mitochondrial genome surgery

Mazunin I.O.


Pathogenic mitochondrial DNA (mtDNA) mutations are often in a state of heteroplasmy. The increasing mtDNA mutation load with age generally related to aggravation of symptoms and is also a one of the main sign of organism aging. Heteroplasmy shifting which can alleviate mitochondrial functionality is most perspective approach to fight mitochondrial diseases. Molecular machines to shift heteroplasmy level recognize mutant mtDNA and cut them. In general the molecular machines could be divided into two groups: mitochondria-targeted protein-only nucleases such as mitoREs, mitoZFNs, mitoTALENs, and RNA-protein systems such as mitoRGENs. The latest seem to be more flexible and offer perspective due to their reliance on Watson-Crick interactions for specific mtDNA site recognition. We discuss also some application area for the mitoRGEN systems.
Genes & Cells. 2018;13(3):32-37
pages 32-37 views

Introduction to 3D-bioprinting: the history, principles and stages

Khesuani Y.D., Sergeeva N.S., Mironov V.A., Mustafin A.G., Kaprin A.D.


3D bioprinting of tissue and organ constructs is one of the most rapidly growing directions in biotechnology and regenerative medicine. Stages of 3D bioprinting process, "classic” bioprinting technologies (ink-jet, extrusion and laser-based) and novel (acoustic, magnetic and in situ) bioprinting technologies are described in the review. Data for hydrogel and cell material (single cells and tissue spheroids) usage in 3D bioprinting was systemized.
Genes & Cells. 2018;13(3):38-45
pages 38-45 views

A biointegration of microand nanocrystalline hydroxyapatite: problems and perspectives

Pankratov A.S., Fadeeva I.S., Minaychev V.V., Kirsanova P.O., Senotov A.S., Yurasova Y.B., Akatov V.S.


Сalcium phosphate materials have been applied in clinical medicine since 1920. Among calcium phosphate materials, hydroxyapatite (HAp) is traditionally of the greatest interest, because HAp is the main inorganic component of bone tissues. However, synthetic HAр ceramics subjected to high-temperature processing, as it turned out, have a rather limited use as an osteoplastic material. Since 1990, due to advances in chemical technology, new materials of pasty nanocrystalline HAр have been developed, which are promising for the directed influence on the process of bone tissue regeneration. This review briefly summarizes the experimental and clinical data related to the application of micro- and nano-sized hydroxyapatite, and evaluated the potential of pasty nanocrystalline HAp as a material for guided bone regeneration.
Genes & Cells. 2018;13(3):46-51
pages 46-51 views

The key stages of iPSCs differentiation into neuronal and glial cells

Salikhova D.I., Fedyunina I., Bukharova T.B., Goldshtein D.V., Kiselev S.L.


Brain's neurodegenerative diseases are one of the most actual problems of neurology and neurobiology. The lack of the modern methods of treating this diseases stimulates to develop new effective approaches based on neuronal and glial cells, which requires studying the signaling mechanisms of neural differentiation. This review considers the key mechanisms and substances involved in the formation of the neuroepithelium in vivo, as well as for obtaining the neural stem cells from iPSCs and its further differentiation in various types of neuronal and glial cells in vitro.
Genes & Cells. 2018;13(3):52-55
pages 52-55 views

The change in the quantity of macrophages and their stabilin-1 + M2 subpopulation in the myocardium in patients during early postinfarction period

Rebenkova M.S., Gombozhapova A.E., Rogovskaya Y.V., Ryabov V.V., Churina E.G., Kzhyshkowska J.G.


Investigation of the role of macrophages and their functional plasticity in reparative process accompanying myocardial infarction (MI) and postinfarction cardiac remodeling is the relevant issue of current medical science. The purpose of the study: to investigate CD68+ and stabilin-1 +-macrophage infiltration and its dynamics in patients with MI in comparison with intact myocardium. The study included patients with fatal MI type 1 (n=41). All patients were divided into 4 groups depending on the onset of death (group 1, n=13, patients who died during the first 24 hours of MI; group 2, n=11, patients who died within 24-72 hours of MI; group 3, n=9, patients who died on days 4-10; and group 4, n=8, patients who died 11-28 days after MI). The control group included patients (n=9) who died due to fatal trauma and who did not suffer from cardiovascular pathology. For evaluation of functional immunopheno-type of macrophages we used immunohistochemistry. We counted cells expressing on their surface a common macrophages marker - CD68 and specific marker of regulatory M2 macrophages that demonstrates an anti-inflammatory activity - stabilin-1 in the infarct area, peri-infarct area, and non-infarct area. In comparison with the intact myocardium (control group) the number of CD68+-macrophages in the infarct area, periinfarct area, and non-infarct area increased from the first day of disease and peaked on day 4-10. The quantity of stabilin-1 + macrophages in all zones investigated during the acute phase of MI was lower than in the intact myocardium and increased on day 4-10 in the infarct area. Furthermore, in the non-infarct zone the quantity of stabilin-1 +-macrophages was lower than its quantity in the control group both during the acute phase and the regenerative phase of MI. The data obtained indicate the participation of stabilin-1 + macrophages in process of postinfarction myocardial healing and the development of the inflammatory immune response in the myocardium during the acute phase of MI and its maintaining at late stages of the disease.
Genes & Cells. 2018;13(3):56-62
pages 56-62 views

A study of physical and biological properties of 3D matrices made from polytrimethylene carbonate and its copolymers

Chernonosova V.S., Gostev A., Kharkova M.V., Pokushalov E., Karpenko A.A., Karaskov A.M., Laktionov P.P.


The development of new materials for using in different parts of medicine (for replacement of affected vessels, cartilage, connective, glandular tissue) has recently become widespread, due to the high rate of occurrence of these pathologies and the need for surgical treatment of these pathologies. One of the promising approaches is the production of tissue engineered matrices from various polymers and their mixtures by the electrospinning. Block polymers (for example, trimethylene carbonate) are of particular interest for fabrication of tissue engineered devices due to the ability to customize the polymer stability by using different sets of blocks. 3D matrices were prepared from solutions of polytrimethylene carbonate (PTMC) and its copolymers with polycaprolactone and lactic acid in various solvents (dichloromethane with dimethylformamide, pure dichloromethane or hexafluoroisopropanol) by electrospinning. Scaffolds were prepared from mixtures of polymers with gelatin. The structure of the matrices was characterized by the scanning electron microscopy method. Hydrophilicity and mechanical strength of the matrices were investigated. The ability of primary human umbilical vein endothelial cells (HUVEC) to attach and proliferate on the surfaces of different matrices was studied. The tensile strength of the matrices, produced from dichloromethane solutions was not more than 0.22 MPa, and the strength of the scaffolds produced from hexafluoroisopropanol solutions reached 4.3 MPa. HUVEC successfully attached to the matrices, but proliferation rate was slow. During storage the matrices produced from the PTMC and its copolymers had a tendency to absorb water vapor, and exhibited shrinkage, fusion of the fibers and strength loss. 3D matrices produced from PTMC cannot be recommended for the manufacture of implantable devices but can tentatively serve as biodegradable scaffolds in tissue engineering without constant hydrodynamic loading, such as areas of connective or glandular tissue.
Genes & Cells. 2018;13(3):63-69
pages 63-69 views

Clinical and pathological features DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and wT1 genes mutations detection in acute myeloid leukemia patients aged 15-45 years old

Vinogradov A.V., Rezaykin A.V., Sazonov S.V., Sergeev A.G.


The frequency of acute myeloid leukemia (AML) increases with age, respectively, the range of identified gene mutations and the pathways involved carcinogenesis can vary and affect the prognosis of treatment. The aim of the study was to estimate the frequency of mutations in DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and WT1 genes in acute myeloid leukemia (AML) patients (pts) aged 15-45 years old using direct automatic sequencing technique. Bone marrow and peripheral blood samples obtained from 36 AML pts aged 15 to 45. Distribution of the pts according to FAB-classification was as follows: AML M0 - 2, M1 - 1, M2 - 15, М3 - 2, M4 - 11, M4eo - 2, M5 - 2, blastic plasmacytoid dendritic cell neoplasm-1. Detection of mutations in ASXL1, DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and WT1 genes performed by automatic direct sequencing technique. The average frequency of functionally significant mutations in all investigated genes among the treated AML pts was 41,7 % (n=15), including 6 cases (40,0 %) with unfavorable cytogenetics, 6 cases (54,5 %) with normal karyotype, 3 cases (37,5 %) with favorable cytogenetics. These data correspond to the average frequency of point mutation in AML with normal and abnormal karyotype. Average frequency of mutations in FLT3 gene exons 12-15 and 19-21 - 21,9 %, NRAS gene exons 1-4 - 13,0 %, WT1 gene exons 6-9 - 11,1%, NPM1 gene exons 9-12 was 10,7 %, KIT gene exons 7-12 and 16-19 - 10,0 %, DNMT3A exons 18-26 - 7,1 %, TP53 gene exons 4-11 - 0,0 %. Multiple point mutations in investigated genes detected in 13.9 % AML specimens (usually KIT gene non-synonymous substitution c. 1621 А>С). Cryptic gene mutations detection using direct sequencing technique allowed to clarify the prognostic stratification of AML from groups of favorable and intermediate prognosis in 36,8 % (n=7). Thus, using of cytogenetic and additional molecular genetic research, a favorable prognosis of overall survival was established in 6 cases (16,7 %), intermediate - in 10 cases (27,8 %), adverse - in 18 cases (50,0 %), and unspecified - in 2 (5,6 %).
Genes & Cells. 2018;13(3):70-74
pages 70-74 views

A combination of small molecular inhibitors YAC increases expression levels of DMRT1 in the culture of sertoli cells from the transitional zone of mouse testis

Kulibin A.Y., Malolina E.A.


There is a cell population capable of active proliferation in culture in the compartment of adult mouse testis consisting of transitional zone of seminiferous tubules and rete testis. These cells were termed Sertoli cells of the transitional zone because they express many specific Sertoli cell genes in culture. A feature of these cells is a low level of Dmrt1 expression, a transcription factor important for Sertoli cell differentiation and male sex determination. In the current research, the culture conditions have been optimized to increase Dmrt1 expression in Sertoli cells of the transitional zone and then functional properties of these cells have been tested. It was shown that a combination of small molecular inhibitors YAC (Y-27632, A-83-01 and CHIR99021) substantially increases the number of Sertoli cells of the transitional zone expressing Dmrt1. It was demonstrated that Sertoli cells of the transitional zone maintained in medium with YAC remain the high level of Dmrt1 expression even after their transfer to 3D culture where they form seminiferous tubule-like structures with neonatal testicular cells. According to immunofluorescence and real-time PCR data Sertoli cells treated with YAC supported germ cell differentiation to the zygotene stage of meiotic prophase I in 3D culture. These results suggest that Sertoli cells of the transitional zone maintained in medium with YAC closely resemble Sertoli cells from seminiferous tubules and can function as Sertoli cells in 3D culture.
Genes & Cells. 2018;13(3):75-81
pages 75-81 views

Angiogenic properties of myocardial c-kit+ cells

Dergilev K.V., Tsokolaeva Z.I., Beloglazova I.B., Ratner E.I., Molokotina Y.D., Parfenova E.V.


Now, great interest is connected with application of the cells received directly from a myocardium as the tool for stimulation of angiogenesis and reparative processes in heart. The aim of the present research is studying of angiogenic properties in vitro and in vivo of c-kit+-cells, obtained from hearts of small rodents. The work was performed on male C57BL/6 mice and male Wistar rats. The study used methods of cytofluorimetry, immuno-fluorescent staining, models of myocardial infarction and subcutaneous angiogenesis in Matrigel™. It was shown, that after acute myocardial infarction c-kit+ cells activated, part of which entered into endothelial differentiation and integrated into de novo formed vessels. C-kit+-expressed the markers of vascular progenitor cells, exhibited endothelial-like behavior in vitro, and after subcutaneous transplantation increased vascularization of Matrigel™. This is achieved both due to the paracrine effects, which stimulate the growth of the recipient's mouse vessels into the Matrigel implant, and partially due to the differentiation of the transplanted cells into the vascular endothelium cells, which was confirmed by vital dye staining. Thus, c-kit+-cells derived from the myocardium can be considered as a promising type of resident cells exhibiting the properties of progenitor cells of the heart vessels for developing approaches to stimulate vascularization of the ischemic myocardium.
Genes & Cells. 2018;13(3):82-88
pages 82-88 views

Analysis of in vitro cytotoxicity of human NK cell line co-expressing a PSMA-specific CAR and an antitumor agent lactaptin

Belovezhets T.N., Matvienko D., Volkova O.Y., Koval O.A., Tkachenko A.V., Kuligina E.V., Taranin A.V., Richter V.


Development of efficient antitumor modalities remains a priority of modern translation medicine. Adoptive transfer of autologous T cells expressing chimeric antigen receptors (CARs) specific for tumor-associated surface targets of B cells has demonstrated encouraging results in recent clinical trials. It is tempting therefore to adapt this approach to solid cancers and move it to universal/allogeneic formats. For this reason, it appears very attractive to use human NK cell lines as CAR carriers. Using lentiviral delivery, human NK cell line YT was modified to express a PSMA-specific CAR and to produce an anticancer peptide lactaptin. "Armored” CAR-YT-Lact cell line obtained shows cytotoxicity against PSMA-positive prostate adenocarcinoma cells. Accordingly, YT-Lact cells display a moderate and non-specific activity against PSMA-negative target cells, which may translate into a tighter control of tumor cell escape via antigen loss.
Genes & Cells. 2018;13(3):89-93
pages 89-93 views

Opportunities of using gene therapy in patient with non-reconstructable critical limb ischemia in proximal reocclusion

Chervyakov Y.V., Ha H.N.


The aim of the study: to evaluate the effect of complex treatment on "no-option” patients with aortoiliac reocclusion using a plasmid-based with VEGF165 gene therapy in the 3-year follow-up study. Material and methods. In total, 3 patients with Leriche's syndrome in stage III, IV of chronic lower limb ischemia (according to the classification of Fontaine-Pokrovsky) were treated and observed in the 3-year follow-up study. All patients were men, the average age was 58 years. All patients underwent surgical reconstruction of the aortoiliac segment. In the period from 1 to 3 years after the initial intervention, there was a reocclusion of the aortoiliac segment. Based on the results of angiography, these patients were classified as non-reconstructable due to total occlusion of lower extremity arteries. All patients received standard conservative treatment in combination with gene therapy. Endpoints of the study: the survival rate, the limb salvage rate. Results: During 3-year follow-up two patients are alive, one dead due to unrelated with Leriche's syndrome reasons, the limb salvage rate was 100 %.
Genes & Cells. 2018;13(3):94-98
pages 94-98 views

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