Vol 13, No 4 (2018)

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Directed myogenic reprogramming of differentiated cells

Indeikin F.A., Mavlikeev M.O., Deev R.V.


A morphological manifestation of myopathies is progressive lesion of muscular tissue with it substitution by connective tissue which makes it necessary to compensate cell loss. To date, methods which can replenish a cell pool in an affected muscle are absent. A method which potentially can correct manifestations of such diseases is a direct cell reprogramming. The undoubted advantage of this approach is an absence of necessity of returning cell in a pluripotent stage which allows to use it in vivo. The great experience in myogenic conversion was accumulated since discovering this method in 1987 by R.L. Davis and H.M. Weintraub. This review is aimed to describe the fundamental bases of direct cell reprogramming, it's positioning in the system of cell fate routes, analysis of achievements in direct cell reprogramming field and discussion about unsolved issues.
Genes & Cells. 2018;13(4):9-16
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The role of skeletal muscle tissue extracellular matrix components in myogenesis

Stupnikova T.V., Eremin I.I., Zorin V.L., Kopnin P.B., Gilmutdinova I.R., Saburina I.N., Pulin A.A.


This review summarizes data on the structure and composition of the extracellular matrix of skeletal muscle tissue. The functions of its main components and their influence on the differentiation of cells in the myogenic direction are considered.
Genes & Cells. 2018;13(4):17-23
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Evaluation of the effect of tissue-engineered constructs based on octacalcium phosphate and gingival stromal cells on dental implants osteointegration

Bozo I.Y., Deev R.V., Volkov A.V., Eremin I.I., Korsakov I.N., Yasinovsky M.I., Ustinov K.D., Trofimov V.O., Ruzin I., Presnyakov E.V., Komlev V.S., Pulin A.A.


Current treatment of patients with partial and complete teeth loss is based on the use of dental implants. As a result of continuous improvement of the medical devices and methods of implantological treatment and according to modern protocols dental implants could be placed immediately after teeth removal, which in most cases required single-stage bone grafting. The aim of this study was to evaluate the features of dental implants osseointegration under simultaneous bone grafting with tissue-engineered construction based on octacalcium phosphate (OCP) and autogenous gingival multipotent mesenchymal stromal cells (MMSC) in rabbits. In the tibial tuberosity of each limb, we performed a complex defect consisting of two adjacent cylindrical defects with diameters of 2.8 and 4 mm, correspondingly, and a depth of 8 mm, the circumferences of which intersected at the level of 5-7 hours of the conditional dial of the upper defect. Dental implants of 3x8 mm were placed in the upper defect, the lower defect was filled with "OCP+MMSC” in direct contact with the exposed surface of the dental implant. We used OCP without cells, autogenous bone tissue, blood clot as controls. Results were assessed 1, 2, 3 months after surgery using CT and histological analysis. Osteointegration was observed in both groups with OCP, while in the case of "OCP+ MMSC” a larger volume of newly formed bone tissue was formed. Autogenous bone fragments showed results similar to a defect filled with a blood clot. Thus, the preclinical evidence makes possible to use tissue-engineering constructs "OCP+MMSC” for single-stage with dental implants placement bone grafting.
Genes & Cells. 2018;13(4):24-30
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Safety and effectiveness evaluation of the injection transplantation method of human pacemaker cardiomyocyte derived from induced pluripotent stem cells

Ponomarenko A.V., Chepeleva E.V., Pavlova S.V., Romanov A.B., Strelnikov A.G., Sergeevichev D.S., Pokushalov E.A.


Arrhythmia is a pathological condition leading to a violation of the frequency, rhythm and sequence of the heart contraction. The cell therapy methods open a new possibility for this group of diseases treatment. This work was aimed to evaluate effectiveness and safeness of cardiomyocytes transplantation in the heart of laboratory animals. In the experiment, two groups of animals were examined: in the first group injection of cardiomyocytes contained in Matrigel was made into the wall of the left ventricle, saline injection was performed in the second group. To reduce the rejection reaction after xenogeneic cell culture transplantation prior to surgery and during the whole observation period, the animals were immunosuppressed by cyclosporin A and prednisolone combination. Electrocardiogram was recorded daily during the postoperative follow-up period to catch the ectopic events. After 5 days from cells transplantation animals were euthanized, the myocardium with transplanted material was taken for histological and immunohistochemical analysis. In the course of the work, it was shown that transplanted cardiomyocytes persist in the heart of experimental animals up to 5 days, but no electrophysiological activity was found. The obtained data indicate the need for additional experimental work with increased immunosuppression, increased time of the cells in the myocardium, an increase in the percentage of pacemaker cells in the used culture.
Genes & Cells. 2018;13(4):31-36
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Regulation of hepatocyte proliferation after subtotal liver resection in rats

Elchaninov A.V., Makarov A.V., Vorobieva I.G., Kananykhina E.Y., Lokhonina A.V., Bolshakova G.B., Glinkina V.V., Goldshtein D.V., Fatkhudinov T.K.


Hepatocyte proliferation is the main cellular mechanism of liver regeneration. However, after removal of more than 80 % of the liver mass, a temporary block of hepatocyte proliferation is observed, which may be the cause of impaired regeneration during transplantation and liver resection in the clinical practice. The current study aims to analyze the molecular mechanisms of hepatocyte proliferation impairment after subtotal liver resection in rats. In male Wistar rats, a model of liver regeneration after subtotal resection is reproduced - removal of more than 80 % of liver mass. Using the methods of immunohistochemistry, PCR-RT, western blot, possible molecular mechanisms of slowing down the proliferation of hepatocytes were studied. It was found that expression of cyclin D1 and E increased only 30 hours after surgery. Their appearance coincides with the beginning of transcription of genes for Cyclins D1 and E1 at 30 h after surgery. The corresponding increase in concentrations of cyclin D, and E proteins is further delayed till 48 h after surgery. These results indicate that, in this particular model, hepatocytes are reluctant to undergo transition between G0- and G1 -phases of cell cycle. We have observed a prolonged decrease in the expression of protooncogene C-met (the hepatocyte growth factor receptor-encoding gene Met). We have also observed an increase in expression of the transforming growth factor beta-1 receptor-encoding gene TgfbrII. At the same time, irreversible block of hepatocyte proliferation was prevented by expression of certain factors, notably of the TWEAK/ Fn14 signaling pathway: concentrations of the corresponding proteins in remnant livers have peaked from 24 h to 48 h after surgery. Thus, after subtotal liver resection, the remaining hepatocytes are exposed to a large scope of both mitogenic and antimitogenic factors. Proliferative behavior of hepatocytes in remnant livers is determined by fine balance of these factors. The prevalence of antimitogenic factors in the early period after surgery delays the onset of hepatocyte proliferation.
Genes & Cells. 2018;13(4):37-42
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Model of optical biopacemaker based on integration of photosensitive cardiomyocytes into cardiac culture

Balashov V.A., Nizamieva A.A., Tsvelaya V.A., Agladze K.I.


The methods of cardiac conduction system recovery with the use of reprogrammed cells and biomaterials, which could provide a stable physiological heart rate throughout the lifetime, are currently studied for possible applications in the heart rhythm disorder treatment. The main issue of intramyocardial transplantation is the transplanted cells' survival and electrophysiological connections formation with the recipient cardiomyocytes. In this paper, in search for working approaches for creating an optical biological pacemaker, we studied the effectiveness of various methods of photosensitive cardiac ChR2-HL-1 line cells integration into neonatal rat cardiac monolayers. For the study, two approaches of co-cultivation were selected: isolated cells and clusters integration of the Ch2-HL-1 line in various concentrations into monolayers. The effectiveness of the obtained model pacemaker was evaluated by the following means: registration of excitation waves initiated by optical stimulation, which affected only cells of the Ch2-HL-1 line, was carried out by optical mapping; immunocytochemical analysis methods were used to characterize the morphology of the obtained co-cultures and to assess the degree of the integration of the embedded structures into the monolayer. In the course of the research it was shown that the most effective method of integration of cells in the primary culture is the cluster method: 100 % of samples with clusters, integrated after 6 hours of monolayer cultivation, showed stable generation of excitation waves at physiologically significant external stimulation frequencies, compared with 88 % for specimens with integrated isolated cells at frequencies lower than physiological. Moreover, the samples with the cluster integration method turned out to be much more resistant (100 % in the cluster method and 25 % in the infusion of isolated cells] to sodium channel inhibitor, lidocaine. The efficiency of integration depends on the conditions of cell growth, which is discussed in more detail in the results of the study. The obtained results are applicable in the development of a biological pacemaker.
Genes & Cells. 2018;13(4):43-50
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Survival and functional activity examination of cardiomyocytes differentiated from human iPSCs, when transplanting in SCID mice

Pavlova S.V., Chepeleva E.V., Dementyeva E.V., Grigor'eva E.V., Sorokoumov E.D., Slotvitsky M.M., Ponomarenko A.V., Dokuchaeva A.A., Malakhova A.A., Sergeevichev D.S., Pokushalov E.A., Zakian S.M.


Conduction and heart rhythm disorders can be caused by both functional pathology and severe organic lesions of the heart. The possibility of using cell-based replacement cell therapy derived from induced pluripotent stem cells to compensate for lost myocardial tissue or the conduction system is currently being studied. The aim of the work is to study the survival and functional activity of cardiomyocytes differentiated from induced human pluripotent stem cells in intramyocardial and subcutaneous abdominal transplantation in a clots of proteins of the basement membrane matrix Matrigel to the SCID mice. After 2 and 5 weeks after intramyocardial and 2, 7, 14, 21 and 28 days after subcutaneous transplantation, the survival and activity of cardiomyocytes were studied by cytological methods. Human cardiomyocytes were detected in mice for at least 35 days. after transplantation and did not cause ectopic electrical activity of the myocardium. When assessing the functional activity of cardiomyocytes in subcutaneous matrigel plugs using the method of optical mapping of calcium ion currents for 2-28 days. after injection, it was shown that only a small fraction of cardiomyocytes after transplantation was able to spontaneously oscillate the calcium ions. We assume that contractile cardiomyocytes obtained from induced pluripotent human cells lose their ability to spontaneous excitation during in vivo transplantation, and we observe only the activity of pacemaker cardiomyocytes in optical mapping.
Genes & Cells. 2018;13(4):51-60
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Unilateral condylar hyperactivity: histogenetic and patomorphological aspects

Sviridov E.G., Redko N.A., Izotov O.I., Anisimova S.A., Deev R.V., Drobyshev A.Y.


Maxillofacial deformations and malocclusions are common pathology that leads to severe functional and aesthetic disturbance. Etiological factors are trauma, genetic disorders, and hormonal imbalance. One of the rare and underexplored forms of congenital growth disorders are hemimandibular growth abnormalities as unilateral condylar hyperactivity, hemifacial elongation, condylar hypoplasia. Unilateral condylar hyperactivity (UCH) is a self-limiting pathology of mandibular condylar bone tissue overgrowth, leading to functional and aesthetic maxillofacial disturbance. The aim of the study was to identify the pathological features of hemimandibular growth abnormalities. We performed diagnostics and treatment of 35 patients (7 male, 28 female) aged from 16 to 37 years with condylar hyper- and hypoplasia. In case of unilateral condylar hyperplasia symptoms we performed high partial condyleectomy as the first step of treatment. In all the patients temporo-mandibular joint function was restored and facial aesthetic was improved as a result of treatment. According to histological features we found the materials from all patients to be divided into two groups: without pronounced continued growth and with signs of enchondral osteohistogenesis. Histological features of the pathological process were detailed in each group.
Genes & Cells. 2018;13(4):61-68
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Personalized cell-based therapy in ophthalmology. III. Clinical efficacy in the treatment of corneal endothelial diseases

Avetisov S.E., Kasparova E.A., Kasparov A.A., Subbot A.M., Antohin A.I., Pavliuk A.S., Fadeeva L.L., Feofanov S.A.


Severe lesions of corneal endothelium usually lead to progressing corneal oedema, sharp decrease in visual acuity and as a result to the need for transplanting donor cornea that can provoke relevant sequelae, thus an active search for alternative impacts to the affected cell layer is underway allowing for keeping out of operative intervention. The purpose of this research is to evaluate the clinical efficacy of a method of personalized cell therapy (aqueous chamber administration of suspension consists of activated autologous leukocytes in serum) aimed to treatment of early postoperative bullous keratopathy and severe form of herpetic keratoiridocyclitis. The results of clinical application of personalized cell therapy in 210 patients with postoperative bullous keratopathy (60) and herpetic keratoiridocyclitis (150) - divided into 2 subgroups: 75 patients received personalized cell therapy (experimental subgroup), the other 75 patients were injected intracamerally with a solution of poludan preparation (control subgroup), are presented in the article. The pronounced therapeutic effect in the treatment of early postoperative bullous keratopathy was achieved in 44 % of cases, with an increase in visual acuity of 0,49±0,27. Straightening of the descemet membrane's folds, significant dehydration of corneal stroma and complete restoration of corneal transparency, a reduction in the thickness of the cornea from 801±112 pm to 582±55 pm have been achieved. In the group of herpetic keratoiridocyclitis treatment, recovery was achieved in 85 % - complete resorption of corneal infiltration and edema and restoration of corneal transparency. The increase in visual acuity in this group was 0,6±0,3. The normalization of the corneal structure after personalized cell-based therapy is also evidenced by in vivo confocal microscopy data. The correlation of the clinical effect with the concentration in the cellular preparation of TNF-α, IL-6 and IL-1 was established. Personalized cell therapy is effective method of curative action on damaged corneal endothelium that does not require keratoplasty.
Genes & Cells. 2018;13(4):69-74
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Long QT syndrome: genetic analysis of patients

Dementyeva E.V., Medvedev S.P., Elisaphenko E.A., Bayramova S.A., Pokushalov E.A., Agladze K.I., Zakian S.M.


Genetic analysis plays an important role in diagnostics of cardiovascular diseases. One of the diseases is long QT syndrome that results in an increased risk of ventricular tachycardia and sudden cardiac death. The syndrome may be caused by mutations in genes responsible for cardiomyocyte ionic channel functioning. The aim of this study is to examine genetics of long QT syndrome. Genetic analysis of 16 patients with long QT syndrome or suspicion of the syndrome was carried out. Long QT syndrome causing mutations, p.Ala178Pro, p.Val254Met, p.Gly325Arg in KCNQ1 and p.Thr613Met in KCNH2, and a long QT syndrome-associated polymorphism, p.Asp85Asn in KCNE1, were found in five patients. Family analysis of p.Ala178Pro and p.Val254Met mutations in KCNQ1 revealed the mutations carriers that had not demonstrated any syndrome manifestations before. In addition, a mutation, p.Gly604Ala in KCNH2, was found. The mutation has not been previously described and its role in long QT syndrome needs to be clarified.
Genes & Cells. 2018;13(4):75-80
pages 75-80 views

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