Cell and Organ Transplantology

Nanocomplexes (NCs) synthesized at the Institute for Scintillation Materials of the National Academy of Sciences of Ukraine, consisting of nanoparticles (NPs) of gadolinium orthovanadate and cholesterol, are promising compounds that can be used as probes and fluorescent labels for tumor cells or experimental oncopathology treatment. However, the biosafety of such substances remains unclear. The purpose of the study was to evaluate the acute toxic effect of nanocomplexes on the healthy mice. Materials and methods. Nanocomplexes containing nanoparticles of GdYVO4:Eu3+ and cholesterol in 5 % glucose solution were administered to BALB/c mice once intraperitoneally in volumes of 0.1 mL, 0.5 mL, 1 mL, 2 mL, which corresponds to 5.9-6, 5 mg, 29.5-32.5 mg, 59.1-65.0 mg, 118.2-130.0 mg/kg body weight. Control animals were injected with the same volumes of 5 % glucose solution. On the 14th day, the morphological characteristics of organs, the number of CD34+CD38– cells among bone marrow total nucleated cells, the activity of gamma-glutamyl transferase (GGT) and glucose-6-phosphate dehydrogenase (G6PD) in liver homogenates were determined. Results. With the administration of NPs at a dose of less than 118.2 mg/kg body weight, no fatalities and symptoms of intoxication were showed, but there was a dose-dependent increase in the content of GGT in the liver of experimental animals. The use of NPs at a dose of 118.2-130.0 mg/kg body weight resulted in the death of 50 % of the animals on the 3rd day. In this group, on the 14th day, there were neoplasms in the spleen of one of the surviving animals, a decrease in the number of bone marrow total nucleated cell on the background of increased hematopoietic stem cells with CD34+CD38– phenotype, necrotic and dystrophic changes in the liver, and decreased activity of the G6PD enzyme. Conclusions. The potential median lethal dose of gadolinium orthovanadate nanoparticles and cholesterol in nanocomplexes was determined, which was 118.2-130.0 mg/kg animal body weight, which allows to classify them as low-toxic substances.

A. Goltsev

M. Bondarovych

N. Babenko

Yu. Gaevska

L. Ostankova

M. Ostankov

N. Volkova

V. Klochkov

The assessment of the toxicity of nanocomplexes containing gadolinium orthovanadate nanoparticles and cholesterol

钆钒酸铋纳米复合物与胆固醇的毒性评估

Demyelinating diseases, especially multiple sclerosis (MS) is not only medical but also socio-economic issue. Unsatisfactory quality of life and high degree of disability in these patients require the implementation of the advanced treatments, such as stem cell transplantation. Numerous experimental and clinical studies are being conducted, revealing new mechanisms of the action of stem cells in demyelinating diseases. Further research is needed to understand many more aspects of clinical use. This review is devoted to the use of regenerative cell technologies in the treatment of demyelinating diseases, the current state and prospects of the approach to the treatment of such pathology with stem cells.

T. Petriv

M. Tatarchuk

Yu. Tsymbaliuk

V. Tsymbaliuk

Transplantation of mesenchymal stem cells for the treatment of demyelinating diseases

间充质干细胞移植治疗脱髓鞘疾病

The pathogenesis of acute respiratory distress syndrome (ARDS) includes neutrophilic alveolitis, alteration of alveolar epithelium and endothelium, formation of hyaline membranes and microvascular thrombosis, which results in an acute hypoxemic respiratory failure. ARDS results in major structural and cellular changes in organs and organ systems. It causes liver dysfunction in critical patients through paracrine action of cytokines and other pro-inflammatory mediators as well as hypoxemia, oxidative stress, toxins and hypoperfusion. Coronavirus disease 2019 (COVID-19)-associated ARDS affects liver through the development of systemic inflammatory response syndrome and hypoxia as well as cytokine storm. Liver injury manifests itself as increased plasma levels of hepatic transaminases and cholestatic liver enzymes. Stem cell therapy is one of the promising modern methods for treating ARDS-induced liver failure. Many studies showed the ability of multipotent mesenchymal stem cells (MMSCs) to differentiate into functional hepatocyte-like cells, which were then successfully used for liver regeneration. MMSCs were proven to be able to prevent the apoptosis of hepatocytes, as well as have anti-fibrotic and anti-inflammatory activity which allows their successful use in the treatment of ARDS-induced liver injury.

O. Redko

A. Dovhalyuk

A. Dovbush

Z. Nebesna

L. Yakubyshyna

I. Krynytska

Liver injury associated with acute respiratory distress syndrome and the prospects of mesenchymal stem cells therapy for liver failure

急性呼吸窘迫综合征相关肝损伤及间充质干细胞治疗肝衰竭的前景

Traumatic brain injury (TBI) is accompanied by an increase in the number of proliferating cells. However, the question of the nature, conditions of production and mechanisms of action of humoral factors secreted by fetal neural cells (FNCs) on reparative processes and neurogenesis in the brain after trauma and FNCs transplantation remains open. The purpose of the study was to establish the possibility of the influence of the conditioned medium of fetal neural cell cultures on the proliferative activity of Ki-67-positive cells in the cortex and subcortical structures of the rat brain after TBI. Materials and methods. TBI was simulated by dropping a metal cylinder on the rat’s head. Rats (E17-18) were used to obtain cultures of neural stem/progenitor cells. Conditioned media from cell cultures with high adhesive properties (HA-CM) and low adhesive properties (LA-CM) were used to treat the effects of experimental TBI in rats by intramuscular injection. The effect of conditioned media on the proliferative activity of Ki-67-positive cells in the cortex and subcortical structures of the brain after TBI was determined by immunohistochemical analysis using antibodies against Ki-67 protein. Results. Immunohistochemical analysis of the brain sections showed that on the 5th day after traumatic brain injury in rats there was a probable increase in the number of Ki-67-positive cells in the cortex, hippocampus and thalamus. It was found that the injection of HA-CM or LA-CM in animals with TBI increased the number of Ki-67-positive cells in the hippocampus compared with the TBI group and their value for the TBI+LA-CM group reached 59.6 ± 6.1, and for the TBI+HA-CM group – 47.2 ± 3.1 cells (p &lt;0.05 compared with the TBI group). In the cortex and thalamus, the number of Ki-67-positive cells in contrast decreased compared with the group of animals with TBI and for the group TBI+LA-CM was 20.2 ± 1.6 and 12.0 ± 1.7, respectively, and for the group TBI+HA-CM – 25.3 ± 2.1 and 13.3 ± 1.3, respectively. Conclusions. The administration of LA-CM or HA-CM to animals with traumatic brain injury increases the number of Ki-67-positive cells in the hippocampus, possibly associated with increased neurogenesis, and decreases in the cortex and thalamus, which may be due to a weakening of reactive gliosis.

M. Lisyany

D. Stanetska

I. Govbakh

O. Tsupykov

The effects of fetal neural cell conditioned medium on cell proliferation in the rat brain after traumatic brain injury

胎儿神经细胞条件培养基对大鼠创伤性脑损伤后脑细胞增殖的影响

Dysfunctions of resident progenitor cells play a significant role in the pathogenesis of decreased myocardial contractility in heart failure, so the most promising approaches for the treatment of heart disease are cardiac-derived stem/progenitor cells (CSCs). Materials and methods. Protocols for progenitor cell cultures from different parts of the heart of newborn FVB/N mice have been developed and their proliferative potential has been characterized. Comparative analysis of the expression of CD31, CD34, CD44, CD45, CD73, CD90, CD105, CD117, CD309 and troponin I by cells from native myocardial biopsies and in the obtained cultures was performed by flow cytometric immunophenotyping. Results. The expression of mesenchymal markers CD44 and CD90 in the absence of the hematopoietic marker CD45 was demonstrated in early passages in mouse myocardial progenitor cell cultures. Relatively high expression of CD34 and CD31 was found. The presence of a minor population of CD44+117+ cells which correspond to the phenotype of cardiac progenitor cells, was detected. Expression of troponin I as one of the key markers of cardiomyocytes as well as the vascular endothelial growth factor receptor has been confirmed in terminally differentiated cultures of cells with contractile activity. Conclusions. It was found that newborn mice in the myocardial tissue contain more cells with the expression of markers of cardiac progenitors than in adult animals. The relative content of such cells is higher in the atria than in the ventricles. Cardiac progenitor cells in neonatal mice derived from the atrial appendages have better proliferative potential than cell cultures isolated from the ventricles.

V. Kyryk

A. Ustymenko

Isolation and phenotyping of cardiac-derived progenitor cells from neonatal mice

新生小鼠心脏来源前体细胞的分离与表型分析

Cardiovascular diseases are a leading cause of disability and mortality among the working population, necessitating the development and implementation of new, more effective treatment and rehabilitation methods for such patients, including the use of modern cellular and tissue technologies. In this review, an analysis and summary of research results over the past decades regarding the effectiveness of various types of stem cells in heart pathology were conducted. Priority directions include the search for more accessible and safe sources of stem cells, the development of new effective methods for their cultivation, and the use of scaffolds for transplantation. Given the pathogenetic mechanisms of cardiovascular pathology and myocardial regeneration, particular interest for clinical application is drawn to tissue-specific progenitors from the myocardium for replacing injured cardiomyocytes, endothelial progenitors for correcting accompanying endothelial dysfunction, and multipotent mesenchymal cells of various origins with low immunogenicity that exhibit trophic, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. Questions regarding the optimal method, dose, and frequency of stem cell administration, as well as the standardization of criteria for their quality and effectiveness, remain open. Additionally, the combined use of different types of stem cells may serve as a new priority strategy in assessing the effectiveness and safety of cell therapy, especially considering the paradigm of repeated transplantation. The successful translation of obtained preclinical results into further large, well-planned, placebo-controlled clinical trials will enhance the safety and effectiveness of cell therapy for cardiovascular diseases, which is one of the current challenges of modern regenerative medicine.

Vitalii Kyryk

Stem cell therapy for cardiac regeneration: key points

干细胞疗法在心脏再生中的关键点

Acute respiratory distress syndrome (ARDS) is a severe pathological condition often accompanied by kidney injury. It is known that mesenchymal stem cells (MSCs) have high potential for treating various diseases due to their ability to paracrinely stimulate the regeneration of damaged cells and tissues and restore impaired organ functions. Purpose: To investigate the nephroprotective effect of human umbilical cord MSCs in a model of ARDS induced in rats by intranasal administration of lipopolysaccharide (LPS). Materials and methods: Seventy-two sexually mature male Wistar rats were randomly divided into nine groups: intact animals, 3 days, 7 days, and 28 days of ARDS development, MSC control, and four treatment groups: 24 hours LPS + 2 days MSCs, 4 days LPS + 3 days MSCs, 14 days LPS + 14 days MSCs, 21 days LPS + 7 days MSCs. MSCs were administered intraperitoneally at a dose of 106 cells/kg body weight. Levels of structural kidney damage were assessed using histological analysis of sections stained with hematoxylin and eosin. The expression of the fibrosis marker TGF-β1 in kidney tissues was evaluated by immunohistochemistry technique. Creatinine, urea, and uric acid levels in blood serum were measured using a kinetic method. Results: The conducted studies revealed the presence of significant damage to the kidney parenchyma, signs of fibrosis, and impaired nephron function in rats with modeled ARDS. The severity of pathological changes increased with the duration of the experiment. The use of human umbilical MSCs as a treatment factor significantly reduced the severity of coagulopathy, tubular necrosis, and destruction of renal corpuscles, inhibited the development of interstitial fibrosis, and improved the levels of renal blood markers. The best nephroprotective effect of MSCs was observed on the 28th day of the experiment in the group 14 daysLPS + 14 daysMSCs. This is likely due to the earlier use and longer duration of action of the stem cells compared to the group 21 daysLPS + 7 daysMSCs. Conclusion: Human umbilical MSCs have regenerative, antifibrotic, and nephroprotective effects in an animal model of kidney injury caused by ARDS. This may indicate the therapeutic potential of umbilical MSCs for the treatment of nephropathies of various origins.

I. Palii

A. Dovgalyuk

S. Kramar

M. Korda

Morphofunctional changes in the kidneys of rats during acute respiratory distress syndrome and its treatment with human umbilical cord-derived mesenchymal stem cells

急性呼吸窘迫综合征期间大鼠肾脏的形态功能变化及其人脐带源间充质干细胞治疗

Cell therapy is a promising direction in the treatment of Parkinson’s disease/parkinsonism and multiple sclerosis, the effectiveness of which can be increased with the help of biologically active factors, in particular melatonin. The purpose of the study: to investigate the colony-forming ability of stromal and hematopoietic cells-progenitors of the bone marrow of mice with experimentally induced neurodegenerative pathology and reveal the possibility to change it under the influence of melatonin in vivo or in vitro. Materials and methods: In adult (6-7 months) male FVB/N (haplotype H-2q) and 129/Sv (haplotype H-2b) mice, the parkinsonism model was reproduced by a single subcutaneous injection of the neurotoxin 1-methyl-4-phenyl -1,2,3,6-tetrahydropyridine (MPTP) at a dose of 30 mg/kg 129/Sv mice also received the neurotoxin cuprizone daily with food (at the rate of 0.2 % of the mass of the pure substance from the daily feed) for three weeks (multiple sclerosis model). Melatonin was administered to the 129/Sv mice intraperitoneally at a dose of 1 mg/kg, daily, at 17.00, from the 8th day of receiving cuprizone, or was added in vitro to the culture of bone marrow cells of mice of both strains with parkinsonism at a dose of 0.1 μg/0.1 mL. In the bone marrow, the absolute number of nucleated cells was counted, the relative content of CD4+ lymphocytes was determined by flow cytometry, and the number of colony-forming precursor cells for fibroblasts (CFU-F) and for granulocyte-macrophages (CFU-GM) in culture in vitro was estimated. Results. In the bone marrow of 129/Sv mice with a model of multiple sclerosis, the number of nucleated cells, CFU-GM and CD4+ cells decrease, while under the influence of exogenous melatonin applied in vivo, the values of these indicators increase to the level of intact animals. After the administration of MPTP in the bone marrow of FVB/N mice, in contrast to 129/Sv mice, the number of nucleated cells and CFU-F decreases. After the incubation with melatonin of bone marrow cells of 129/Sv mice with a model of parkinsonism, an increase in the amount of CFU-F was observed compared to control values, and there were no changes in the indicator values in FVB/N mice. Conclusions. In the bone marrow of mice with the MPTP-model of parkinsonism, a decrease in the absolute amount of CFU-F was found, and in mice with the cuprizone model of multiple sclerosis – CFU-GM. The application of melatonin in vitro increases the colony-forming potential of progenitor cells for fibroblasts in the bone marrow of mice with the MPTP model of parkinsonism. The use of melatonin in vivo increases the colony-forming ability of progenitor cells for granulocyte-macrophages and the relative content of CD4+ cells in the bone marrow of mice with the cuprizone model of multiple sclerosis. Changes in the amount of CFU-F in the bone marrow in parkinsonism and under the influence of melatonin in vitro depend on the H-2 haplotype mice, which can be the basis for the development of personalized cell therapy for this pathology.

I. Labunets

T. Panteleymonova

A. Rodnichenko

Colony-forming potential of murine bone marrow-derived progenitor cells in experimental neurodegenerative pathology and under the impact of melatonin in vivo or in vitro

小鼠骨髓来源前体细胞在实验性神经退行性病理中的集落形成潜力及褪黑素对其在体内外的影响

Uterine leiomyoma is one of the most common gynaecological diseases, which often leads to loss of fertility. It is known that in this pathology, damage to the tissues of the uterus is accompanied by oxidative stress, and the mechanisms of its compensation play a decisive role in the process of myometrial regeneration, especially when performing organ-preserving operations. The aim of the study was to determine the levels of melatonin, reproductive hormones and state of angiogenesis, antioxidant system and lipid peroxidation in women of reproductive age who were diagnosed with uterine leiomyoma. Material and methods. 60 women of reproductive age with uterine leiomyoma (study group) were examined. The control group consisted of 20 healthy women of the same age group. Melatonin levels in women's blood were determined once, on an empty stomach, at 8 a.m.; the concentrations of estradiol and progesterone in the follicular phase of the menstrual cycle were also measured. The state of the angiogenesis system was studied by examining the levels of vascular endothelial growth factor (VEGF) and the content of the final metabolites of nitric oxide NO in blood plasma. The activity of the antioxidant system was assessed by blood plasma concentrations of reduced glutathione, glutathione peroxidase, and glutathione transferase. Indicators of lipid peroxidation were investigated by the content of malondialdehyde (MDA) in blood plasma and erythrocytes. Results. It was found that in the patients of the study group with leiomyoma, there was a significantly lower level of melatonin in blood plasma (111.1 ± 18.5 ng/mL) compared to the control group (153.5 ± 8.5 ng/mL), while the concentration of estradiol was almost three times higher (107.4 ± 25.3 pg/mL) compared to the control group (36.2 ± 3.2 pg/mL), and the concentration of progesterone was 1.9 times higher (2.1 ± 0.4 ng/mL compared to 1.1 ± 0.5 ng/mL in the control group). The level of VEGF in blood plasma in women with uterine leiomyoma was also higher (90.4 ± 23.6 pg/mL) compared to the control group (35.1 ± 8.3 pg/mL), as well as the concentration of final metabolites of nitric oxide, which reached 25.3 ± 5.9 pg/mL compared to 9.9 ± 3.9 pg/mL in the control group. The reduced glutathione level in the blood plasma of women with uterine leiomyoma was significantly lower (0.77 ± 0.13 µmol/L) compared to healthy women (1.02 ± 0.14 µmol/L) in the control group, while the concentrations of glutathione-S-transferase and glutathione peroxidase enzymes were higher (161.3 ± 22.3 ng/mL and 235.7 ± 35.9 ng/mL, respectively), whereas in the control group these indicators were 118.9 ± 18.0 ng/mL and 105.3 ± 41.2 ng/mL, respectively. The MDA content in women of the study group was higher, measuring 5.2 ± 0.8 nmol/L in plasma and 10.8 ± 1.1 nmol/L in erythrocytes compared to 2.3 ± 0.8 nmol/L and 5.3 ± 0.8 nmol/L in the control group, respectively. Conclusions. The levels of melatonin and reduced glutathione in the blood plasma of women with uterine leiomyoma were significantly lower, while the concentrations of estradiol, progesterone, glutathione-S-transferase, glutathione peroxidase, VEGF, final metabolites of nitric oxide, as well as the average MDA content in plasma and erythrocytes, were significantly higher compared to healthy women. In the study group, the relationship between the level of progesterone in blood plasma and the content of malondialdehyde in erythrocytes was described using a linear regression equation, which, as we suggest, indicates an activating effect of progesterone on oxidative stress mechanisms in the myometrium. In our opinion, oxidative stress in uterine leiomyoma occurs due to inadequate activity of the antioxidant system, an integral part of which is melatonin, leading to enhanced angiogenesis against the background of estrogen-induced myometrial proliferation.

B. Sokolov

A. Berbets

Shashi Kant

O. Yuzko

Levels of melatonin and some indicators of angiogenesis, antioxidant system and lipid peroxidation in blood plasma in women with uterine leiomyoma

血浆中褪黑素水平及血管生成、抗氧化系统和脂质过氧化的某些指标在子宫平滑肌瘤女性中的变化

Antiphospholipid syndrome is an autoimmune disease characterized by vascular thrombosis and/or obstetric pathology and the presence of antibodies against membrane phospholipids or certain phospholipid-related proteins. Objective. The aim of the research is to study the effect of mesenchymal stem cells, nitric oxide modulators (L-arginine and aminoguanidine) on the level of cytokines in bronchoalveolar lavage in experimental antiphospholipid syndrome in mice. Material and methods. Antiphospholipid syndrome was modeled on female BALB/c mice by intramuscular injections of cardiolipin 1.2 mg/kg 4 times with a 14-day interval. Cryopreserved human umbilical cord-derived mesenchymal stem cells (5×106 cells/kg) were injected once intraperitoneally, L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were administered intraperitoneally 1 time per day during 10 days after APS had developed. The cytokines concentration in bronchoalveolar lavage from the lungs was assessed by means of ELISA in 10 days after APS development. Results. In the bronchoalveolar lavage of the BALB/c mice with experimental APS, an increased level of pro-inflammatory cytokines IL-1β, IL-6, TNF-α and decreased level of anti-inflammatory IL-4 and IL-10 were found. It was established that in cases of APS and administration of stem cells the concentration of proinflammatory cytokines decreased: IL-1β by 32.4 %, IL-6 by 30.6 % and TNF-α by 36.1 %, respectively, compare to the APS animals. At the same time the level of IL-4 increased by 50.5 % and IL-10 – by 57.5 % in the group of animals administered with stem cells compare to those with APS. Conclusion. In cases of correction of modeled antiphospholipid syndrome in mice using mesenchymal stem cells and combined application of mesenchymal stem cells and nitric oxide modulators (L-arginine and aminoguanidine), a decrease in the level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α ) and an increase in the level of anti-inflammatory cytokines (IL-4 and IL-10) in bronchoalveolar lavage has been established.

N. Mekhno

O. Yaremchuk

Human umbilical cord-derived mesenchymal stem cells and nitric oxide modulators attenuate the proinflammatory cytokine pattern in experimental antiphospholipid syndrome in mice

人脐带源间充质干细胞与一氧化氮调节剂减轻小鼠实验性抗磷脂综合征中的促炎细胞因子模式

涉及主题	医学生物遗传学内科学化学细胞生物学生物化学病理免疫学外科心理学内分泌学干细胞神经科学移植计算机科学精神科解剖
出版信息	出版商: Institute of Cell Therapy，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 2019，原创研究文献占比: 0.00%，自引率:N.A.， Gold OA占比: 0.00%

Cell and Organ Transplantology

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