Platelets play an important part in the progression and pathological angiogenesis of brain glioma because of the different granules content and release of microvesicles that are the source of numerous mediators and bioactive substances, which probably provides a "strategy" for the tumour survival. The objective of study was exploring the effect of platelet-released secretion products of patients with brain glioma on the experimental model of tumour growth in vitro. For this purpose, the cells of glioma C6 were cultured for 72 hours under the addition of modified media containing platelet-released secretion products or conditioned media of peripheral blood cells of patients with glioma as well as persons of the comparison group without rough somatic pathology. In control glioma C6 cultures in standard conditions cell clusters were formed by the type of "spheroids", from which radial cell migration occurred, a tense cellular or reticular growth zone was formed, and tumour cells preserved their ability to mitotic division. Under the influence of platelet-released secretion products of patients with glioma, differently directed effects on cell mitotic activity and the number of cell clusters in glioma C6 cultures were detected depending on the degree of tumour malignancy: stimulating effect under the influence of platelet factors of patients with high-malignancy glioma (G4) and inhibitory effect – due to the influence of platelet factors of patients with differentiated glioma (G2). In contrast to the thrombocyte-released factors, the conditioned media of a common pool of peripheral blood cells of patients with G4 glioma suppressed the mitotic activity of tumour cells and did not affect the number of cell clusters. No changes in glioma C6 cultures were revealed after the influence of platelet-released secretion products of persons of the comparison group. The obtained data confirm the important role of platelets in the pathogenesis of brain glioma, pointing to the fundamental difference in the spectrum of biologically active molecules that are released by platelets of patients depending on the degree of tumour malignancy and are able to regulate the cell cycle and proliferative activity of the glioma tumour cells, which may have application as a diagnostic marker as well as predictive marker of response to antitumour therapy.
A potential strategy for recovery and regeneration of brain damage due to traumatic brain injury is considered to be the transplantation of neurogenic stem and/or progenitor cells (NSCs/NPCs). The key factors of the regenerative non-targeted effects of NSCs/NPCs (so-called bystander effects) include the signal molecules produced by them into the extracellular environment (secretome). The purpose is to study the regenerative bystander effects of rat fetal brain neurogenic cells (FBNCs) in the in vitro model of neurotrauma. Materials and methods. In cell culture of FBNCs from rat fetuses (E14-16), neurotrauma was modeled in vitro by mechanical scratching of monolayer and conditioned medium obtained from 24-h cultures of rat FBNCs was added. Cell phenotype was evaluated by morphological features and by immunocytochemical staining for Nestin and GFAP. The density and length of processes, migration capacity, the cell growth rate and monolayer density in the scratched area were compared. Morphometric study included analysis of the width of the scratched area, the number of migrating cells, the distance of migration and mitotic activity in the intact monolayer. Results. Under the conditions of the nutrient medium of standard composition in the scratched area the signs of endogenous regeneration are shown during 24-48 h of cultivation. The overgrowth of cell processes from monolayer and short distance migration of single undifferentiated or poorly differentiated cells were shown. In the next 72-96 h of observation, the degeneration of migrated cells and processes in the scratched area was detected. Under the influence of conditioned media from 24-h cultures of FBNCs by single addition immediately after scratching at dose of 0.1 mg/ml for protein content the stimulation of regeneration were detected up to 96 hours of cultivation. The migration of cell processes from the monolayer simultaneously with undifferentiated or poorly differentiated cells at 24 hours was shown. The formation of cell clusters and their differentiation (at 48 h), as well as migration of differentiated cells with partial or complete overgrowth of scratched area (72-96 h) were observed. The morphological signs of degeneration of migrated cells in the scratched area appeared only on the 8th day of cultivation. Conditioned media does not affect qualitative and quantitative properties of the culture of rat FBNCs in the intact area where mitotic activity was average. Conclusions. Conditioned medium from 24-h cultures of rat FBNC can stimulate reparation in the in vitro model of neurotrauma in neural cell culture for at least 7 days at a single addition, without affecting the cellular composition and mitotic activity of the intact monolayer.
Spinal cord injury (SCI) is one of the most common severe injuries to the central nervous system, resulting in motor dysfunction and sensory loss. Cell therapy using stem/progenitor cells (SCs/PCs), regenerative biomaterials, tissue engineering technologies and their combinations is a promising area of regenerative medicine for the treatment of this pathology. Wharton's jelly (hWJ-MSCs) on the recovery process of rat spinal cord (SC) tissue after lateral hemisection in the lower thoracic-upper lumbar region. THE PURPOSE of the research was to study the effect of implantation of fibrin matrix (FM) associated with rat neonatal brain cells (rNBCs) or human mesenchymal stromal cells of MATERIALS AND METHODS. Four experimental groups were formed: 1) comparison group -SCI without additional treatment (self-recovery); 2) SCI + implantation of cell-free FM fragment in the injury area (SCI+FM); 3) SCI + implantation of FM with incorporated hWJ-MSCs(1•10 6 /mL) in the injury area (SCI+FM+hWJ-MSCs), 4) SCI + implantation of FM with incorporated rNBCs (1•10 6 /mL) in the injury area (SCI+FM+rNBCs). The fragments of the SC tissue for morphological examination were obtained in the long-term period (7-9 months) after SCI. Serial longitudinal thin 5-7 μm sections of the tissue were prepared and immunohistochemical and morphometric studies were performed. RESULTS. In the long-term period after SCI, the traumatic cavity is replaced by elements of glia and connective tissue. A fragment of cellfree FM implanted in the traumatic area serves as a structural framework that creates a niche for cell migration (gliocytes, neural SCs/PCs(NSCs/NPCs) and, possibly, endogenous regeneration of the defect thanks to its own NSCs/NPCs. In the perifocal zone around the traumatic area, there is an increase in dystrophic changes in neurons, the formation of a gliofibrous capsule. The FM associated with the hWJ-MSCs and implanted in the traumatic cavity creates the conditions for hWJ-MSCs survival and, probably, their initial differentiation in the glial direction; incorporated hWJ-MSCs have a neuroprotective effect on the neurons of the perifocal zone, which can serve as a basis for the restoration of SC functions. The FM associated with the rNBCs and implanted in the traumatic cavity creates conditions for the structural recovery of SC tissue (replacement by terminally differentiated astrocytes and neurons); incorporated rNBCs have a neuroprotective effect on the neurons of the perifocal zone, which can be the basis for the functional recovery of SC. CONCLUSION.The implantation of fibrin matrix associated with hWJ-MSCs or rNBCs is more effective, compared to the cell-free analogue, in terms of structural recovery of spinal cord and neuroprotective effect after its traumatic transection.
This review presents recent data on the biological properties of cancer stem cells in brain gliomas. The possibilities of using of experimental methods of cell culture and immunohistochemical identification of tumor stem cells as a part of neurospheres (tumorospheres)
One of the directions of cell therapy being developed for brain gliomas is the use of the neurogenic stem and progenitor cells (NSCs/NPCs). There are data on the anti-tumor and immunomodulating properties of the NSCs/NPCs the mechanisms of which were not disclosed yet. One of the potential targets for tumor therapy is the transforming growth factor β (TGF-β1) which is thought to be one of the key molecules in the regulation of proliferation, differentiation and cell survival or apoptosis. In the view of available information about the possibility of TGF-β1 production by the mammalian multipotent NSCs/NPCs, the aim of this work was to study the TGF-β1-positive cells in the dynamics of cultivation of fetal brain neurogenic cells as a potential source of anti-tumor or immunomodulating effects of these cells.Material and methods. The fetal rat brain cells on 14th (E14) day of gestation were used as the source for cultivation in standard conditions (DМЕМ + 1 % fetal bovine serum) and studied on the 2nd and 37thday by morphometry and immunocytochemistry.Results. In the fetal rat brain cell cultures, the TGF-β1-positive cells made 22.04 ± 2.33 % and the nestin-positive cells made 49.16 ± 10.60 % of the total cells number. The morphometric parameters of TGF-β1-positive cells exceeded the corresponding values of negative cells (average values of cross-sectional areas of the cytoplasm, cross-sectional areas of the nucleus, nuclear-cytoplasmic ratio). During cultivation the relative amount of TGF-β1-positive cells was slightly decreased 15.27 ± 9.80 % (p = 0.7) and their sizes were increased. On the 37th day of cultivation the sizes of TGF-β1-positive and their nuclei were smaller in the comparison with the TGF-β1-negative cells.Conclusions. The presence of TGF-β1 expression by part of neurogenic cells of fetal rat brain (E14) in vitro was found, which persisted throughout cultivation (~5 weeks). Significant quantitative differences of morphometric parameters of TGF-β1-positive and negative cells were detected.
Treatment of malignant gliomas of the brain remains a serious problem on a global scale, despite intensive research into the causes and mechanisms of their progression. When using traditional surgical approaches and imaging methods tumor cell infiltrates may be overlooked, as a result of which, malignant gliomas relapse often occurs near the marginal region of the surgical cavity. A method that allows visual identification of tumor tissue and at the same time provides an opportunity to selectively destroy it is photodynamic therapy (PDT) ‒ a two-stage treatment that includes the introduction (intravenous, intraperitoneal, local or oral) of a light-sensitive chemical agent (photosensitizer (PS)) followed by its activation at a certain wavelength of light.The principle of PDT is based on the cytotoxic effects caused by PS, which selectively accumulates in malignant tumor cells and is activated by light rays of the appropriate wavelength, generating singlet oxygen and free radicals, which trigger photochemical reactions in tumor cells with subsequent destruction of protein structures. Tumor tissue has a higher affinity for PSs. PSs are divided into 1st, 2nd and 3rd generation molecules. So far, 3rd generation PSs have not yet been approved for clinical use. In vitro and in vivo experimental studies confirmed the effectiveness of PDT of brain tumors using 2nd generation PSs.The simultaneous use of surgery under the control of fluorescence and PDT enables both the visualization of tumor cells and their selective destruction. Regardless of PDT, PSs are used for the purpose of auxiliary delineation of tumor borders for maximum tumor removal during fluorescence-guided surgery.The review examines the development of PDT in a historical aspect, the contribution of domestic scientists, in particular, scientists of the Institute of Neurosurgery named after acad. A. P. Romodanov, National Academy of Medical Sciences of Ukraine to the development of the problem of PDT in neuro-oncology; preclinical studies of PDT and experimental approaches to increase the efficiency of PDT are characterized. Analysis of data from clinical trials confirms that using PDT as an adjunctive treatment of malignant gliomas administered immediately after maximal resection is safe, reduces the risk of recurrence by targeting residual tumor cells in the resection cavity, improves survival and quality of life of patients. The absence of information on the development of resistance to multiple PDT sessions suggests the possibility of repeated treatments of tumor cells not removed during surgery.
Ischemic stroke is one of the leading causes of mortality and disability worldwide. Dispite the progress of medical knowledge and technologies, the rate of permanent neurological impairment in patients after stroke remains high and effective strategy of restorative treatment is still at the stage of experimental development. Restoration of nervous system functions after stroke implies the activation of endogenous reparative processes, such as angiogenesis, using sources of regenerative medicine, including cell and tissue transplantation. Development of optimal and safe methods of neurotransplantation for stroke is one of the priorities of experimental research in this field. PURPOSE: to study the effect of post-stroke angiogenesis, stimulated by transplantation of cell suspension from embryonic nervous tissue (TCS-ENT) and bone marrow (TCS-BM), on restoration of motor functions in rats with experimental stroke. MATERIALS AND METHODS. 160 adult (3-4 months old) outbred albino rats weighing between 280-320 g were divided into groups and subgroups depending on the experimental procedure: with isolated middle cerebral artery occlusion (MCAO), intracerebral allotransplantation of cell suspension from embryonic nervous tissue (MCAO + TCS-ENT), intracerebral autotransplantation of cell suspension from bone marrow (MCAO + TCS-BM) or phosphate-buffered 0.9 % saline infusion (MCAO + PBS) on the 2 nd day after MCAO. MCAO was conducted using the modified method of intraluminal monofilament occlusion with blocking of collaterals. Volume of infarction zone was estimated using
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