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Immunomodulatory mechanisms of stem cells and their use for therapy of ocular disorders
Heřmánková, Barbora ; Holáň, Vladimír (advisor) ; Heissigerová, Jarmila (referee) ; Indrová, Marie (referee)
Stem cell-based therapy represents a perspective approach for the treatment of many so far incurable diseases. Mesenchymal stem cells (MSC) are currently the most studied stem cells. They are able to differentiate into different cell types, to produce growth and trophic factors and can suppress the functions of cells of the immune system. During the study of the immunomodulatory properties of MSC, we focused on their effect on B cells. The mechanism of impact of interferon-γ (IFN-γ) on MSC and their effect on the production of interleukin 10 (IL-10) by B cells was analysed. We have demonstrated that MSC-treated with IFN-γ inhibit production of IL-10 by activated B cells via the cyclooxygenase-2 involving pathway. Due to their regenerative and immunomodulatory properties, MSC can be for treatment of many diseases. In this study we focused on the disease and damage of the eye. The limbal stem cells (LSC) are used for the treatment of damaged ocular surface, however their isolation is difficult and they can not be used in all cases of damage. Appropriate candidates in these cases are MSC. Therefore we have decided to compare the therapeutic potential of LSC and MSC isolated from bone marrow or adipose tissue. The study have shown that MSC isolated from bone marrow have a similar regenerative effect on...
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The use of immunoregulatory properties of mesenchymal stem cells/ and their therapeutic potential
Javorková, Eliška
Mesenchymal stem cells (MSCs) have the potential to differentiate into various cell types, possess potent immunomodulatory properties and can influence various functions of immune cells. Since the immunomodulatory properties of MSCs can be modified by cytokines, we compered the effect of unstimulated MSCs and MSCs pretreated with interleukin (IL)-1, interferon (IFN)- , transforming growth factor (TGF)- and IL-10 on the development of regulatory T cells (Treg) and T helper 17 (Th17) cells in vitro and on the inflammatory environment in the eye. MSCs can produce significant levels of TGF- and IL-6. These cytokines represent the key factors that reciprocally regulate the development of naive T cells into Treg and Th17 cells. Unstimulated MSCs produce TGF- , but not IL-6, and the production of TGF- can be further enhanced by IL-10 or TGF- . In the presence of IL-1, MSCs secrete significant levels of IL-6, in addition to spontaneous production of TGF- . MSC producing TGF- induced preferentially expression of Foxp3 and activation of Treg lymphocytes, whereas MSCs supernatants containing TGF- together with IL-6 supported ROR t expression and development of Th17 cells. We demonstrated that MSCs and their products effectively control the development of Tregs and Th17 cells in a population of...
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Use of biological materials for tissue substitution in plastic surgery
Měšťák, Ondřej ; Sukop, Andrej (advisor) ; Brychta, Pavel (referee) ; Dražan, Luboš (referee)
Užití biologických materiálů k náhradě tkání v plastické chirurgii ! Abstrakt v angličtině Background: Biological meshes are biomaterials consisted of extracellular matrix and used in surgery particularly for hernia treatment or thoracic wall reconstruction. They are capable of vascularization, that decreases risk of infection, expecially when used in contaminated fields. This study compared the strength of incorporation and biocompatibility of two porcine-derived grafts (cross-linked and non-cross-linked) in a rat hernia model. In addition, we hypothesized that combination of extracellular matrices with autologous mesenchymal stem cells used for hernia repair would result in increased vascularization and increased strength of incorporation. Methods: Standardized 2 x 4 cm fascial defect was created in 42 Wistar rats and repaired with a cross-linked or a non-cross-linked graft either enriched or non-enriched with stem cells. The rats were sacrificed 3, 6 and 12 months later. The strength of incorporation, vascularization, cellular invasion, foreign body reaction and capsule formation were evaluated. Results: Comparison of stem cell enriched and non-enriched groups showed no significant differences in the capsule thickness, foreign body reaction, cellularization or vascularization. In the non-cross-linked...
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Immunomodulatory properties of mesenchymal stem cells from patients with amyotrophic lateral sclerosis and healthy donors
Matějčková, Nicole
Mesenchymal stem cells (MSC) possess a multilineage differentiation potential and have the ability to regulate reactivity of the immune system. They are usually isolated and expanded from the bone marrow, adipose tissue or umbilical cord. MSC represent promising cell population for the treatment of some severe diseases, such as amyotrofic lateral sclerosis (ALS), due to the combination of regenerative and immunomodulatory properties. The aim of this study is to compare MSC from ALS patients and healthy donors in their phenotype, proliferative activity and mainly their immunomodulatory properties. The assessment of impact of the disease on the properties of MSC is important for their autologous use in clinical trials. In this study we used MSC isolated from bone marrow of 14 ALS patients and 15 patients undergoing mostly orthopedic surgery as control group. We also used MSC stimulated for 24 hours by poinflammatory cytokines. Cells were compared in terms of immunophenotype, differentiation in adipocytes and osteoblasts, metabolic activity, expression of selected genes for immunomodulatory molecules and for inhibition of lymphocyte proliferation. Further experiments were focused on evaluation of immunomodulatory properties of MSC. The effect of MSC on peripheral blood mononuclear cells stimulated...
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Immunomodulatory mechanisms of stem cells and their use for therapy of ocular disorders
Heřmánková, Barbora
Stem cell-based therapy represents a perspective approach for the treatment of many so far incurable diseases. Mesenchymal stem cells (MSC) are currently the most studied stem cells. They are able to differentiate into different cell types, to produce growth and trophic factors and can suppress the functions of cells of the immune system. During the study of the immunomodulatory properties of MSC, we focused on their effect on B cells. The mechanism of impact of interferon-γ (IFN-γ) on MSC and their effect on the production of interleukin 10 (IL-10) by B cells was analysed. We have demonstrated that MSC-treated with IFN-γ inhibit production of IL-10 by activated B cells via the cyclooxygenase-2 involving pathway. Due to their regenerative and immunomodulatory properties, MSC can be for treatment of many diseases. In this study we focused on the disease and damage of the eye. The limbal stem cells (LSC) are used for the treatment of damaged ocular surface, however their isolation is difficult and they can not be used in all cases of damage. Appropriate candidates in these cases are MSC. Therefore we have decided to compare the therapeutic potential of LSC and MSC isolated from bone marrow or adipose tissue. The study have shown that MSC isolated from bone marrow have a similar regenerative effect on...
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The therapeutic potential of mesenchymal stem cells in a mouse experimental model
Hájková, Michaela
Due to their immunomodulatory and regenerative potential, mesenchymal stem cells (MSCs) represent a promising therapeutic tool for cell-based therapy, organ transplantation or tissue engineering. To improve clinical applicability of MSCs, new methods to increase their delivery and efficacy have been tested in the latest years but the mechanism of observed alterations has not yet been described. In the present project we focused on studying the effect of several factors that can significantly affect the therapeutic success of MSC-based treatment. Initially, we analysed the therapeutic effect of MSCs applied locally on nanofiber scaffold with incorporated cyclosporine A (CsA) in a mouse model of allogeneic skin transplantation. Our results indicate that application of MSCs in the presence of CsA direct M1/M2 macrophage polarization towards regulatory phenotype. This phenotype switching is accompanied by decreased production of nitric oxide (NO) and interferon (IFN-) and increase production of interleukin 10 (IL-10), and may result in suppression of the local inflammatory reaction. The next goal of proposed study was to analyse the effect of the treatment based on MSCs combined with immunosuppressive drugs with different mechanism of action on the balance among distinct T cell subpopulations. We...
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Immunomodulatory and regenerative potential of mesenchymal stem cells in the treatment of degenerative retinal disorders in mice
Palacká, Kateřina ; Heřmánková, Barbora (advisor) ; Grobárová, Valéria (referee)
Retinal degenerative disease are the leading cause of vision loss in adult patients. Important role in the development of these types of disease play gradual death of retinal cells and an inflammatory reaction that leads to the production of cytokines, formation of inflamasome, increased angiogenesis and scar formation. These pathologies result in irreversible degeneration of retinal cells. Retinal pigmenetd epithelium cells, photoreceptors and ganglion cells are the most frequently damaged cell types in this conditions. The available treatments are currently very limited and effective only at the early stages of the disease. Therefore, the use of stem cell- based therapy could be a promising option. For therapeutic purposes it would be possible to use mesenchymal stem cells (MSCs) which may be isolated for example from bone marrow or adipose tissue. MSCs are capable of production of neuroprotective factors, differentiation into the variety of cells types and regulation of immune response. In this study we tested the therapeutic potential of MSC administered locally to the damaged retina in an experimental model of retinal degeneration. We focused on the protective effect of MSCs on photoreceptor cells, regulation of the local immune response and expression of genes for cytokines involved in...
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Effect of endogenous factors on mesenchymal stem cells
Černá, Kristýna ; Krulová, Magdaléna (advisor) ; Kubinová, Šárka (referee)
Maintaining of homeostasis is essential for the survival of the organism. Stress disturbs the homeostasis and prepares the organism for mental or physical stress. During the stress situation, the endogenous stress factors are released. Through these factors stress affects tissue regeneration, the immune system and other metabolic processes. Chronic stress impacts many parts of body and mind and has a negative effect on these processes. Acute stress has the opposite effect. Mesenchymal stem cells (MSCs) participate in regenerative processes and modulate the immune system. Therefore, it can be assumed that stress will affect on MSCs. The aim of this study was to investigate the effect of stress factors, norepinephrine and corticosterone on the properties and function of MSCs in acute and chronic stress model. In our study, stress factors did not affect the morphology, vitality and differentiation of MSCs. However, the metabolic activity of MSCs was reduced regardless of the duration of their action. The action of stress factors also affected the production of some immunologically relevant molecules and proteins. Unfortunately, the results did not show a clear effect of stress factors on the lymphocyte modulation by MSCs. Key words: mesenchymal stem cells, catecholamines, adrenergic receptors,...
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Dual effect of mesenchymal stem cells on cancer: its suppression or progression?
Matsakyanová, Victoria ; Hubálek Kalbáčová, Marie (advisor) ; Dibus, Michal (referee)
Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic cells, capable of differentiation into osteogenic, adipogenic and chondrogenic cell types and can be isolated from bone marrow, adipose tissue or umbilical cord. Due to their differentiation, trophic and immunomodulatory properties, and also their ability to migrate spontaneously to the site of inflammation, damaged tissue or tumor microenvironment, MSCs bring a great potential to become not only a tool to support tissue repair and regeneration, but also for anticancer therapy. Their potential can be also supported by genetic manipulations, which may enhance their antitumor effect. However, in the context of tumor growth, the effect of MSCs in not so clear. While in some cases, MSCs play antitumorigenic role, in other cases they contribute to the development of tumor growth. This dual effect of MSCs on tumor growth is the result of many factors, which modulate the interaction between MSCs and tumor cells. This thesis summarizes the current knowledge of the dual effect of MSC on tumor cells and demonstrates the most promising factors that play the role in the dual effect of MSC. Key words: mesenchymal stem cells, cancer, tumor tropism, cancer suppression, cancer progression
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Effect of Wharton's jelly-derived mesenchymal stem cells secretome in the treatment of rat spinal cord injury
Jančová, Pavlína ; Chudíčková, Milada (advisor) ; Grobárová, Valéria (referee)
As previously shown, transplantation of Wharton's jelly-derived mesenchymal stem cells in the experimental model of spinal cord injury leads to the motor and sensory functions improvement, supports neuroregeneration, angiogenesis and provides immunomodulation. On the other hand, these cells have limited migration and survival capacity, and their therapeutic effect is mediated mostly by their secretome. Therefore, application of mesenchymal stem cells derived conditioned medium is studied as an alternative option for cell therapy. In this thesis, therapeutic effect of repeated intrathecal delivery of human Wharton's jelly-derived mesenchymal stem cells and their conditioned media in the treatment of spinal cord injury was compared. After induction of a balloon ischemic compression lesion, stem cells or conditioned media were administered weekly in three doses. Behavioral analyses were carried out up to nine weeks after spinal cord injury and revealed significant improvement of both treated groups compared to the untreated saline control. Application of stem cells and conditioned media also resulted in a higher amount of spared tissue and enhanced expression of genes related to neuroregeneration, although the size of glial scar was not reduced. Compared to application of stem cells, application of...
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