Retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy or glaucoma, represent the main causes of a decreased quality of vision or even blindness worldwide. However, despite considerable efforts, the treatment possibilities for these disorders remain very limited. A perspective is offered by cell therapy using mesenchymal stem cells (MSCs). These cells can be obtained from the bone marrow or adipose tissue of a particular patient, expanded in vitro and used as the autologous cells. MSCs possess potent immunoregulatory properties and can inhibit a harmful inflammatory reaction in the diseased retina. By the production of numerous growth and neurotrophic factors, they support the survival and growth of retinal cells. In addition, MSCs can protect retinal cells by antiapoptotic properties and could contribute to the regeneration of the diseased retina by their ability to differentiate into various cell types, including the cells of the retina. All of these properties indicate the potential of MSCs for the therapy of diseased retinas. This view is supported by the recent results of numerous experimental studies in different preclinical models. Here we provide an overview of the therapeutic properties of MSCs, and their use in experimental models of retinal diseases and in clinical trials.

• Keywords
• clinical trials, experimental models, mesenchymal stem cells, retinal degenerative diseases, stem cell therapy,
• MeSH
• Transplantation, Autologous MeSH
• Cell- and Tissue-Based Therapy methods   MeSH
• Cell Differentiation MeSH
• Bone Marrow Cells cytology   metabolism   MeSH
• Diabetic Retinopathy genetics   metabolism   pathology   therapy   MeSH
• Glaucoma genetics   metabolism   pathology   therapy   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Macular Degeneration genetics   metabolism   pathology   therapy   MeSH
• Mesenchymal Stem Cells cytology   metabolism   MeSH
• Intercellular Signaling Peptides and Proteins genetics   metabolism   MeSH
• Disease Models, Animal MeSH
• Nerve Growth Factors genetics   metabolism   MeSH
• Retina metabolism   pathology   MeSH
• Retinitis Pigmentosa genetics   metabolism   pathology   therapy   MeSH
• Mesenchymal Stem Cell Transplantation methods   MeSH
• Adipose Tissue cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Intercellular Signaling Peptides and Proteins MeSH
• Nerve Growth Factors MeSH

Retinal degenerative disorders are characterized by a local upregulation of inflammatory factors, infiltration with cells of the immune system, a vascular dysfunction and by the damage of retinal cells. There is still a lack of treatment protocols for these diseases. Mesenchymal stem cell (MSC)-based therapy using immunoregulatory, regenerative and differentiating properties of MSCs offers a promising treatment option. In this study, we analyzed the immunomodulatory properties of mouse bone marrow-derived MSCs after their intravitreal delivery to the inflammatory environment in the eye, caused by the application of pro-inflammatory cytokines IL-1β, TNF-α and IFN-γ. The intravitreal administration of these cytokines induces an increased expression of pro-inflammatory molecules such as IL-1α, IL-6, inducible nitric oxide synthase, TNF-α and vascular endothelial growth factor in the retina. However, a significant decrease in the expression of genes for all these pro-inflammatory molecules was observed after the intravitreal injection of MSCs. We further showed that an increased infiltration of the retina with immune cells, mainly with macrophages, which was observed after pro-inflammatory cytokine application, was significantly reduced after the intravitreal application of MSCs. The similar immunosuppressive effects of MSCs were also demonstrated in vitro in cultures of cytokine-stimulated retinal explants and MSCs. Overall, the results show that intravitreal application of MSCs inhibits the early retinal inflammation caused by pro-inflammatory cytokines, and propose MSCs as a promising candidate for stem cell-based therapy of retinal degenerative diseases.

• Keywords
• Cytokines, Immunomodulation, Inflammation, Mesenchymal stem cells, Retina,
• MeSH
• Antiviral Agents pharmacology   MeSH
• Cytokines metabolism   MeSH
• Immunomodulation drug effects   immunology   MeSH
• Interferon-gamma pharmacology   MeSH
• Interleukin-1beta pharmacology   MeSH
• Inflammation Mediators pharmacology   MeSH
• Mesenchymal Stem Cells cytology   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Nitric Oxide metabolism   MeSH
• Retina cytology   drug effects   immunology   metabolism   MeSH
• Tumor Necrosis Factor-alpha pharmacology   MeSH
• Inflammation immunology   metabolism   pathology   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antiviral Agents MeSH
• Cytokines MeSH
• IL1B protein, mouse MeSH Browser
• Interferon-gamma MeSH
• Interleukin-1beta MeSH
• Inflammation Mediators MeSH
• Nitric Oxide MeSH
• Tumor Necrosis Factor-alpha MeSH

Pathogenesis of amyotrophic lateral sclerosis (ALS) involves several mechanisms resulting in a shift from a neuroprotective to a neurotoxic immune reaction. A promising tool for ALS treatment is represented by mesenchymal stem cells (MSCs), which possess both regenerative potential and immunomodulatory properties. In this study, we aimed to compare the immunomodulatory properties of MSCs isolated from the bone marrow of patients suffering from ALS and healthy donors. Moreover, the influence of proinflammatory cytokines on the immunoregulatory functions of MSCs was also evaluated. We found that MSCs from ALS patients and healthy donors comparably affected mitogen-stimulated peripheral blood mononuclear cells and reduced the percentage of T helper (Th)1, Th17 and CD8+CD25+ lymphocytes. These MSCs also equally increased the percentage of Th2 and CD4+FOXP3+ T lymphocytes. On the other hand, MSCs from ALS patients decreased more strongly the production of tumour necrosis factor-α than MSCs from healthy donors, but this difference was abrogated in the case of MSCs stimulated with cytokines. Significant differences between cytokine-treated MSCs from ALS patients and healthy donors were detected in the effects on the percentage of CD8+CD25+ and CD4+FOXP3+ T lymphocytes. In general, treatment of MSCs with cytokines results in a potentiation of their effects, but in the case of MSCs from ALS patients, it causes stagnation or even restriction of some of their immunomodulatory properties. We conclude that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. Graphical Abstract Treatment of mesenchymal stem cells (MSCs) with cytokines results in a potentiation of their effects, but in the case of MSCs from amyotrophic lateral sclerosis (ALS) patients, it causes stagnation (an equal reduction of the percentage of CD8+CD25+ T lymphocytes) or even restriction (no increase of proportion of CD4+FOXP3+ T lymphocytes) of some of their immunomodulatory properties. It means that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines.

• Keywords
• Amyotrophic lateral sclerosis, CD4+FOXP3+ T lymphocytes, Helper T lymphocytes, Immunomodulation, Mesenchymal stem cells, Proinflammatory cytokines,
• MeSH
• Amyotrophic Lateral Sclerosis immunology   MeSH
• Bone Marrow Cells immunology   MeSH
• Cytokines metabolism   MeSH
• Immunologic Factors pharmacology   MeSH
• Immunomodulation MeSH
• Leukocytes, Mononuclear drug effects   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mesenchymal Stem Cells immunology   MeSH
• Mitogens pharmacology   MeSH
• T-Lymphocytes, Helper-Inducer drug effects   immunology   MeSH
• Tumor Necrosis Factor-alpha biosynthesis   MeSH
• Healthy Volunteers MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cytokines MeSH
• Immunologic Factors MeSH
• Mitogens MeSH
• Tumor Necrosis Factor-alpha MeSH

Retinal degenerative diseases, which include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma, mostly affect the elderly population and are the most common cause of decreased quality of vision or even blindness. So far, there is no satisfactory treatment protocol to prevent, stop, or cure these disorders. A great hope and promise for patients suffering from retinal diseases is represented by stem cell-based therapy that could replace diseased or missing retinal cells and support regeneration. In this respect, mesenchymal stem cells (MSCs) that can be obtained from the particular patient and used as autologous cells have turned out to be a promising stem cell type for treatment. Here we show that MSCs can differentiate into cells expressing markers of retinal cells, inhibit production of pro-inflammatory cytokines by retinal tissue, and produce a number of growth and neuroprotective factors for retinal regeneration. All of these properties make MSCs a prospective cell type for cell-based therapy of age-related retinal degenerative diseases.

• Keywords
• age-related retinal degenerative diseases, mesenchymal stem cells, stem cell therapy,
• MeSH
• Cell Differentiation genetics   physiology   MeSH
• Retinal Degeneration metabolism   therapy   MeSH
• Mesenchymal Stem Cells cytology   metabolism   MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Retinal Diseases metabolism   therapy   MeSH
• Prospective Studies MeSH
• Stem Cell Transplantation methods   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Immunosuppressive drugs are widely used to treat undesirable immune reaction, however their clinical use is often limited by harmful side effects. The combined application of immunosuppressive agents with mesenchymal stem cells (MSCs) offers a promising alternative approach that enables the reduction of immunosuppressive agent doses and simultaneously maintains or improves the outcome of therapy. The present study aimed to determinate the effects of immunosuppressants on individual T cell subpopulations and to investigate the efficacy of MSC-based treatment combined with immunosuppressive drugs. We tested the effect of five widely used immunosuppressants with different action mechanisms: cyclosporine A, mycophenolate mofetil, rapamycin, and two glucocorticoids - prednisone and dexamethasone in combination with MSCs on mouse CD4+ and CD8+ lymphocyte viability and activation, Th17 (RORγt+), Th1 (T-bet+), Th2 (GATA-3+) and Treg (Foxp3+) cell proportion and on the production of corresponding key cytokines (IL-17, IFNγ, IL-4 and IL-10). We showed that MSCs modulate the actions of immunosuppressants and in combination with immunosuppressive drugs display distinct effect on cell activation and balance among different T lymphocytes subpopulations and exert a suppressive effect on proinflammatory T cell subsets while promoting the functions of anti-inflammatory Treg lymphocytes. The results indicated that MSC-based therapy could be a powerful strategy to attenuate the negative effects of immunosuppressive drugs on the immune system.

• Keywords
• Immunomodulation, Immunosuppressive drugs, Mesenchymal stem cells, Stem cell therapy, T cells,
• MeSH
• Lymphocyte Activation drug effects   immunology   MeSH
• Cyclosporine pharmacology   MeSH
• Cytokines metabolism   MeSH
• Dexamethasone pharmacology   MeSH
• Glucocorticoids pharmacology   MeSH
• Immunosuppressive Agents pharmacology   MeSH
• Coculture Techniques MeSH
• Cells, Cultured MeSH
• Mycophenolic Acid pharmacology   MeSH
• Mesenchymal Stem Cells cytology   immunology   metabolism   MeSH
• Mice, Inbred BALB C MeSH
• Prednisone pharmacology   MeSH
• Cell Proliferation drug effects   MeSH
• Flow Cytometry MeSH
• Sirolimus pharmacology   MeSH
• T-Lymphocyte Subsets cytology   drug effects   immunology   MeSH
• Mesenchymal Stem Cell Transplantation methods   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cyclosporine MeSH
• Cytokines MeSH
• Dexamethasone MeSH
• Glucocorticoids MeSH
• Immunosuppressive Agents MeSH
• Mycophenolic Acid MeSH
• Prednisone MeSH
• Sirolimus MeSH

Mesenchymal stem cells (MSCs) represent a population of cells which have the ability to regulate reactivity of T and B lymphocytes by multiple mechanisms. The immunoregulatory activities of MSCs are strictly influenced by the cytokine environment. Here we show that two functionally distinct cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), significantly potentiate the ability of MSCs to inhibit IL-10 production by activated regulatory B cells (Bregs). However, MSCs in the presence of IL-4 or IFN-γ inhibit the IL-10 production by different mechanisms. Preincubation of MSCs with IFN-γ led to the suppression, but pretreatment with IL-4 of neither MSCs nor B cells resulted in the suppression of IL-10 production. The search for candidate regulatory molecules expressed in cytokine-treated MSCs revealed different patterns of the gene expression. Pretreatment of MSCs with IFN-γ, but not with IL-4, induced expression of indoleamine-2,3-dioxygenase, cyclooxygenase-2 and programmed cell death-ligand 1. To identify the molecule(s) responsible for the suppression of IL-10 production, we used specific inhibitors of the putative regulatory molecules. We found that indomethacine, an inhibitor of cyclooxygenase-2 (Cox-2) activity, completely abrogated the inhibition of IL-10 production in cultures containing MSCs and IFN-γ, but had no effect on the suppression in cell cultures containing MSCs and IL-4. The results show that MSCs can inhibit the response of B cells to one stimulus by different mechanisms in dependence on the cytokine environment and thus support the idea of the complexity of immunoregulatory action of MSCs.

• Keywords
• Cyclooxygenase 2, Cytokine environment, Gene expression, IFN-γ, IL-10, IL-4, Immunoregulation, Mesenchymal stem cells, Regulatory B cells,
• MeSH
• Lymphocyte Activation drug effects   immunology   MeSH
• Programmed Cell Death 1 Receptor genetics   immunology   metabolism   MeSH
• Cellular Microenvironment drug effects   immunology   MeSH
• Cyclooxygenase 2 genetics   immunology   metabolism   MeSH
• Cytokines immunology   metabolism   pharmacology   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Gene Expression drug effects   genetics   immunology   MeSH
• Indoleamine-Pyrrole 2,3,-Dioxygenase genetics   immunology   metabolism   MeSH
• Interferon-gamma pharmacology   MeSH
• Interleukin-10 immunology   metabolism   MeSH
• Interleukin-4 pharmacology   MeSH
• Interleukin-6 genetics   immunology   metabolism   MeSH
• Coculture Techniques MeSH
• Cells, Cultured MeSH
• Mesenchymal Stem Cells drug effects   immunology   metabolism   MeSH
• Mice MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• B-Lymphocytes, Regulatory drug effects   immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Programmed Cell Death 1 Receptor MeSH
• Cyclooxygenase 2 MeSH
• Cytokines MeSH
• IL4 protein, human MeSH Browser
• Indoleamine-Pyrrole 2,3,-Dioxygenase MeSH
• Interferon-gamma MeSH
• Interleukin-10 MeSH
• Interleukin-4 MeSH
• Interleukin-6 MeSH
• PDCD1 protein, human MeSH Browser

Oxidative stress is involved in many ocular diseases and injuries. The imbalance between oxidants and antioxidants in favour of oxidants (oxidative stress) leads to the damage and may be highly involved in ocular aging processes. The anterior eye segment and mainly the cornea are directly exposed to noxae of external environment, such as air pollution, radiation, cigarette smoke, vapors or gases from household cleaning products, chemical burns from splashes of industrial chemicals, and danger from potential oxidative damage evoked by them. Oxidative stress may initiate or develop ocular injury resulting in decreased visual acuity or even vision loss. The role of oxidative stress in the pathogenesis of ocular diseases with particular attention to oxidative stress in the cornea and changes in corneal optical properties are discussed. Advances in the treatment of corneal oxidative injuries or diseases are shown.

• MeSH
• Alkalies toxicity   MeSH
• Ophthalmic Solutions therapeutic use   MeSH
• Oxidative Stress * drug effects   radiation effects   MeSH
• Corneal Injuries drug therapy   metabolism   pathology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Cornea drug effects   radiation effects   MeSH
• Ultraviolet Rays MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Alkalies MeSH
• Ophthalmic Solutions MeSH
• Reactive Oxygen Species MeSH