Stem cell-based therapy represents a promising approach for the treatment of numerous currently uncurable diseases. However, wider application of this therapy is still bound by various limitations. To increase the effectiveness of cell therapy, a combined application of stem cells with various types of chemicals or agents, which could support the immunoregulatory and therapeutic properties of stem cells, has been proposed and tested. One prospective approach is offered by the co-application of mesenchymal stem cells (MSCs), which have potent immunomodulatory and regenerative properties, and selected metal nanoparticles (NPs) which have been used in various fields of medicine for their immunomodulatory, anti-oxidant and antibacterial properties. It has been shown that the main mechanism of the therapeutic action of MSCs is the production of immunomodulatory molecules and growth factors, and that the secretory activity of MSCs can be modified by different types of NPs. For this purpose, metal NPs are extremely useful. They possess unique characteristics and can influence the growth and repair of tissues, exert strong antimicrobial activity and serve as nanocarriers. Thus, treatment based on the simultaneous application of MSCs and selected NPs combines the therapeutic effects of MSCs and impacts of NPs on applied MSCs, and on the cells and tissues of the recipient. In this review we outline the current state of studies combining the administration of MSCs and the application of metal NPs, with a focus on perspectives to use such treatment for corneal and retinal injuries and diseases.

• Keywords
• combined application, mesenchymal stem cells, metal nanoparticles, ocular disorders, therapeutic effect,
• MeSH
• Combined Modality Therapy methods   MeSH
• Metal Nanoparticles * chemistry   therapeutic use   MeSH
• Humans MeSH
• Mesenchymal Stem Cells * cytology   MeSH
• Eye Diseases * therapy   MeSH
• Mesenchymal Stem Cell Transplantation * methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The eye represents a highly specialized organ, with its main function being to convert light signals into electrical impulses. Any damage or disease of the eye induces a local inflammatory reaction that could be harmful for the specialized ocular cells. Therefore, the eye developed several immunoregulatory mechanisms which protect the ocular structures against deleterious immune reactions. This protection is ensured by the production of a variety of immunosuppressive molecules, which create the immune privilege of the eye. In addition, ocular cells are potent producers of numerous growth and trophic factors which support the survival and regeneration of diseased and damaged cells. If the immune privilege of the eye is interrupted and the regulatory mechanisms are not sufficiently effective, the eye disease can progress and result in worsening of vision or even blindness. In such cases, external immunotherapeutic interventions are needed. One perspective possibility of treatment is represented by mesenchymal stromal/stem cell (MSC) therapy. MSCs, which can be administered intraocularly or locally into diseased site, are potent producers of various immunoregulatory and regenerative molecules. The main advantages of MSC therapy include the safety of the treatment, the possibility to use autologous (patient's own) cells, and observations that the therapeutic properties of MSCs can be intentionally regulated by external factors during their preparation. In this review, we provide a survey of the immunoregulatory and regenerative mechanisms in the eye and describe the therapeutic potential of MSC application for corneal damages and retinal diseases.

• Keywords
• cell therapy, corneal damages, immunoregulation, mesenchymal stem cells, retinal diseases, tissue regeneration,
• MeSH
• Humans MeSH
• Mesenchymal Stem Cells * cytology   MeSH
• Retinal Diseases * therapy   immunology   MeSH
• Corneal Injuries * therapy   MeSH
• Mesenchymal Stem Cell Transplantation * methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Some metal nanoparticles (NP) are characterized by antimicrobial properties with the potential to be used as alternative antibiotics. However, NP may negatively impact human organism, including mesenchymal stem cells (MSC), a cell population contributing to tissue growth and regeneration. To address these issues, we investigated the toxic effects of selected NP (Ag, ZnO, and CuO) in mouse MSC. MSC were treated with various doses of NP for 4 h, 24 h, and 48 h and multiple endpoints were analyzed. Reactive oxygen species were generated after 48 h CuO NP exposure. Lipid peroxidation was induced after 4 h and 24 h treatment, regardless of NP and/or tested dose. DNA fragmentation and oxidation induced by Ag NP showed dose responses for all the periods. For other NP, the effects were observed for shorter exposure times. The impact on the frequency of micronuclei was weak. All the tested NP increased the sensitivity of MSC to apoptosis. The cell cycle was most affected after 24 h, particularly for Ag NP treatment. In summary, the tested NP induced numerous adverse changes in MSC. These results should be taken into consideration when planning the use of NP in medical applications where MSC are involved.

• Keywords
• antimicrobial properties, mesenchymal stem cells, metal nanoparticles, toxicity,
• Publication type
• Journal Article MeSH

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

Retinal degenerative disorders, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration or glaucoma, represent the most common causes of loss of vision and blindness. In spite of intensive research, treatment options to prevent, stop or cure these diseases are limited. Newer therapeutic approaches are offered by stem cell-based therapy. To date, various types of stem cells have been evaluated in a range of models. Among them, mesenchymal stem/stromal cells (MSCs) derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases. MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repair-promoting/regenerative effects on retinal cells. However, MSCs also produce numerous factors that could have negative impacts on retinal regeneration. The secretory activity of MSCs is strongly influenced by the cytokine environment. Therefore, the interactions among the molecules produced by the diseased retina, cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases. Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs, and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.

• Keywords
• Cytokines, Degenerative diseases, Growth factors, Mesenchymal stem cells, Retina, Stem cell therapy,
• Publication type
• Journal Article MeSH
• Review MeSH

Morphine is an analgesic drug therapeutically administered to relieve pain. However, this drug has numerous side effects, which include impaired healing and regeneration after injuries or tissue damages. It suggests negative effects of morphine on stem cells which are responsible for tissue regeneration. Therefore, we studied the impact of morphine on the properties and functional characteristics of human bone marrow-derived mesenchymal stem cells (MSCs). The presence of μ-, δ- and κ-opioid receptors (OR) in untreated MSCs, and the enhanced expression of OR in MSCs pretreated with proinflammatory cytokines, was demonstrated using immunoblotting and by flow cytometry. Morphine modified in a dose-dependent manner the MSC phenotype, inhibited MSC proliferation and altered the ability of MSCs to differentiate into adipocytes or osteoblasts. Furthermore, morphine rather enhanced the expression of genes for various immunoregulatory molecules in activated MSCs, but significantly inhibited the production of the vascular endothelial growth factor, hepatocyte growth factor or leukemia inhibitory factor. All of these observations are underlying the selective impact of morphine on stem cells, and offer an explanation for the mechanisms of the negative effects of opioid drugs on stem cells and regenerative processes after morphine administration or in opioid addicts.

• Keywords
• Cytokines, Gene expression, Growth factors, Mesenchymal stem cells, Morphine, Opioid receptors,
• MeSH
• Cell Differentiation drug effects   MeSH
• Humans MeSH
• Mesenchymal Stem Cells metabolism   pathology   MeSH
• Morphine pharmacology   MeSH
• Osteoblasts metabolism   MeSH
• Receptors, Opioid metabolism   MeSH
• Adipocytes metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Morphine MeSH
• Receptors, Opioid 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

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

The aim of this study was to examine whether mesenchymal stem cells (MSCs) and/or corneal limbal epithelial stem cells (LSCs) influence restoration of an antioxidant protective mechanism in the corneal epithelium and renewal of corneal optical properties changed after alkali burns. The injured rabbit corneas (with 0.25 N NaOH) were untreated or treated with nanofiber scaffolds free of stem cells, with nanofiber scaffolds seeded with bone marrow MSCs (BM-MSCs), with adipose tissue MSCs (Ad-MSCs), or with LSCs. On day 15 following the injury, after BM-MSCs or LSCs nanofiber treatment (less after Ad-MSCs treatment) the expression of antioxidant enzymes was restored in the regenerated corneal epithelium and the expressions of matrix metalloproteinase 9 (MMP9), inducible nitric oxide synthase (iNOS), α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and vascular endothelial factor (VEGF) were low. The central corneal thickness (taken as an index of corneal hydration) increased after the injury and returned to levels before the injury. In injured untreated corneas the epithelium was absent and numerous cells revealed the expressions of iNOS, MMP9, α-SMA, TGF-β1, and VEGF. In conclusion, stem cell treatment accelerated regeneration of the corneal epithelium, restored the antioxidant protective mechanism, and renewed corneal optical properties.

• MeSH
• Alkalies MeSH
• Antioxidants therapeutic use   MeSH
• Cell Differentiation drug effects   MeSH
• Burns, Chemical enzymology   genetics   pathology   therapy   MeSH
• Immunohistochemistry MeSH
• Rabbits MeSH
• Limbus Corneae cytology   MeSH
• Matrix Metalloproteinase 9 metabolism   MeSH
• Mesenchymal Stem Cells cytology   drug effects   MeSH
• Protective Agents pharmacology   therapeutic use   MeSH
• Corneal Pachymetry MeSH
• Gene Expression Regulation drug effects   MeSH
• Epithelium, Corneal pathology   MeSH
• Superoxide Dismutase metabolism   MeSH
• Nitric Oxide Synthase Type II metabolism   MeSH
• Transforming Growth Factor beta genetics   metabolism   MeSH
• Mesenchymal Stem Cell Transplantation * MeSH
• Adipocytes cytology   drug effects   MeSH
• Vascular Endothelial Growth Factor A metabolism   MeSH
• Corneal Opacity complications   therapy   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Retracted Publication MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alkalies MeSH
• Antioxidants MeSH
• Matrix Metalloproteinase 9 MeSH
• Protective Agents MeSH
• Superoxide Dismutase MeSH
• Nitric Oxide Synthase Type II MeSH
• Transforming Growth Factor beta MeSH
• Vascular Endothelial Growth Factor A MeSH