Mesenchymal stem cells (MSCs) represent the promising options for retinal therapy and combined therapy with nanoparticles (NPs) could currently provide increased immunoregulatory and neuroprotective effects. Therefore, we tested the effect of silver (Ag)NPs on the properties of MSCs in an experimental model of chronic retinal degeneration. The results showed that simultaneous administration had no effect on the survival of MSCs, but a less effective local regulation of Iba-1 expression compared to MSC- or AgNP-only treated groups was observed. In addition, MSCs applied alone or in combination with AgNPs and sorted from the degenerated retina had increased expression of genes for retinal markers (rhodopsin, S-antigen, recoverin), and for TGF-β and IGF-1. These effects were confirmed also on protein level by increased production of IGF-1 and proportion of rhodopsin+ MSCs. Nevertheless, the increased expression of the gene for GDNF was observed only in the MSCs combined with AgNPs. Regarding the immune response, the application of MSCs with AgNPs triggered increased expression of the IL-6 gene in the CD45 cells separated from the retina. In conclusion, applications of MSCs or AgNPs, as a single therapy, were able to modulate the inflammation. However, the combined applications decreased the immunomodulatory effects of MSCs or AgNPs.

• Keywords
• Mesenchymal stem cells, Retina, Retinal microglia, Silver nanoparticles,
• MeSH
• Retinal Degeneration * therapy   chemically induced   pathology   MeSH
• Iodates toxicity   MeSH
• Combined Modality Therapy MeSH
• Metal Nanoparticles * chemistry   administration & dosage   MeSH
• Mesenchymal Stem Cells * metabolism   cytology   drug effects   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Retina metabolism   pathology   MeSH
• Silver * chemistry   pharmacology   MeSH
• Mesenchymal Stem Cell Transplantation * methods   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Iodates MeSH
• sodium iodate MeSH Browser
• Silver * MeSH

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

It is becoming increasingly evident that selecting an optimal source of mesenchymal stromal cells (MSCs) is crucial for the successful outcome of MSC-based therapies. During the search for cells with potent regenerative properties, Sertoli cells (SCs) have been proven to modulate immune response in both in vitro and in vivo models. Based on morphological properties and expression of surface markers, it has been suggested that SCs could be a kind of MSCs, however, this hypothesis has not been fully confirmed. Therefore, we compared several parameters of MSCs and SCs, with the aim to evaluate the therapeutic potential of SCs in regenerative medicine. We showed that SCs successfully underwent osteogenic, chondrogenic and adipogenic differentiation and determined the expression profile of canonical MSC markers on the SC surface. Besides, SCs rescued T helper (Th) cells from undergoing apoptosis, promoted the anti-inflammatory phenotype of these cells, but did not regulate Th cell proliferation. MSCs impaired the Th17-mediated response; on the other hand, SCs suppressed the inflammatory polarisation in general. SCs induced M2 macrophage polarisation more effectively than MSCs. For the first time, we demonstrated here the ability of SCs to transfer mitochondria to immune cells. Our results indicate that SCs are a type of MSCs and modulate the reactivity of the immune system. Therefore, we suggest that SCs are promising candidates for application in regenerative medicine due to their anti-inflammatory and protective effects, especially in the therapies for diseases associated with testicular tissue inflammation.

• Keywords
• Mesenchymal stem cells. Sertoli cells. Immunomodulation. Mitochondrial transfer,
• MeSH
• Anti-Inflammatory Agents MeSH
• Immunity MeSH
• Humans MeSH
• Mesenchymal Stem Cells * MeSH
• Mitochondria MeSH
• Sertoli Cells * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Inflammatory Agents 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, 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

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

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

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

UNLABELLED: Stem cell-based therapy has become an attractive and promising approach for the treatment of severe injuries or thus-far incurable diseases. However, the use of stem cells is often limited by a shortage of available tissue-specific stem cells; therefore, other sources of stem cells are being investigated and tested. In this respect, mesenchymal stromal/stem cells (MSCs) have proven to be a promising stem cell type. In the present study, we prepared MSCs from bone marrow (BM-MSCs) or adipose tissue (Ad-MSCs) as well as limbal epithelial stem cells (LSCs), and their growth, differentiation, and secretory properties were compared. The cells were grown on nanofiber scaffolds and transferred onto the alkali-injured eye in a rabbit model, and their therapeutic potential was characterized. We found that BM-MSCs and tissue-specific LSCs had similar therapeutic effects. Clinical characterization of the healing process, as well as the evaluation of corneal thickness, re-epithelialization, neovascularization, and the suppression of a local inflammatory reaction, were comparable in the BM-MSC- and LSC-treated eyes, but results were significantly better than in injured, untreated eyes or in eyes treated with a nanofiber scaffold alone or with a nanofiber scaffold seeded with Ad-MSCs. Taken together, the results show that BM-MSCs' therapeutic effect on healing of injured corneal surface is comparable to that of tissue-specific LSCs. We suggest that BM-MSCs can be used for ocular surface regeneration in cases when autologous LSCs are absent or difficult to obtain. SIGNIFICANCE: Damage of ocular surface represents one of the most common causes of impaired vision or even blindness. Cell therapy, based on transplantation of stem cells, is an optimal treatment. However, if limbal stem cells (LSCs) are not available, other sources of stem cells are tested. Mesenchymal stem cells (MSCs) are a convenient type of cell for stem cell therapy. The therapeutic potential of LSCs and MSCs was compared in an experimental model of corneal injury, and healing was observed following chemical injury. MSCs and tissue-specific LSCs had similar therapeutic effects. The results suggest that bone marrow-derived MSCs can be used for ocular surface regeneration in cases when autologous LSCs are absent or difficult to obtain.

• Keywords
• Alkali-injured ocular surface, Corneal regeneration, Limbal stem cells, Mesenchymal stem cells, Stem cell-based therapy,
• MeSH
• Biomarkers metabolism   MeSH
• Cell- and Tissue-Based Therapy methods   MeSH
• Cell Differentiation MeSH
• Bone Marrow Cells cytology   physiology   MeSH
• Burns, Chemical pathology   therapy   MeSH
• Epithelial Cells cytology   physiology   transplantation   MeSH
• Gene Expression MeSH
• Neovascularization, Physiologic MeSH
• Rabbits MeSH
• Limbus Corneae blood supply   injuries   MeSH
• Mesenchymal Stem Cells cytology   physiology   MeSH
• Primary Cell Culture MeSH
• Cell Proliferation MeSH
• Re-Epithelialization physiology   MeSH
• Epithelium, Corneal blood supply   injuries   MeSH
• Tissue Scaffolds MeSH
• Mesenchymal Stem Cell Transplantation * MeSH
• Adipose Tissue cytology   physiology   MeSH
• Adipocytes cytology   physiology   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Biomarkers MeSH