Polycomb repressive complexes maintain transcriptional repression of genes encoding crucial developmental regulators through chromatin modification. Here we investigated the role of Polycomb repressive complex 2 (PRC2) in retinal development by inactivating its key components Eed and Ezh2. Conditional deletion of Ezh2 resulted in a partial loss of PRC2 function and accelerated differentiation of Müller glial cells. In contrast, inactivation of Eed led to the ablation of PRC2 function at early postnatal stage. Cell proliferation was reduced and retinal progenitor cells were significantly decreased in this mutant, which subsequently caused depletion of Müller glia, bipolar, and rod photoreceptor cells, primarily generated from postnatal retinal progenitor cells. Interestingly, the proportion of amacrine cells was dramatically increased at postnatal stages in the Eed-deficient retina. In accordance, multiple transcription factors controlling amacrine cell differentiation were upregulated. Furthermore, ChIP-seq analysis showed that these deregulated genes contained bivalent chromatin (H3K27me3+ H3K4me3+). Our results suggest that PRC2 is required for proliferation in order to maintain the retinal progenitor cells at postnatal stages and for retinal differentiation by controlling amacrine cell generation.

• MeSH
• buněčná diferenciace fyziologie   MeSH
• chromatin metabolismus   MeSH
• EZH2 protein metabolismus   MeSH
• histony metabolismus   MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• metylace MeSH
• myši MeSH
• neurogeneze MeSH
• neuroglie metabolismus   MeSH
• PRC2 metabolismus   MeSH
• proliferace buněk MeSH
• retina metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Onemocnění sítnice představují rozsáhlou skupinu dědičných i získaných chorob, které často vedou až ke ztrátě zraku. V současné době neexistuje účinná terapie degenerace sítnice, proto je u mnoha onemocnění používána pouze podpůrná terapie. Perspektivu léčby onemocnění sítnice představuje buněčná terapie založená na využití kmenových buněk. Vhodnými kandidáty mezi kmenovými buňkami jsou mezenchymální kmenové buňky, které kromě svých schopností diferenciace v buňky sítnice mají i protektivní vliv a schopnost imunomodulace.

Retinal diseases represent a large group of hereditary and acquired diseases that often lead to loss of vision. There is currently no effective treatment of retinal degeneration, only supportive therapy is used for treating numerous diseases. Perspective treatment of retinal diseases represent a cell therapy using stem cells. Suitable candidates for the stem cell therapy are mesenchymal stem cells due to their differentiating properties, protective effect and also immunomodulation.

• MeSH
• buněčná a tkáňová terapie * metody   MeSH
• kmenové buňky MeSH
• lidé MeSH
• mezenchymální kmenové buňky fyziologie   MeSH
• nemoci retiny * terapie   MeSH
• transplantace kmenových buněk MeSH
• transplantace mezenchymálních kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem 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.

• MeSH
• buněčná diferenciace genetika   fyziologie   MeSH
• degenerace retiny metabolismus   terapie   MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nemoci retiny metabolismus   terapie   MeSH
• prospektivní studie MeSH
• transplantace kmenových buněk metody   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• buněčná a tkáňová terapie * metody   MeSH
• kmenové buňky MeSH
• lidé MeSH
• mezenchymální kmenové buňky fyziologie   MeSH
• nemoci retiny * terapie   MeSH
• transplantace kmenových buněk MeSH
• transplantace mezenchymálních kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem 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.

• MeSH
• autologní transplantace MeSH
• buněčná a tkáňová terapie metody   MeSH
• buněčná diferenciace MeSH
• buňky kostní dřeně cytologie   metabolismus   MeSH
• diabetická retinopatie genetika   metabolismus   patologie   terapie   MeSH
• glaukom genetika   metabolismus   patologie   terapie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• makulární degenerace genetika   metabolismus   patologie   terapie   MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   MeSH
• mezibuněčné signální peptidy a proteiny genetika   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• neurotrofní faktory genetika   metabolismus   MeSH
• retina metabolismus   patologie   MeSH
• retinopathia pigmentosa genetika   metabolismus   patologie   terapie   MeSH
• transplantace mezenchymálních kmenových buněk metody   MeSH
• tuková tkáň cytologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication, and DNA repair. However, the contribution of these complexes to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of the Snf2h gene during the development of the mammalian retina. We show that Snf2h is expressed in both retinal progenitors and post-mitotic retinal cells. Using Snf2h conditional knockout mice (Snf2h cKO), we found that when Snf2h is deleted, the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. The depletion of Snf2h did not influence the ability of retinal progenitors to generate all the differentiated retinal cell types. Instead, the Snf2h function is critical for the proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although all retinal cell types appear to be specified in the absence of the Snf2h function, cell-cycle defects and concomitantly increased apoptosis in Snf2h cKO result in abnormal retina lamination, complete destruction of the photoreceptor layer, and consequently, a physiologically non-functional retina.

• MeSH
• adenosintrifosfatasy * metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• chromatin * metabolismus   MeSH
• chromozomální proteiny, nehistonové * metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• proliferace buněk MeSH
• restrukturace chromatinu * MeSH
• retina MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The vertebrate eye is derived from the neuroepithelium, surface ectoderm, and extracellular mesenchyme. The neuroepithelium forms an optic cup in which the spatial separation of three domains is established, namely, the region of multipotent retinal progenitor cells (RPCs), the ciliary margin zone (CMZ)-which possesses both a neurogenic and nonneurogenic potential-and the optic disk (OD), the interface between the optic stalk and the neuroretina. Here, we show by genetic ablation in the developing optic cup that Meis1 and Meis2 homeobox genes function redundantly to maintain the retinal progenitor pool while they simultaneously suppress the expression of genes characteristic of CMZ and OD fates. Furthermore, we demonstrate that Meis transcription factors bind regulatory regions of RPC-, CMZ-, and OD-specific genes, thus providing a mechanistic insight into the Meis-dependent gene regulatory network. Our work uncovers the essential role of Meis1 and Meis2 as regulators of cell fate competence, which organize spatial territories in the vertebrate eye.

• MeSH
• buněčná diferenciace genetika   MeSH
• genový knockdown MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• kmenové buňky cytologie   metabolismus   MeSH
• obratlovci MeSH
• retina cytologie   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Článek seznamuje stručně se současnými možnostmi léčby dystrofií sítnice. V počínajících stadiích chorob mají své uplatnění medikamentózní léčba zahrnující vitaminoterapii a farmakologickou léčbu, elektrostimulace a genová terapie. Zkoumána je účinnost neuroprotektivních substancí aplikovaných prostřednictvím technologie tzv. „opouzdřených buněk“ a systémové imunoterapie. V pokročilých stadiích sítnicových chorob spojených se ztrátou fotoreceptorů se používají elektronické sítnicové protézy a ověřuje se možnost použití kmenových buněk, transplantace buněk a tkání a optogenetické léčby.

There is a brief review of actual treatment possibilities of retinal dystrophies in this article. Vitaminotherapy, electrostimulation and gene therapy are used in beginning stages of disorders. The efficiency of neuroprotective substances that are applied intravitreally using encapsulated cell technology is examined, as well as influence of systemic immunotherapy. In advanced stages of retinal diseases that are connected with loss of photoreceptors are used electronic retinal prostheses. Effectivity of treatment with stem cells, transplantation of cells and tissues and optogenetic therapy are evaluated.

• MeSH
• elektrická stimulace MeSH
• genetická terapie MeSH
• genetické nemoci vrozené MeSH
• klinické zkoušky jako téma MeSH
• kmenové buňky MeSH
• lidé MeSH
• nemoci retiny * genetika   terapie   MeSH
• neuroprotektivní látky MeSH
• optogenetika MeSH
• protézy a implantáty MeSH
• retina metabolismus   MeSH
• terapie * trendy   MeSH
• vitamin A aplikace a dávkování   terapeutické užití   MeSH
• výzkum MeSH
• Check Tag
• lidé 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.

• MeSH
• antivirové látky farmakologie   MeSH
• cytokiny metabolismus   MeSH
• imunomodulace účinky léků   imunologie   MeSH
• interferon gama farmakologie   MeSH
• interleukin-1beta farmakologie   MeSH
• mediátory zánětu farmakologie   MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• oxid dusnatý metabolismus   MeSH
• retina cytologie   účinky léků   imunologie   metabolismus   MeSH
• TNF-alfa farmakologie   MeSH
• zánět imunologie   metabolismus   patologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The aim of our study was to compare the effect of bone marrow mononuclear cell and peripheral blood progenitor cell therapies in patients with diabetic foot disease and critical limb ischaemia unresponsive to revascularization with conservative therapy. METHODS: Twenty-eight patients with diabetic foot disease (17 treated by bone marrow cells and 11 by peripheral blood cell) were included into an active group and 22 patients into a control group without cell treatment. Transcutaneous oxygen pressure and rate of major amputation, as the main outcome measures, were compared between bone marrow cells, peripheral blood cell and control groups over 6 months; both cell therapy methods were also compared by the characteristics of cell suspensions. Possible adverse events were evaluated by changes of serum levels of angiogenic cytokines and retinal fundoscopic examination. RESULTS: The transcutaneous oxygen pressure increased significantly (p < 0.05) compared with baseline in both active groups after 6 months, with no significant differences between bone marrow cells and peripheral blood cell groups; however, no change of transcutaneous oxygen pressure in the control group was observed. The rate of major amputation by 6 months was significantly lower in the active cell therapy group compared with that in the control group (11.1% vs. 50%, p = 0.0032), with no difference between bone marrow cells and peripheral blood cell. A number of injected CD34+ cells and serum levels of angiogenic cytokines after treatment did not significantly differ between bone marrow cells and peripheral blood cell. CONCLUSIONS: Our study showed a superior benefit of bone marrow cells and peripheral blood cell treatments of critical limb ischaemia in patients with diabetic foot disease when compared with conservative therapy. There was no difference between both cell therapy groups, and no patient demonstrated signs of systemic vasculogenesis.

• MeSH
• antigeny CD34 metabolismus   MeSH
• autologní transplantace MeSH
• cytokiny krev   MeSH
• diabetická noha imunologie   patofyziologie   chirurgie   terapie   MeSH
• dolní končetina MeSH
• ischemie etiologie   prevence a kontrola   MeSH
• leukocyty mononukleární imunologie   metabolismus   transplantace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• senioři MeSH
• transkutánní měření krevních plynů MeSH
• transplantace kostní dřeně * škodlivé účinky   imunologie   MeSH
• transplantace periferních kmenových buněk * škodlivé účinky   MeSH
• záchrana končetiny * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH