Sphingosine-1-Phosphate Is a Crucial Signal for Migration of Retina Müller Glial Cells

Simón, M. Victoria; Spalm, Facundo H. Prado; Politi, Luis E.; Rotstein, Nora P.

doi:10.1167/iovs.14-16195

Cited by 27 publications

(23 citation statements)

References 43 publications

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“…Although the mechanisms responsible for glial proliferation are not completely elucidated, the X‐linked inhibitor for apoptosis protein (XIAP) has been implicated in the induction of this process (Sun et al., ). While the migratory capacity is regulated by stimuli of a different nature, such as protease inhibitors (α 2 M), trophic factors (IGF‐1) and lipids (Sphingosine‐1‐Phosphate) (Barcelona, Jaldin‐Fincati, Sanchez, & Chiabrando, ; Lorenc et al., ; Simon, Prado Spalm, Politi, & Rotstein, ).…”

Section: Gliosismentioning

confidence: 99%

A journey into the retina: Müller glia commanding survival and death

Subirada

Paz

Ridano

et al. 2018

Eur J of Neuroscience

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Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?

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Section: Gliosismentioning

confidence: 99%

A journey into the retina: Müller glia commanding survival and death

Subirada

Paz

Ridano

et al. 2018

Eur J of Neuroscience

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“…Purified cultures of M€ uller glial cells were prepared using adapted protocols previously described (Sim on et al 2015). Briefly, eyes from 3-to 4-day-old female CD1 mice pups were excised and incubated overnight in Dulbecco's modified Eagle's medium (DMEM) (Gibco) at 18-22°C and then treated with trypsin (1 mg/mL; Gibco, Rockville, MD, USA) and type 2 collagenase (2 mg/mL; Sigma, St Louis, MO, USA) for 10 min at 37°C.…”

Section: M€ Uller Cells Enriched Primary Culturementioning

confidence: 99%

Epigenetic control of early neurodegenerative events in diabetic retinopathy by the histone deacetylase SIRT6

Zorrilla-Zubilete

Yeste

Quintana

et al. 2017

Journal of Neurochemistry

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Diabetic retinopathy (DR) is one of the common complications associated with diabetes mellitus and the leading cause of blindness worldwide. Recent research has demonstrated that DR is not only a microvascular disease but may be a result of neurodegenerative processes. Moreover, glucose-induced neuron and glial cell damage may occur shortly after the onset of diabetes which makes the disease hard to diagnose at early stages. SIRT6, a NAD-dependent sirtuin deacylase, modulates aging, energy metabolism, and neurodegeneration. In previous studies we showed that SIRT6 deficiency causes major retinal transmission defects, changes in the expression of glycolytic genes, and elevated levels of apoptosis. Given the importance of glucose availability for retinal function and the critical role of SIRT6 in modulating glycolysis, we aimed to analyze SIRT6 participation in the molecular machinery that regulates the development of experimental DR. Using non-obese diabetic mice, we determined by western blot that 2 weeks after the onset of the disease, high glucose concentrations induced retinal increase in a neovascularization promoting factor (vascular endothelial growth factor, VEGF), and the loss of a neuroprotective factor (brain-derived neurotrophic factor, BDNF) associated with reduced levels of SIRT6 and increased acetylation levels of its substrates (H3K9 and H3K56) suggesting a deregulation of key neural factors. Noteworthy, retinas from CNS conditionally deleted SIRT6 mice showed a resemblance to diabetic retinas exhibiting lower protein levels of BDNF factor and increased protein levels of VEGF. Moreover, cultured Müller glial cells subjected to high glucose concentrations exhibited decreased levels of SIRT6 and increased levels of H3K56 acetylation. In addition, the increment of VEGF levels induced by high glucose was reverted by the over-expression of SIRT6 in this cell type. Accordingly, siRNA experiments showed that, when SIRT6 was silenced, VEGF levels increased. Our findings suggest that epigenetically regulated neurodegenerative events may occur at an early diabetic stage prior to the characteristic proliferative and vascular changes observed at a later diabetic stage.

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“…S1P, the catalytic product of Sphk2, is known to participate in stimulating angiogenesis and vessel maturation. 43 The functional role of S1P in the retina has been investigated in recent studies, creating evidence for its important contribution to retinal pathologies, 29 retinal and choroidal neovascularization, 30 and profibrotic and proinflammatory responses in pigment epithelium cells. 44,45 We demonstrate that genetic modulation of Sphk2 with corresponding changes of retinal S1P levels leads to a profound alteration of angiogenesis and accelerated neovascularization during OIR.…”

Section: Discussionmentioning

confidence: 99%

“…However, S1P is a key regulator of angiogenesis and vessel stabilization [26][27][28] and a decisive factor in retinal pathologies, 19 contributing to retinal and choroidal neovascularization. [29][30][31][32] S1P mainly exerts its biological effects via five membranebound G protein-coupled receptors, S1PR1 to S1PR5. 33 In addition, Sphk2 inhibition was reported to reduce disease severity in diabetic retinopathy.…”

mentioning

confidence: 99%

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

Eresch

Stumpf

Koch

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neovascularization is a major cause of blindness in various ocular diseases. Bioactive sphingosine 1-phosphate (S1P), synthesized by two sphingosine kinases (Sphk1, Sphk2), emerged as a key player in a multitude of cellular processes, including cell survival, proliferation, inflammation, migration, and angiogenesis. We investigated the role of Sphk2, S1P, and S1P receptors (S1PR) during retinal neovascularization using the oxygen-induced retinopathy mouse model (OIR). METHODS. Sphk2 overexpressing (tgSphk2) and Sphk2 knockout (Sphk2) mice were used in the OIR model, exposed to 75% O 2 over 5 days from postnatal day (P)7 to 12 to initiate vessel regression. After returning to room air, these mice developed a marked neovascularization. Retinae recovered from untreated and treated eyes at P7, P12, P14, and P17 were used for lectin-stained retinal whole mounts, mass spectrometry, and quantitative real-time PCR.RESULTS. tgSphk2 mice showed higher retinal S1P concentrations, accelerated retinal angiogenesis, and increased neovascularization. Expression of S1PR, vascular endothelial growth factor a (VEGFa), and angiopoietin 1 and 2 was differentially regulated during the course of OIR in the different genotypes. Sphk2À/À displayed a markedly reduced retinal angiogenesis and neovascularization as well as decreased VEGFa and angiopoietin expression.CONCLUSIONS. Using genetic models of Sphk2 overexpression or deletion we demonstrate a strong impact of Sphk2/S1P on retinal vasculopathy and expression of vascular growth factors like VEGF and angiopoietin in the retina. Consequently, Sphk2, S1P, and S1PR may offer attractive novel therapeutic targets for ischemic retinopathies.

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Sphingosine-1-Phosphate Is a Crucial Signal for Migration of Retina Müller Glial Cells

Cited by 27 publications

References 43 publications

A journey into the retina: Müller glia commanding survival and death

A journey into the retina: Müller glia commanding survival and death

Epigenetic control of early neurodegenerative events in diabetic retinopathy by the histone deacetylase SIRT6

Sphingosine Kinase 2 Modulates Retinal Neovascularization in the Mouse Model of Oxygen-Induced Retinopathy

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