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Pigment epithelium-derived factor released by Müller glial cells exerts neuroprotective effects on retinal ganglion cells.

Unterlauft JD, Eichler W, Kuhne K, Yang XM, Yafai Y, Wiedemann P, Reichenbach A, Claudepierre T - Neurochem. Res. (2012)

Bottom Line: Using Müller cell-RGC-co-cultures we observed that activity of Müller-cell derived soluble mediators can attenuate hypoxia-induced damage and RGC loss.Finally, neutralizing the activity of PEDF in glia-conditioned media partially abolished the neuroprotective effect of glia, leading to an increased neuronal death in hypoxic condition.Altogether our results suggest that PEDF is crucially involved in the neuroprotective process of reactive Müller cells towards RGC.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Liebigstrasse 10-14, 04103, Leipzig, Germany.

ABSTRACT
Survival of retinal ganglion cells (RGC) is compromised in several vision-threatening disorders such as ischemic and hypertensive retinopathies and glaucoma. Pigment epithelium-derived factor (PEDF) is a naturally occurring pleiotropic secreted factor in the retina. PEDF produced by retinal glial (Müller) cells is suspected to be an essential component of neuron-glial interactions especially for RGC, as it can protect this neuronal type from ischemia-induced cell death. Here we show that PEDF treatment can directly affect RGC survival in vitro. Using Müller cell-RGC-co-cultures we observed that activity of Müller-cell derived soluble mediators can attenuate hypoxia-induced damage and RGC loss. Finally, neutralizing the activity of PEDF in glia-conditioned media partially abolished the neuroprotective effect of glia, leading to an increased neuronal death in hypoxic condition. Altogether our results suggest that PEDF is crucially involved in the neuroprotective process of reactive Müller cells towards RGC.

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Effect of neutralizing anti-PEDF antibody Müller cell-promoted RGC survival in co-cultures is suppressed by a neutralizing anti-PEDF antibody in both normoxic and hypoxic conditions (n = 4; anti-PEDF vs. control cultures, *P < 0.05; control hypoxic versus normoxic control cultures, •P < 0.05). Co-cultures were maintained in the presence of an anti-PEDF antibody (+) or normal goat immunoglobulin in control cultures (−)
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Fig4: Effect of neutralizing anti-PEDF antibody Müller cell-promoted RGC survival in co-cultures is suppressed by a neutralizing anti-PEDF antibody in both normoxic and hypoxic conditions (n = 4; anti-PEDF vs. control cultures, *P < 0.05; control hypoxic versus normoxic control cultures, •P < 0.05). Co-cultures were maintained in the presence of an anti-PEDF antibody (+) or normal goat immunoglobulin in control cultures (−)

Mentions: To determine whether Müller-cell derived PEDF contributes to the observed neuroprotection, a neutralizing anti-PEDF antibody was added to the cultures (Fig.4). We previously used this antibody to neutralize PEDF-mediated functions in retinal endothelial cells [9] and employed it here at 3 μg/ml to fully deplete the glia-conditioned medium from PEDF. Under normoxic and hypoxic conditions, the increasing survival rate induced by Müller-cell derived soluble mediators (71 ± 6% and 46 ± 2% respectively) was significantly impaired by the antibody treatment of co-cultures with a resulting survival rate of 50 ± 6% and 34 ± 3% in normoxia and hypoxia respectively. In homotypic RGC cultures, there was no effect of antibody treatment on RGC survival, which amounted to a level similar to that in the absence of PEDF, indicating the absence of antibody toxicity toward RGC (data not shown). Overall, these results suggest that PEDF represents an essential soluble mediator contributing to the survival-enhancing activity of Müller cell-derived factors.Fig. 4


Pigment epithelium-derived factor released by Müller glial cells exerts neuroprotective effects on retinal ganglion cells.

Unterlauft JD, Eichler W, Kuhne K, Yang XM, Yafai Y, Wiedemann P, Reichenbach A, Claudepierre T - Neurochem. Res. (2012)

Effect of neutralizing anti-PEDF antibody Müller cell-promoted RGC survival in co-cultures is suppressed by a neutralizing anti-PEDF antibody in both normoxic and hypoxic conditions (n = 4; anti-PEDF vs. control cultures, *P < 0.05; control hypoxic versus normoxic control cultures, •P < 0.05). Co-cultures were maintained in the presence of an anti-PEDF antibody (+) or normal goat immunoglobulin in control cultures (−)
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368109&req=5

Fig4: Effect of neutralizing anti-PEDF antibody Müller cell-promoted RGC survival in co-cultures is suppressed by a neutralizing anti-PEDF antibody in both normoxic and hypoxic conditions (n = 4; anti-PEDF vs. control cultures, *P < 0.05; control hypoxic versus normoxic control cultures, •P < 0.05). Co-cultures were maintained in the presence of an anti-PEDF antibody (+) or normal goat immunoglobulin in control cultures (−)
Mentions: To determine whether Müller-cell derived PEDF contributes to the observed neuroprotection, a neutralizing anti-PEDF antibody was added to the cultures (Fig.4). We previously used this antibody to neutralize PEDF-mediated functions in retinal endothelial cells [9] and employed it here at 3 μg/ml to fully deplete the glia-conditioned medium from PEDF. Under normoxic and hypoxic conditions, the increasing survival rate induced by Müller-cell derived soluble mediators (71 ± 6% and 46 ± 2% respectively) was significantly impaired by the antibody treatment of co-cultures with a resulting survival rate of 50 ± 6% and 34 ± 3% in normoxia and hypoxia respectively. In homotypic RGC cultures, there was no effect of antibody treatment on RGC survival, which amounted to a level similar to that in the absence of PEDF, indicating the absence of antibody toxicity toward RGC (data not shown). Overall, these results suggest that PEDF represents an essential soluble mediator contributing to the survival-enhancing activity of Müller cell-derived factors.Fig. 4

Bottom Line: Using Müller cell-RGC-co-cultures we observed that activity of Müller-cell derived soluble mediators can attenuate hypoxia-induced damage and RGC loss.Finally, neutralizing the activity of PEDF in glia-conditioned media partially abolished the neuroprotective effect of glia, leading to an increased neuronal death in hypoxic condition.Altogether our results suggest that PEDF is crucially involved in the neuroprotective process of reactive Müller cells towards RGC.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, Liebigstrasse 10-14, 04103, Leipzig, Germany.

ABSTRACT
Survival of retinal ganglion cells (RGC) is compromised in several vision-threatening disorders such as ischemic and hypertensive retinopathies and glaucoma. Pigment epithelium-derived factor (PEDF) is a naturally occurring pleiotropic secreted factor in the retina. PEDF produced by retinal glial (Müller) cells is suspected to be an essential component of neuron-glial interactions especially for RGC, as it can protect this neuronal type from ischemia-induced cell death. Here we show that PEDF treatment can directly affect RGC survival in vitro. Using Müller cell-RGC-co-cultures we observed that activity of Müller-cell derived soluble mediators can attenuate hypoxia-induced damage and RGC loss. Finally, neutralizing the activity of PEDF in glia-conditioned media partially abolished the neuroprotective effect of glia, leading to an increased neuronal death in hypoxic condition. Altogether our results suggest that PEDF is crucially involved in the neuroprotective process of reactive Müller cells towards RGC.

Show MeSH
Related in: MedlinePlus