Abstract
Retinal degenerative diseases result from oxidative stress and mitochondrial dysfunction, leading to the loss of visual acuity. Damaged retinal pigment epithelial (RPE) and photoreceptor cells undergo mitophagy. Pigment epithelium-derived factor (PEDF) protects from oxidative stress in RPE and improves mitochondrial functions. Overexpression of PEDF in placenta-derived mesenchymal stem cells (PD-MSCs; PD-MSCsPEDF) provides therapeutic effects in retinal degenerative diseases. Here, we investigated whether PD-MSCsPEDF restored the visual cycle through a mitophagic mechanism in RPE cells in hydrogen peroxide (H2O2)-injured rat retinas. Compared with naïve PD-MSCs, PD-MSCsPEDF augmented mitochondrial biogenesis and translation markers as well as mitochondrial respiratory states. In the H2O2-injured rat model, intravitreal administration of PD-MSCsPEDF restored total retinal layer thickness compared to that of naïve PD-MSCs. In particular, PTEN-induced kinase 1 (PINK1), which is the major mitophagy marker, exhibited increased expression in retinal layers and RPE cells after PD-MSCPEDF transplantation. Similarly, expression of the visual cycle enzyme retinol dehydrogenase 11 (RDH11) showed the same patterns as PINK1 levels, resulting in improved visual activity. Taken together, these findings suggest that PD-MSCsPEDF facilitate mitophagy and restore the loss of visual cycles in H2O2-injured rat retinas and RPE cells. These data indicate a new strategy for next-generation MSC-based treatment of retinal degenerative diseases.
Highlights
Retinal degenerative diseases are heterogeneous conditions and include diabetic retinopathy and age-related macular degeneration (AMD) [1]
We found that overexpressed pigment epithelium-derived factor (PEDF) in placenta-derived mesenchymal stem cells (PD-mesenchymal stem cell (MSC)) (PD-MSCsPEDF) improved antioxidant effects and mitochondrial biogenesis associated with retinal regeneration in a H2O2-injured rat model and retinal pigment epithelial (RPE) cells [22]
We focused on recovery of the visual cycle through mitophagy and mitochondrial functions by PD-MSCPEDF in a H2O2-injured rat model and RPE cells
Summary
Retinal degenerative diseases are heterogeneous conditions and include diabetic retinopathy and age-related macular degeneration (AMD) [1]. The stages of AMD include hard drusen, which is associated with localized malfunctions of the retinal pigment epithelium, soft drusen associated with diffuse dysfunction of the retinal pigment epithelium, and damage to photoreceptors [4]. Pigment epithelium-derived factor (PEDF), which is produced in retinal pigment epithelial (RPE) cells and maintains retinal homeostasis, is decreased, while the expression of vascular endothelial growth factor (VEGF) is increased [5,6]. In a diabetic mouse model, PEDF has antioxidant effects that protect against oxidative stress by promoting cell survival and reducing pathological angiogenesis [10]. PEDF treatment prevents oxidative stress by improving mitochondrial structure and function and activating the PI3K/AKT and MAPK pathways in H2O2-injured RPE cells [11]
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