Overexpression of pigment epithelium-derived factor in placenta-derived mesenchymal stem cells promotes mitochondrial biogenesis in retinal cells

Abstract

Pigment epithelium-derived factor (PEDF) plays a role in protecting retinal pigment epithelial (RPE) cells from oxidative stress (OS), a causative factor of RPE cell death. Genetically modified mesenchymal stem cells (MSCs) can be used to treat critical and incurable retinal diseases. Here, we overexpressed PEDF in placenta-derived MSCs (PD-MSCsPEDF, PEDF+) using a nonviral gene delivery system and evaluated the characteristics of PD-MSCsPEDF and their potential regenerative effects on RPE cells damaged by H2O2-induced OS. PD-MSCsPEDF maintained their stemness, cell surface marker, and differentiation potential characteristics. Compared to naive cells, PD-MSCsPEDF promoted mitochondrial respiration by enhancing biogenesis regulators (e.g., NRF1, PPARGC1A, and TFAM) as well as antioxidant enzymes (e.g., HMOXs, SODs, and GPX1). Compared to OS-damaged RPE cells cocultured with naive cells, OS-damaged RPE cells cocultured with PD-MSCsPEDF showed PEDF upregulation and VEGF downregulation. The expression levels of antioxidant genes and RPE-specific genes, such as RPE65, RGR, and RRH, were significantly increased in RPE cells cocultured with PD-MSCsPEDF. Furthermore, OS-damaged RPE cells cocultured with PD-MSCsPEDF had dramatically enhanced mitochondrial functions, and antiapoptotic effects improved due to cell survival signaling pathways. In the H2O2-induced retinal degeneration rat model, compared to administration of the naive counterpart, intravitreal administration of PD-MSCsPEDF alleviated proinflammatory cytokines and restored retinal structure and function by increasing PEDF expression and decreasing VEGF expression. Intravitreal administration of PD-MSCsPEDF also protected retinal degeneration against OS by increasing antioxidant gene expression and regulating the mitochondrial ROS levels and biogenesis. Taken together, PEDF overexpression in PD-MSCs improved the mitochondrial activities and induced OS-damaged RPE cell regeneration by regulating the oxidative status and mitochondrial biogenesis in vitro and in vivo. These data suggest that genetic modification of PEDF in PD-MSCs might be a new cell therapy for the treatment of retinal degenerative diseases.

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Fig. 1: Characteristics of PEDF-overexpressing PD-MSCs (PD-MSCsPEDF, PEDF+).
Fig. 2: PEDF overexpression enhances mitochondrial biogenesis in PD-MSCs.
Fig. 3: PD-MSCsPEDF promote antioxidant activities and RPE-specific gene expression in oxidative stress-induced RPE cells by H2O2.
Fig. 4: PD-MSCsPEDF decrease the cellular ROS levels in oxidative stress-induced RPE cells by H2O2.
Fig. 5: PD-MSCsPEDF decrease the mitochondrial ROS levels and promote mitochondrial biogenesis in oxidative stress-induced RPE cells by H2O2.
Fig. 6: PD-MSCsPEDF promote antiapoptotic activities and cell survival in oxidative stress-induced RPE cells through the JNK/ERK signaling pathway.
Fig. 7: Administration of PD-MSCsPEDF restores retinal functions by alleviating inflammation in the oxidative stress-induced animal model.
Fig. 8: PD-MSCsPEDF have a prominent effect on mitochondrial biogenesis to protect against oxidative stress in H2O2-injured rats.
Fig. 9: Summarized illustration of the effect of PD-MSCsPEDF on mitochondrial function for RPE regeneration.

Data availability

All data analyzed for this study are included in this article.

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Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI16C1559) and by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (grant number: 2019R1l1A1A01057255). We thank Ho Jeong Kim (CHA University) for helping us with the graphical abstract.

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JYK: analysis of data, data interpretation, manuscript drafting; SP: data interpretation and manuscript drafting; SHP: animal experiment and data interpretation; DL, GHK, and JEN: data interpretation and analysis of data; KJL: critical discussion; GJK: conception and design, manuscript drafting, financial support, and final approval of manuscript.

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Correspondence to Gi Jin Kim.

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Kim, J.Y., Park, S., Park, S.H. et al. Overexpression of pigment epithelium-derived factor in placenta-derived mesenchymal stem cells promotes mitochondrial biogenesis in retinal cells. Lab Invest (2020). https://doi.org/10.1038/s41374-020-0470-z

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