Overexpression of pigment epithelium-derived factor in placenta-derived mesenchymal stem cells promotes mitochondrial biogenesis in retinal cells
| Autor: | Jae Yeon Kim, Gyu Hyun Kim, Gi Jin Kim, Jung Eun Noh, Sohae Park, Kea Joo Lee, Dongsook Lee, Sohyun Park |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Retinal degeneration Mitochondrial ROS MAP Kinase Signaling System Retinal Pigment Epithelium Mesenchymal Stem Cell Transplantation Antioxidants Pathology and Forensic Medicine Rats Sprague-Dawley Cell therapy 03 medical and health sciences 0302 clinical medicine PEDF medicine Animals Humans Regeneration Nerve Growth Factors NRF1 Eye Proteins Molecular Biology Serpins Organelle Biogenesis Chemistry Retinal Degeneration Mesenchymal stem cell Mesenchymal Stem Cells Cell Biology TFAM medicine.disease Mitochondria Cell biology Oxidative Stress 030104 developmental biology Mitochondrial biogenesis 030220 oncology & carcinogenesis sense organs Reactive Oxygen Species |
| Zdroj: | Laboratory Investigation. 101:51-69 |
| ISSN: | 0023-6837 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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