Abstract
Dedifferentiation of retinal pigment epithelium (RPE) cells is a crucial contributing factor to the pathology of retinal degenerative diseases, including age-related macular degeneration (AMD). Herein, we aim to reveal the roles of microRNAs (miRNAs) in RPE dedifferentiation and seek for potential therapeutic targets. Based on the microarray data, miR-184 was sorted out as the most up-regulated signature along with the differentiation from human induced pluripotent stem cells (hiPSC) to RPE cells, suggesting its potential promotive role in RPE differentiation. In vitro study indicated that miR-184 insufficiency suppressed RPE differentiation, typified by reduction of RPE markers, and promoted cell proliferation and migration. The role of miR-184 in maintaining regular RPE function was further proved in zebrafish studies. We also noticed that miR-184 expression was reduced in the macular RPE-choroid from a donor with RPE dysfunction compared to a healthy control. We next demonstrated that RAC-beta serine/threonine-protein kinase (AKT2) was a direct target for miR-184. MiR-184 promoted RPE differentiation via suppression of AKT2/mammalian target of rapamycin (mTOR) signaling pathway. We also found that AKT2 was up-regulated in macular RPE-choroid of the donor with RPE dysfunction and dry AMD patients. Taken together, our findings suggest that miR-184 insufficiency is involved in the pathogenesis of dry AMD. MiR-184 promotes RPE differentiation via inhibiting the AKT2/mTOR signaling pathway. MiR-184 based supplementary therapeutics and mTOR blocker, like rapamycin, are prospective options for AMD treatment.
Highlights
Retinal pigment epithelium (RPE) is a cuboidal, polarized, and pigmented epithelial cell layer located in the outer retina between the light-sensitive outer segments of photoreceptors and choroidal vasculature forming a part of the blood/retina barrier [1, 2]
Pluripotency of the undifferentiated human induced pluripotent stem cells colonies was confirmed via positive immunostaining for four pluripotency relevant markers, including octamer-binding protein 4 (Oct-4) (Figure 1A), transcription factor SOX-2 (Figure 1B), stagespecific embryonic antigen-4 (SSEA-4) (Figure 1C), and
We showed that AKT2 overexpression abrogated the hsa-miR-184 mediated retinal pigment epithelium (RPE) differentiation (Figure 5F)
Summary
Retinal pigment epithelium (RPE) is a cuboidal, polarized, and pigmented epithelial cell layer located in the outer retina between the light-sensitive outer segments of photoreceptors and choroidal vasculature forming a part of the blood/retina barrier [1, 2]. Age-related macular degeneration (AMD), among the most common polygenic retinal degenerative diseases, is a worldwide leading cause for irreversible visual impairments in people aged over 55 [7,8,9]. Atrophic AMD is characterized by subepithelial deposits and degeneration of RPE and photoreceptors involving but not limited to the macular region [8]. Epithelium dedifferentiation, typified by reduction of RPE markers and cellular hypertrophy, has been identified as a crucial process in atrophic AMD [1].
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