學術資源整合系統-相關推薦
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| 作者 | Peng SY, Chen CY, Chen H, Yang YP,;Wang ML, Tsai FT, Chien CS, Weng PY, Tsai ET,;Wang IC, Hsu CC, Lin TC, Hwang DK,;Chen SJ, Chiou SH, Chiao C.-C., Chien Y. |
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| 出版日期 | 2024 |
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| 著作名稱 | Inhibition of angiogenesis by the secretome from iPSC-derived retinal ganglion cells with Leber's hereditary optic neuropathy-like phenotypes
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| 刊名 | Biomed Pharmacother |
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| 期 | 178 |
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| 被收錄索引 | SCI |
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| 主題 | 動物 |
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| 關鍵字 | Leber’s hereditary optic neuropathy; Retinal ganglion cells (RGCs); Rotenone; Human umbilical vein endothelial cells; Angiogenesis |
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| 摘要 | The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature. |
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| DOI | https://doi.org/10.1016/j.biopha.2024.117270 |
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| 系統號 | NO000007257 |
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