1. Inhibition of angiogenesis by the secretome from iPSC-derived retinal ganglion cells with Leber's hereditary optic neuropathy-like phenotypes.
- Author
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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 CC, and Chien Y
- Subjects
- Humans, Mitochondria drug effects, Mitochondria metabolism, Phenotype, Reactive Oxygen Species metabolism, Rotenone pharmacology, Culture Media, Conditioned pharmacology, Apoptosis drug effects, Electron Transport Complex I metabolism, Membrane Potential, Mitochondrial drug effects, Neovascularization, Pathologic metabolism, Angiogenesis, Optic Atrophy, Hereditary, Leber metabolism, Optic Atrophy, Hereditary, Leber pathology, Optic Atrophy, Hereditary, Leber genetics, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells drug effects, Retinal Ganglion Cells metabolism, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells pathology
- Abstract
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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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