Inhibition of angiogenesis by the secretome from iPSC-derived retinal ganglion cells with Leber's hereditary optic neuropathy-like phenotypes.

Autor: Peng SY; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC., Chen CY; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC., Chen H; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC; Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC., Yang YP; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC; Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan, ROC., Wang ML; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC; Institute of Food Safety and Health Risk Assessment, School of Pharmaceutical Sciences, National Yang-Ming Chiao Tung University, Taipei 11221, Taiwan, ROC., Tsai FT; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC., Chien CS; Institute of Physiology, National Yang Ming Chiao Tung University, Taiwan, ROC., Weng PY; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC., Tsai ET; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC., Wang IC; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC., Hsu CC; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC., Lin TC; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC., Hwang DK; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC., Chen SJ; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC., Chiou SH; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC; Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan, ROC; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC; Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC. Electronic address: shchiou@vghtpe.gov.tw., Chiao CC; Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC. Electronic address: ccchiao@life.nthu.edu.tw., Chien Y; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC. Electronic address: g39005005@gmail.com.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2024 Sep; Vol. 178, pp. 117270. Date of Electronic Publication: 2024 Aug 11.
DOI: 10.1016/j.biopha.2024.117270
Abstrakt: 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.)
Databáze: MEDLINE
Externí odkaz: