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

Shih-Yuan Peng; Chih-Ying Chen; Hsin Chen; Yi-Ping Yang; Mong-Lien Wang; Fu-Ting Tsai; Chian-Shiu Chien; Pei-Yu Weng; En-Tung Tsai; I-Chieh Wang; Chih-Chien Hsu; Tai-Chi Lin; De-Kuang Hwang; Shih-Jen Chen; Shih-Hwa Chiou; Chuan-Chin Chiao; Yueh Chien

Biomedicine & Pharmacotherapy (Sep 2024)

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

Shih-Yuan Peng,
Chih-Ying Chen,
Hsin Chen,
Yi-Ping Yang,
Mong-Lien Wang,
Fu-Ting Tsai,
Chian-Shiu Chien,
Pei-Yu Weng,
En-Tung Tsai,
I-Chieh Wang,
Chih-Chien Hsu,
Tai-Chi Lin,
De-Kuang Hwang,
Shih-Jen Chen,
Shih-Hwa Chiou,
Chuan-Chin Chiao,
Yueh Chien

Affiliations

Shih-Yuan Peng: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC
Chih-Ying Chen: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC
Hsin Chen: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC; Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC
Yi-Ping Yang: 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
Mong-Lien Wang: 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
Fu-Ting Tsai: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC
Chian-Shiu Chien: Institute of Physiology, National Yang Ming Chiao Tung University, Taiwan, ROC
Pei-Yu Weng: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC
En-Tung Tsai: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC
I-Chieh Wang: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC
Chih-Chien Hsu: Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC
Tai-Chi Lin: Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC
De-Kuang Hwang: Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC
Shih-Jen Chen: Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan, ROC
Shih-Hwa Chiou: 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; Corresponding author at: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC.
Chuan-Chin Chiao: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300044, Taiwan, ROC; Corresponding authors.
Yueh Chien: Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ROC; Corresponding authors.

Journal volume & issue: Vol. 178
p. 117270

Abstract

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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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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