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Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis

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  • Katerina Rohlenova, Leuven Cancer Institute, Leuven, Belgium
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  • Jermaine Goveia, Leuven Cancer Institute, Leuven, Belgium
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  • Melissa García-Caballero, Leuven Cancer Institute, Leuven, Belgium
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  • Abhishek Subramanian, Leuven Cancer Institute, Leuven, Belgium
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  • Joanna Kalucka
  • Lucas Treps, Leuven Cancer Institute, Leuven, Belgium
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  • Kim D Falkenberg, Leuven Cancer Institute, Leuven, Belgium
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  • Laura P M H de Rooij, Leuven Cancer Institute, Leuven, Belgium
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  • Yingfeng Zheng, Sun Yat-Sen University
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  • Lin Lin
  • Liliana Sokol, Leuven Cancer Institute, Leuven, Belgium
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  • Laure-Anne Teuwen, Leuven Cancer Institute, Leuven, Belgium, Translational Cancer Research Unit, GZA Hospitals, Sint-Augustinus & University of Antwerp, Antwerp, Belgium.
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  • Vincent Geldhof, Leuven Cancer Institute, Leuven, Belgium
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  • Federico Taverna, Leuven Cancer Institute, Leuven, Belgium
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  • Andreas Pircher, Leuven Cancer Institute, Leuven, Belgium
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  • Lena-Christin Conradi, Leuven Cancer Institute, Leuven, Belgium
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  • Shawez Khan, Leuven Cancer Institute, Leuven, Belgium
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  • Steve Stegen, KU Leuven
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  • Dena Panovska, KU Leuven
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  • Frederik De Smet, KU Leuven
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  • Frank J T Staal, Leiden University Medical Center
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  • Rene J Mclaughlin, Leiden University Medical Center
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  • Stefan Vinckier, Leuven Cancer Institute, Leuven, Belgium
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  • Tine Van Bergen, OXURION NV, Leuven 3001, Belgium.
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  • Nadine Ectors, KU Leuven
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  • Patrik De Haes, OXURION NV, Leuven 3001, Belgium.
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  • Jian Wang, BGI-Shenzhen, China National GeneBank
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  • Lars Bolund
  • Luc Schoonjans, Leuven Cancer Institute, Leuven, Belgium, Sun Yat-Sen University
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  • Tobias K Karakach, Leuven Cancer Institute, Leuven, Belgium
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  • Huanming Yang, BGI-Shenzhen, China National GeneBank
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  • Geert Carmeliet, KU Leuven
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  • Yizhi Liu, Sun Yat-Sen University
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  • Bernard Thienpont, KU Leuven
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  • Mieke Dewerchin, Leuven Cancer Institute, Leuven, Belgium
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  • Guy Eelen, Leuven Cancer Institute, Leuven, Belgium
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  • Xuri Li, Sun Yat-Sen University
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  • Yonglun Luo
  • Peter Carmeliet

Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell-cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets.

Original languageEnglish
JournalCell Metabolism
Volume31
Issue4
Pages (from-to)862-877.e14
Number of pages30
ISSN1550-4131
DOIs
Publication statusPublished - Apr 2020

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