2. Academic Validation
  3. Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis

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

  • Cell Metab. 2020 Apr 7;31(4):862-877.e14. doi: 10.1016/j.cmet.2020.03.009.
Katerina Rohlenova 1,  Jermaine Goveia 1,  Melissa García-Caballero 1,  Abhishek Subramanian 1,  Joanna Kalucka 1,  Lucas Treps 1,  Kim D Falkenberg 1,  Laura P M H de Rooij 1,  Yingfeng Zheng 2,  Lin Lin 3,  Liliana Sokol 1,  Laure-Anne Teuwen 4,  Vincent Geldhof 1,  Federico Taverna 1,  Andreas Pircher 1,  Lena-Christin Conradi 1,  Shawez Khan 1,  Steve Stegen 5,  Dena Panovska 6,  Frederik De Smet 6,  Frank J T Staal 7,  Rene J Mclaughlin 7,  Stefan Vinckier 1,  Tine Van Bergen 8,  Nadine Ectors 6,  Patrik De Haes 8,  Jian Wang 9,  Lars Bolund 3,  Luc Schoonjans 10,  Tobias K Karakach 1,  Huanming Yang 9,  Geert Carmeliet 5,  Yizhi Liu 2,  Bernard Thienpont 11,  Mieke Dewerchin 1,  Guy Eelen 1,  Xuri Li 12,  Yonglun Luo 13,  Peter Carmeliet 14
Affiliations

Affiliations

  • 1 Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China.
  • 3 Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China.
  • 4 Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; Translational Cancer Research Unit, GZA Hospitals Sint-Augustinus, Antwerp 2610, Belgium; Center for Oncological Research, University of Antwerp, Antwerp 2000, Belgium.
  • 5 Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven 3000, Belgium.
  • 6 Laboratory for Precision Cancer Medicine, Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven 3000, Belgium.
  • 7 Department of Immunology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
  • 8 OXURION NV, Leuven 3001, Belgium.
  • 9 BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China.
  • 10 Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China.
  • 11 Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium.
  • 12 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China. Electronic address: lixr6@mail.sysu.edu.cn.
  • 13 Department of Biomedicine, Aarhus University, Aarhus 8000, Denmark; Lars Bolund Institute of Regenerative Medicine, BGI-Qingdao, Qingdao 266555, China; BGI-Shenzhen, Shenzhen 518083, China; China National GeneBank, BGI-Shenzhen, Shenzhen 518120, China. Electronic address: alun@biomed.au.dk.
  • 14 Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven 3000, Belgium; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong, China. Electronic address: peter.carmeliet@kuleuven.vib.be.
PMID: 32268117 DOI: 10.1016/j.cmet.2020.03.009
Abstract

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.

Keywords

angiogenesis; choroidal neovascularization; endothelial cells; metabolism; scRNA-seq; tumor angiogenesis.

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