Single-cell RNA sequencing maps endothelial metabolic plasticity in pathological angiogenesis

Rohlenova, Katerina; Goveia, Jermaine; Garcia-Caballero, Melissa; Subramanian, Abhishek; Kalucka, Joanna; Treps, Lucas; Falkenberg, Kim; De Rooij, Laura; Zheng, Yingfeng; Lin, Lin; Sokol, Liliana; Teuwen, Laure-Anne; Geldhof, Vincent; Taverna, Federico; Pircher, Andreas; Conradi, Lena-Christin; Khan, Shawez; Stegen, Steve; Panovska, Dena; De Smet, Frederik; Staal, Frank; McLaughlin, Rene; Vinckier, Stefan; Van Bergen, Tine; Ectors, Nadine; De Haes, Patrik; Wang, Jian; Bolund, Lars; Schoonjans, Luc; Karakach, Tobias; Yang, Huanming; Carmeliet, Gertrudis; Liu, Yizhi; Thienpont, Bernard; Dewerchin, Mieke; Eelen, Guy; Li, Xuri; Luo, Yonglun; Carmeliet, Peter

doi:10.1016/j.cmet.2020.03.009

Single-cell RNA sequencing maps endothelial metabolic plasticity in pathological angiogenesis

Author:

Rohlenova, Katerina

Goveia, Jermaine ; Garcia-Caballero, Melissa ; Subramanian, Abhishek ; Kalucka, Joanna ; Treps, Lucas ; Falkenberg, Kim ; De Rooij, Laura ; Zheng, Yingfeng ; Lin, Lin ; Sokol, Liliana ; Teuwen, Laure-Anne ; Geldhof, Vincent ; Taverna, Federico ; Pircher, Andreas ; Conradi, Lena-Christin ; Khan, Shawez ; Stegen, Steve ; Panovska, Dena ; De Smet, Frederik ; Staal, Frank ; McLaughlin, Rene ; Vinckier, Stefan ; Van Bergen, Tine ; Ectors, Nadine ; De Haes, Patrik ; Wang, Jian ; Bolund, Lars ; Schoonjans, Luc ; Karakach, Tobias ; Yang, Huanming ; Carmeliet, Gertrudis ; Liu, Yizhi ; Thienpont, Bernard ; Dewerchin, Mieke ; Eelen, Guy ; Li, Xuri ; Luo, Yonglun ; Carmeliet, Peter

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Endocrinology & Metabolism, VON-WILLEBRAND-FACTOR, MATRIX GLA-PROTEIN, GENE-EXPRESSION, MATRICELLULAR PROTEIN, MACULAR DEGENERATION, IDENTIFICATION, REVEALS, CYCLE, RECONSTRUCTION, HETEROGENEITY, angiogenesis, choroidal neovascularization, endothelial cells, metabolism, scRNA-seq, tumor angiogenesis, Animals, Endothelial Cells, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Lung Neoplasms, Macular Degeneration, Male, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome, TECNEC - 743074;info:eu-repo/grantAgreement/EC/H2020/743074, C14/17/084#54271203, C24/17/077#54270838, G0B7920N#55522276, METH/14/08#53009403, IDN/19/039#55225089, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

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 cellcycle 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.