Epithelial Vegfa Specifies a Distinct Endothelial Population in the Mouse Lung

• Published in: Developmental cell Vol. 52; no. 5; pp. 617 - 630.e6
• Main Authors: Vila Ellis, Lisandra, Cain, Margo P., Hutchison, Vera, Flodby, Per, Crandall, Edward D., Borok, Zea, Zhou, Bin, Ostrin, Edwin J., Wythe, Joshua D., Chen, Jichao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.03.2020
• Subjects: Alveolar Epithelial Cells - cytology; Alveolar Epithelial Cells - metabolism; alveologenesis; angiogenesis; Animals; CAR4; Carbonic Anhydrase IV - genetics; Carbonic Anhydrase IV - metabolism; Cells, Cultured; endothelial cell; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Lung - cytology; Lung - growth & development; Lung - metabolism; lung alveolar type 1 cell; lung development; lung vasculature; Mice; Morphogenesis; Myofibroblasts - cytology; Neovascularization, Physiologic; single-cell RNA-seq; vascular biology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VEGF; angiogenesis; VEGF; endothelial cell; lung alveolar type 1 cell; single-cell RNA-seq; lung vasculature; vascular biology; lung development; alveologenesis; CAR4
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2020.01.009

The lung microvasculature is essential for gas exchange and commonly considered homogeneous. We show that VEGFA from the epithelium is required for a distinct endothelial cell (EC) population in the mouse lung. Vegfa is predominantly expressed by alveolar type 1 (AT1) cells and locally required to specify a subset of ECs. Single-cell RNA sequencing (scRNA-seq) reveals that ∼15% of lung ECs are transcriptionally distinct—marked by Carbonic anhydrase 4 (Car4)—and arise from bulk ECs, as suggested by trajectory analysis. Car4 ECs have extensive cellular projections and are separated from AT1 cells by a limited basement membrane without intervening pericytes. Car4 ECs are specifically lost upon epithelial Vegfa deletion; without Car4 ECs, the alveolar space is aberrantly enlarged despite the normal appearance of myofibroblasts. Lung Car4 ECs and retina tip ECs have common and distinct features. These findings support a signaling role of AT1 cells and shed light on alveologenesis. [Display omitted] •AT1 epithelial cells express VEGFA, which promotes local alveolar angiogenesis•scRNA-seq identifies a molecularly distinct lung EC population, labeled by CAR4•CAR4 ECs display extended morphology and are lost upon epithelial Vegfa deletion•CAR4 ECs contribute to alveolar morphogenesis independent of myofibroblasts Using imaging and single-cell RNA-seq, Vila Ellis et al. identify a lung endothelial cell (EC) population with a unique transcriptome, location, morphology, and function in lung development. These ECs are involved in alveolar morphogenesis independent of myofibroblasts.