47Pulmonary endothelial cells (ECs) are an essential component of the gas exchange 48 machinery of the lung alveolus. Despite this, the extent and function of lung EC heterogeneity 49 remains incompletely understood. Using single-cell analytics, we identify multiple EC 50 populations in the mouse lung, including macrovascular endothelium (maEC), microvascular 51 endothelium (miECs), and a new population we have termed Car4-high ECs. Car4-high ECs 52 express a unique gene signature, and ligand-receptor analysis indicates they are primed to 53 receive reparative signals from alveolar type I cells. After acute lung injury, they are 54 preferentially localized in regenerating regions of the alveolus. Influenza infection reveals the 55 emergence of a population of highly proliferative ECs that likely arise from multiple miEC 56 populations and contribute to alveolar revascularization after injury. These studies map EC 57 heterogeneity in the adult lung and characterize the response of novel EC subpopulations 58 required for tissue regeneration after acute lung injury. 59 Significance 60Using transcriptional profiling of the pulmonary vascular endothelium and confirmation at 61 the RNA and protein levels, we have revealed extensive EC heterogeneity throughout the 62 vasculature of the lungs. We show that a subpopulation of endothelium re-enters the cell cycle 63 and proliferates in response to acute injury, whereas another subpopulation is enriched in 64 vasculogenic gene expression. These data provide foundational information regarding the 65 biological complexity of lung ECs, which will contribute to the development of novel tools to 66 enhance regeneration of the lung following injury. 67 whether such EC subpopulations contribute to in vivo tissue homeostasis and response to injury 93 in the adult lung remains unknown. 94To address these questions and to define pulmonary EC heterogeneity at homeostasis 95 and during regeneration, we utilized single cell RNA sequencing (scRNA-seq) analysis of the 96 adult mouse lung, both uninjured and after acute influenza-induced viral injury. In addition to 97 identifying microvascular (miEC) and both arterial and venous macrovascular (maEC) 98 populations, we identified a new population we have termed Car4-high ECs that possess a 99 unique transcriptome. Car4-high ECs express high levels of Car4 and Cd34, are found 100 throughout the lung periphery at homeostasis, and are primed to respond to Vegfa signaling 101 based on their high expression of Vegf receptors, which corresponds to a receptor-ligand 102 interaction analysis between Car4-high ECs and AT1 cells, their epithelial co-partners in gas 103 exchange. Car4-high ECs are enriched in the regenerating zones surrounding the most 104 damaged regions of the lung following influenza-or bleomycin-induced lung injury during the 105 subsequent tissue regeneration process. Influenza injury revealed the emergence of a unique 106 population of highly proliferative ECs, which are closely related to Car4-low miECs in gene 107 expression ...
Transcription factors (TFs) are dosage-sensitive master regulators of gene expression, with haploinsufficiency frequently leading to life-threatening disease. Numerous mechanisms have evolved to tightly regulate the expression and activity of TFs at the transcriptional, translational, and posttranslational levels. A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors in the genome, but the regulatory relationship between these lncRNAs and their neighboring TFs is unclear. We identified a regulatory feedback loop between the TF Foxa2 and a downstream lncRNA, Falcor (Foxa2-adjacent long noncoding RNA). Foxa2 directly represses Falcor expression by binding to its promoter, while Falcor functions in cis to positively regulate the expression of Foxa2. In the lung, loss of Falcor is sufficient to lead to chronic inflammatory changes and defective repair after airway epithelial injury. Moreover, disruption of the Falcor-Foxa2 regulatory feedback loop leads to altered cell adhesion and migration, in turn resulting in chronic peribronchial airway inflammation and goblet cell metaplasia. These data reveal that the lncRNA Falcor functions within a regulatory feedback loop to fine-tune the expression of Foxa2, maintain airway epithelial homeostasis, and promote regeneration.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.