Single Cell Transcriptomic Atlas of Lung Microvascular Regeneration after Targeted Endothelial Cell Ablation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE211335 | GEO | 2023/08/03
REPOSITORIES: GEO
Similar Datasets
Project description:Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life-threatening critical syndrome with no effective pharmacotherapy. Extracellular vesicles (EVs) are considered as a new way of long-distance communication between cells. Our previous research using an ex vivo perfused human ALI model suggested that endothelial cell-derived EVs (EC-EVs) mediate the development of ALI/ARDS. However, how EC-EVs aggravate lung injury remains largely unknown. Here we demonstrated that EC-EVs released under inflammatory stimulation are preferentially taken up by monocytes and reprogram the differentiation of monocytes towards M1 type macrophage. These findings demonstrate a previously unidentified mechanism by which distant infections could lead to ALI/ARDS, providing novel targets and strategies for the prevention and treatment of sepsis-related ALI/ARDS.
2024-03-20 | GSE236215 | GEO
Project description:Single Cell Transcriptomic Atlas of Lung Microvascular Regeneration after Targeted Endothelial Cell Ablation
| PRJNA869770 | ENA
Project description:Angiogenesis-inhibitor (AI) drugs targeting vascular endothelial growth factor (VEGF) signalling to the endothelial cell (EC) are used to treat various cancers types. However, primary or secondary resistance to therapy is common. Clinical and pre-clinical studies suggest that other alternative pro-angiogenic factors are up-regulated after VEGF-pathway inhibition. Therefore, identification alternative pro-angiogenic pathway(s) is critical for the development of more effective anti-angiogenic therapy. Here we study the role of apelin as a pro-angiogenic G-protein coupled receptor (GPCR) ligand in tumor growth and angiogenesis. We applied single-cell RNA-sequencing to Mouse Lewis lung carcinoma (LLC1) or B16F10 mouse melanoma cell lines (1 X 106) implanted subcutaneously into the flanks of 12 weeks old Apln-/y or littermate control mice in combination with sunitinib or control (vehicle) treatment. We found apelin loss reduced angiogenic sprouting and tip cell marker gene expression in comparison to the sunitinib-alone treated mice and prevented EC tip cell differentiation.
2023-04-06 | E-MTAB-11663 | biostudies-arrayexpress
Project description:Evaluation of microRNAs that are downstream of apelin/APJ signaling in the pulmonary artery endothelial cells. Triplicates per group, subjected to: 1) control siRNA, 2) apelin siRNA, 3) APJ siRNA, 4) apelin + APJ siRNA
2012-12-04 | E-GEOD-42343 | biostudies-arrayexpress
Project description:We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post-injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post-injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor-positive endothelial progenitors responsible for the regeneration of the lung microvasculature.
| S-EPMC10181823 | biostudies-literature
Project description:Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate endothelial cell (EC) regenerative programs and thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Here, we addressed mechanisms of generation of S1PR1+ EC, which may prevent endothelial injury. Studies were made using inducible EC-S1PR1-/- (iEC-S1PR1-/-) mice and S1PR1-GFP reporter mice to trace the generation of S1PR1+ EC. We observed in a mouse model of endotoxemia that S1P generation induced the programming of S1PR1lo to S1PR1+ EC, which comprised 80% of lung EC. The transition of these cells was required for reestablishing the endothelial barrier. We also observed that conditional deletion of S1PR1 in EC increased vascular permeability. RNA-seq analysis of S1PR1+ EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively. The activation of transcription factors EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively, to increase S1P production that served to amplify S1PR1+ EC transition. Transplantation of S1PR1+ EC into injured lung vasculature restored endothelial integrity. Our findings show that generation of a S1PR1+ EC population activates the endothelial regenerative program mediating vascular endothelial repair, thus raising the possibility of harnessing this pathway to restore vascular homeostasis in inflammatory injury.
2023-01-15 | GSE165000 | GEO
Project description:The heterogeneity of endothelial cells (ECs), lining blood vessels, across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomic data from 11 tissues of the model organism Mus musculus. We propose a new classification of EC phenotypes based on transcriptome signatures and inferred putative biological features. We identified top-ranking markers for ECs from each tissue. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) resembled each other across tissues, but only arterial, venous and lymphatic (not capillary) ECs shared markers, illustrating a greater heterogeneity of capillary ECs. We identified high-endothelial-venule and lacteal-like ECs in the intestines, and angiogenic ECs in healthy tissues. Metabolic transcriptomes of ECs differed amongst spleen, lung, liver, brain and testis, while being similar for kidney, heart, muscle and intestines. Within tissues, metabolic gene expression was heterogeneous amongst ECs from different vascular beds, altogether highlighting large EC heterogeneity.
2020-02-13 | E-MTAB-8077 | biostudies-arrayexpress
Project description:Evaluation of microRNAs that are downstream of apelin/APJ signaling in the pulmonary artery endothelial cells.
2012-12-04 | GSE42343 | GEO
Project description:We have identified the apelin-APJ axis as a mechanism of protection mediated by AHR signalling in lund=g endothelial cells. This RNAseq experiment will compare the effects of apelin receptor blockade on endothelial and epithelial responses in the lung during influenza infection.
2023-05-23 | GSE225958 | GEO
Project description:Mechanical forces generated through adhesive interaction of endothelial cells (EC) influence nuclear envelope and thereby gene transcription. Alteration in EC mechanical forces may trigger aberrant gene transcription leading to lethal vascular diseases including acute lung injury (ALI). The intrinsic pathways that instruct EC nuclear-mechanotransduction and thereby maintains vascular homeostasis remain elusive. We have identified focal adhesion kinase (FAK)-mediated mechanotransduction at the nuclear envelope in instructing transcription of EC-barrier protective genes. We show that loss of EC-FAK increases intracellular tension, which in turn activates nuclear envelop protein emerin, and DNA methyltransferase 3a (DNMT3a). Methylation of transcription factor KLF2 promoter by DNMT3a impaired KLF2 synthesis and transcription of the crucial barrier-maintaining gene, S1PR1. Restoring KLF2 or S1PR1 expression or impairing emerin or DNMT3a activity rescued vascular homeostasis in lungs with FAK-deficient or WT-damaged endothelium. Thus, FAK protects against tension-induced aberrant DNA methylation in EC and is a promising target to prevent ALI.
2022-07-11 | GSE207789 | GEO