Endothelial to Mesenchymal Transition in Neonatal Hyperoxic Lung Injury: Role of sex as a biological variable
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PROVIDER: PRJNA962106 | ENA |
REPOSITORIES: ENA
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Project description:Bronchopulmonary dysplasia (BPD) is characterized by an arrest in alveolarization, abnormal vascular development and variable interstitial fibroproliferation in the premature lung. Endothelial to mesenchymal transition (Endo-MT) may be a source of pathologic fibrosis in many organ systems. Whether Endo-MT contributes to the pathogenesis of BPD is not known. We tested the hypothesis that pulmonary endothelial cells will show increased expression of Endo-MT markers upon exposure to hyperoxia and that sex as a biological variable will modulate differences in expression. WT and Cdh5-PAC CreERT2 (endothelial reporter) neonatal male and female mice (C57BL6) were exposed to hyperoxia (0.95 FiO2) either during the saccular stage of lung development (95% FiO2; PND1-5) or through the saccular and early alveolar stages of lung development (75% FiO2; PND1-14). Expression of Endo-MT markers were measured in whole lung and endothelial cell mRNA. Sorted lung endothelial cells were subjected to bulk RNA-Seq. We show that exposure of the neonatal lung to hyperoxia leads to upregulation of key markers of EndoMT Neonatal male mice show higher expression of genes related to EndoMT. Furthermore, using lung sc-RNAseq data from neonatal lung we were able to show that xxx. Markers related to Endo-MT are upregulated in the neonatal lung upon exposure to hyperoxia and show sex-specific differences. Mechanisms mediating EndoMT in the injured neonatal lung can modulate the response of the neonatal lung to hyperoxic injury and need further investigation.
2023-11-08 | GSE230672 | GEO
Project description:Recovery from lung injury during the neonatal period requires the orchestration of many biological pathways. Modulation of biological pathways can drive the developing lung towards proper repair or persistent maldevelopment after injury that can lead to a disease phenotype. Sex as a biological variable can modulate these pathways differently in the male and female lung exposed to neonatal hyperoxia. In this study, we assessed the contribution of cellular diversity in the male and female neonatal lung following injury. Our objective was to investigate sex and cell-type specific transcriptional changes that drive repair or persistent injury in the neonatal lung at single-cell resolution and delineate the alterations in the immune-endothelial cell communication networks in the developing lung using single cell RNA sequencing (sc-RNAseq) in a murine model of hyperoxic lung injury. We generated transcriptional profiles of >55,000 cells isolated from the lungs of postnatal day 1 (PND 1) andpostnatal day 21 (PND 21) neonatal male and female C57BL/6 mice exposed to 95% FiO2between PND 1-5 (saccular stage of lung development).We show the presence of sex-based differences in the transcriptional states of lung endothelial and immune cells at PND 1 and PND 21. Furthermore, we demonstrate that biological sex significantly influences the response to injury, with a greater number of differentially expressed genes showing sex-specific patterns than those shared between male and female lungs. Pseudotime trajectory analysis highlighted genes needed for lung development that were altered by hyperoxia. Finally, we show intercellular communication between endothelial and immune cells at saccular and alveolar stages of lung development with sex-based biases in the cross-talk and identify novel ligand-receptor pairs. Our findings provide valuable insights into the cell diversity, transcriptional state, developmental trajectory, and cell-cell communication underlying neonatal lung injury, with implications for understanding lung development and therapeutic interventions while highlighting the crucial role of sex as a biological variable.
2023-11-15 | GSE237944 | GEO
Project description:Modulation of Recovery from Neonatal Hyperoxic Lung Injury by Sex as a Biological Variable
| PRJNA997284 | ENA
Project description:Role of sex as a biological variable in neonatal alveolar macrophages
| PRJNA1111874 | ENA
Project description:Remarkable Lung Heterogeneity at Single-Cell Resolution and the Role of Sex as a Biological Variable in Neonatal Hyperoxic Lung Injury
| PRJNA869954 | ENA
Project description:Sex chromosomes versus gonadal hormones in neonatal hyperoxic lung injury
| PRJNA683593 | ENA
Project description:Cellular senescence in hyperoxic neonatal rat lung
| PRJNA1013085 | ENA
Project description:Growth Differentiation Factor 15 (GDF15) is a divergent member of the TGF-β superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine BPD models, and GDF15 loss exacerbates oxidative stress and decreases viability in vitro in pulmonary epithelial and endothelial cells. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15-/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% O2) for 5 days after birth. The mice were euthanized on PND 21. Gdf15 -/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Upon exposure to hyperoxia, female mice had higher alveolar simplification in the Gdf15-/- group than the female WT group. Gdf15-/- and WT mice showed no difference in the degree of the arrest in angiogenesis upon exposure to hyperoxia. Gdf15-/- mice showed lower macrophage count in the lungs compared to WT mice. Our results suggest that Gdf15 deficiency decreases the tolerance to hyperoxic lung injury with evidence of sex-specific differences.
2023-07-20 | GSE211744 | GEO
Project description:The goal of the project was to delineate sex-specific differences in the neonatal lung exposed to postnatal hyperoxia to model the pathophysiologic mechanisms in the human disease; bronchopulmonary dysplasia (BPD).
2022-10-25 | GSE211356 | GEO
Project description:Recovery from lung injury during the neonatal period requires the orchestration of many biological pathways. The modulation of such pathways can drive the developing lung towards proper repair or persistent maldevelopment that can lead to a disease phenotype. Sex as a biological variable can regulate these pathways differently in the male and female lung exposed to neonatal hyperoxia. In this study, we assessed the contribution of cellular diversity in the male and female neonatal lung following injury. Our objective was to investigate sex and cell-type specific transcriptional changes that drive repair or persistent injury in the neonatal lung and delineate the alterations in the immune-endothelial cell communication networks using single cell RNA sequencing (sc-RNAseq) in a murine model of hyperoxic injury. We generated transcriptional profiles of >55,000 cells isolated from the lungs of postnatal day 1 (PND 1; pre-exposure), PND 7, and PND 21neonatal male and female C57BL/6 mice exposed to 95 % FiO2 between PND 1-5 (saccular stage of lung development). We show the presence of sex-based differences in the transcriptional states of lung endothelial and immune cells at PND 1 and PND 21. Furthermore, we demonstrate that biological sex significantly influences the response to injury, with a greater number of differentially expressed genes showing sex-specific patterns than those shared between male and female lungs. Pseudotime trajectory analysis highlighted genes needed for lung development that were altered by hyperoxia. Finally, we show intercellular communication between endothelial and immune cells at saccular and alveolar stages of lung development with sex-based biases in the crosstalk and identify novel ligand-receptor pairs. Our findings provide valuable insights into the cell diversity, transcriptional state, developmental trajectory, and cell-cell communication underlying neonatal lung injury, with implications for understanding lung development and possible therapeutic interventions while highlighting the crucial role of sex as a biological variable.
| S-EPMC10628633 | biostudies-literature