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Published on: December 9, 2013
Modulation of recovery from neonatal hyperoxic lung injury by sex as a biological variable
Abiud Cantu1, Manuel Cantu Gutierrez1, Xiaoyu Dong2
1Department of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Insights
Neonatal lung injury shows sex-based differences in cell responses and communication. Understanding these sex-specific patterns is crucial for developing targeted therapies for lung development disorders.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Immunology
Background:
- Neonatal lung injury can lead to persistent maldevelopment and disease.
- Sex-specific biological pathways influence lung development and injury response.
- Understanding cellular and communication changes is key to effective interventions.
Purpose of the Study:
- To investigate sex and cell-type specific transcriptional changes in neonatal lung injury.
- To delineate alterations in immune-endothelial cell communication networks.
- To identify sex-based differences in response to hyperoxic injury.
Main Methods:
- Single cell RNA sequencing (sc-RNAseq) on neonatal mouse lungs.
- Analysis of transcriptional profiles from male and female mice at different postnatal days.
- Pseudotime trajectory analysis and intercellular communication network analysis.
Main Results:
- Sex-based transcriptional differences were observed in lung endothelial and immune cells.
- Biological sex significantly influenced the response to hyperoxic injury.
- Sex-specific biases in immune-endothelial cell crosstalk and novel ligand-receptor pairs were identified.
Conclusions:
- Neonatal lung injury exhibits significant sex-based transcriptional and communication differences.
- Sex is a critical variable influencing lung development and injury repair.
- Findings offer insights for sex-specific therapeutic strategies in neonatal lung disease.
Abstract:
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.
