Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Cantu, Abiud; Gutierrez, Manuel Cantu; Dong, Xiaoyu; Leek, Connor; Lingappan, Krithika

doi:10.1101/2022.08.19.504541

Cited by 4 publications

References 142 publications

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The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns

Willis

Silverberg

Martin

et al. 2023

Preprint

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Rationale: Bronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut microbial communities contribute to multiple lung diseases, and alterations of the gut microbiome may be a factor in BPD pathogenesis. Objective: To determine if features of the multikingdom gut microbiome predict the development of BPD in very low birthweight newborns. Methods: We performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 147 very low birthweight infants with BPD or post-prematurity respiratory disease (PPRD) by sequencing bacterial 16S and fungal ITS2 ribosomal RNA. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, quantitative confocal microscopy, lung morphometry, and oscillometry. Measurements and Main Results: We analyzed 100 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants with PPRD (P = 0.0209). Instead of fungal communities dominated by Candida and Saccharomyces, the microbiota of infants who developed BPD were characterized by the abundance of Aureobasidium and a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine lung and intestinal microbiomes and transcriptional alterations associated with augmented lung injury. Conclusions: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.

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The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns

Willis

Silverberg

Martin

et al. 2023

Preprint

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Modulation of Recovery from Neonatal Hyperoxic Lung Injury by Sex as a Biological Variable

Cantu,

Gutierrez,

Dong

et al. 2023

Preprint

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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) and postnatal day 21 (PND 21) neonatal 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.

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Genetic variation in the activity of a TREM2-p53 signaling axis determines oxygen-induced lung injury

Abe,

Spann,

Tang

et al. 2024

Preprint

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Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common major complication of preterm birth. Supplemental oxygen administration, while lifesaving in the neonatal period, remains a key determinant of BPD pathophysiology. Exposure of the immature lung to increased levels of oxygen elicits an inflammatory response resulting in abnormal lung development. However, not every premature infant is equally sensitive to develop BPD. Using genetically diverse mouse strains, we show that the innate immune response activated in the lungs of mice sensitive to hyperoxia that develop BPD-like lung injury differs from mice resilient to disease. Specifically, we identified a selective upregulation of triggering receptor expressed on myeloid cells 2 (TREM2) on lung macrophages and monocytes in the hyperoxia-sensitive C57BL/6J mouse strain. We show that loss of function of TREM2 signaling in myeloid cells resulted in a dramatically improved phenotype after neonatal hyperoxia exposure characterized by a dampened immune response, preserved alveolar structure, and preserved cell proliferative potential supporting normal lung development. At the molecular level, inhibition of TREM2 signaling dampened the magnitude of p53 activation and resulted in cell cycle arrest instead of apoptosis. These findings show that TREM2 is a critical regulator of the pathogenic innate immune response to hyperoxia and highlight its importance as a potential therapeutic target for mitigating injury in the hyperoxia-exposed developing lung.

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Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Cited by 4 publications

References 142 publications

The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns

The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns

Modulation of Recovery from Neonatal Hyperoxic Lung Injury by Sex as a Biological Variable

Genetic variation in the activity of a TREM2-p53 signaling axis determines oxygen-induced lung injury

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