Biology subjects

Deutsch, G. H.

Publications and source records attributed to Deutsch, G. H..

5 recordsLinked to original sources

bioRxiv2025

Clinical Interventions and Inflammatory Signaling Shape the Transcriptional and Cellular Architecture of the Early Postnatal Lung

The early postnatal period in human development is characterized by extensive remodeling of the distal lung to support gas exchange, but this critical period remains poorly understood. Here, we constructed a comprehensive cellular atlas of the early postnatal human lung (0 to 2 years) using single-nucleus RNA sequencing of histologically normal specimens from 23 individuals. Our analysis identified two previously unknown and mutually exclusive transcriptional states of alveolar type 2 (AT2) cells, one defined by upregulation of genes involved in lipid metabolism and identified by unique expression of FMO5, and the other defined by upregulation of inflammatory response genes and identified by unique expression of CFTR. Using spatial transcriptomics, we discovered that AT2 cell states reside in specific niches and interact with distinct alveolar fibroblast subtypes. Clinical data and organoid experiments further suggest that the environment dictates which state prevails as the pro-inflammatory/pro-regenerative signals TNF- and IL-1{beta} promoted the CFTR+ state in vitro, while patients treated with the anti-inflammatory drug dexamethasone (Dex) had more abundant FMO5+ AT2 cells, and Dex induced the FMO5+ state in vitro. These observations link inflammatory signaling and anti-inflammatory clinical interventions to shifts in transcriptional state of the alveolar epithelium. We benchmarked two neonatal lung diseases, bronchopulmonary dysplasia and pulmonary interstitial glycogenosis, revealing a profound disruption in the balance of AT2 states, a broad arrest of postnatal cellular development, and impaired cellular maturation. Our work uncovers a fundamental new understanding of early postnatal human lung biology, linking pro- and anti-inflammatory signaling to AT2 transcriptional phenotypes and providing a new framework for understanding lung disease.

developmental biology↗

bioRxiv2025

Viral replication and interferon responses in bronchial epithelia is enhanced by Th17 cells

RationaleThe impact of Th17 lymphocytes on epithelial responses to rhinovirus infection in asthma is poorly characterized. MethodsBronchial epithelial cells (BECs) from children with asthma were differentiated to an organotypic epithelium and primed via co-culture with healthy donor Th17 lymphocytes for 4 days prior to apical infection with human rhinovirus-16 (RV-16). RNA sequencing with WGCNA analysis was performed to identify modules of gene expression altered by Th17 priming or RV-16 infection in BECs or Th17 cells. Gene expression was correlated with viral copy number and with secreted protein levels. ResultsAnalysis identified 4,030 genes grouped into 9 named modules with differential gene expression in BECs due to Th17 priming and viral infection. Modules with increased expression with Th17 priming and RV-16 infection included Interferon, MAP-kinase and TNF Signaling modules, while expression of Cilia structure/function and Metabolism modules were decreased. Th17 cells co-cultured with RV-16 infected BECs exhibited increased expression of an Interferon and Viral Response Module without detectable direct viral infection of Th17 cells.Increased expression of the Interferon Signaling in BECs and Interferon Response in Th17 cells was correlated with increased viral copy number in BECs. Th17 priming of BECs led to increased secretion of IFN-, IFN-{gamma}, and IL-1{beta} following RV-16 as compared to BECs alone. ConclusionsTh17 lymphocytes enhance epithelial interferon responses to RV-16 infection in bronchial epithelium from asthmatic children.

cell biology↗

bioRxiv2025

Pulmonary Vascular Endothelial Dysfunction is Induced by Non-Pulsatile Pulmonary Blood Flow in an Ovine Classic Glenn Model

Structured AbstractO_ST_ABSBackgroundC_ST_ABSPulmonary vascular disease (PVD) in patients with single ventricular heart disease following the partial cavalpulmonary connection (Glenn) is a significant source of morbidity. However, the etiology of pulmonary vascular endothelial cell (EC) dysfunction, an established precursor to PVD, is incompletely understood but may involve abnormal blood flow patterns, hypoxemia, and polycythemia. HypothesisUtilizing an ovine Glenn model, we hypothesized that non-pulsatile pulmonary blood flow (PBF) induces pulmonary vascular EC dysfunction, independent of hypoxemia or polycythemia. MethodsSeven lambs (6-8 weeks old) underwent a Glenn procedure. Eight weeks later, Glenn and age-matched controls were studied. The response to the endothelium-dependent vasodilator acetylcholine (Ach) was determined in isolated pulmonary arteries (PA). Nitric oxide (NO) and endothelin-1 (ET-1) signaling was determined in right lung tissues. Indices of cell proliferation, angiogenesis, and apoptosis were determined in PA endothelial cells (PAECs). Comparisons were made by unpaired t-test and ANOVA. ResultsThere were no differences in age, hemoglobin, or oxygen saturation between groups. Mean PA pressure and left PA flow were higher, and right lung blood flow was lower in Glenn lambs compared to controls (p<0.05). All other baseline hemodynamics were similar. Glenn PAs had impaired relaxation to Ach. Glenn lung NO metabolite levels (NOx) and eNOS protein were lower, and ET-1 levels and prepro-ET-1 protein were higher than controls (p<0.05). Glenn PAECs had higher rates of proliferation and angiogenesis, and decreased apoptosis (p < 0.05). ConclusionsThe initiation of non-pulsatile PBF following the Glenn induces early EC dysfunction independent of hypoxemia and polycythemia.

physiology↗

bioRxiv2025

Infants who develop BPD have an airway endotype defined by vimentin expression and ciliary loss

RationaleBronchopulmonary Dysplasia (BPD) results from abnormal lung development after preterm birth, with structural deficits at every respiratory tree level. BPD with lower airway disease is emerging as a clinically significant phenotype with increased mortality, and there is a significant knowledge gap in the molecular mechanisms whereby preterm birth disrupts normal airway development. ObjectivesTo develop a human model of lower airway disease after preterm birth and to characterize a molecular endotype of evolving BPD (eBPD) at baseline and in response to injury. MethodsWe used a combination of an ex vivo organotypic Airway Epithelial Cell (AEC models) and well-characterized pathologic and transcriptomic patient samples for quantitative immunohistochemistry and RNA sequencing analyses. Measurements and Main ResultsCompared to AECs from healthy patients, eBPD- derived AECs have a molecular endotype of reduced proliferation, impaired differentiation to ciliated epithelium, and an expanded vimentin-positive population with a transcriptional shift toward stromal cell-associated genes. With hyperoxia exposure, eBPD-derived AECs exhibited a pronounced vimentin response ex vivo, which parallels the increased vimentin expression of airway cells observed in lung tissue from human infants with BPD. ConclusionsIn this organotypic model of neonatal airway differentiation, we find that infants with eBPD have impaired differentiation, increased expression of vimentin, and concomitant loss of cilia, with an exaggerated increase in vimentin expression after hyperoxia injury, findings that mimic the effects of prematurity in airway cells in human patients. These data provide a foundation for future mechanistic studies interrogating the role of intermediate filaments in epithelial differentiation and repair.

cell biology↗

bioRxiv2025

A spatial transcriptomic atlas of acute neonatal lung injury across development and disease severity

A molecular understanding of lung organogenesis requires delineation of the timing and regulation of the cellular transitions that ultimately form and support a surface capable of gas exchange. While the advent of single-cell transcriptomics has allowed for the discovery and identification of transcriptionally distinct cell populations present during lung development, the spatiotemporal dynamics of these transcriptional shifts remain undefined. With imaging-based spatial transcriptomics, we analyzed the gene expression patterns in 17 human infant lungs at varying stages of development and injury, creating a spatial transcriptomic atlas of [~]1.2 million cells. We applied computational clustering approaches to identify shared molecular patterns among this cohort, informing how tissue architecture and molecular spatial relationships are coordinated during development and disrupted in disease. Recognizing that all preterm birth represents an injury to the developing lung, we created a simplified classification scheme that relies upon the routinely collected objective measures of gestational age and life span. Within this framework, we have identified cell type patterns across gestational age and life span variables that would likely be overlooked when using the conventional "disease vs. control" binary comparison. Together, these data represent an open resource for the lung research community, supporting discovery-based inquiry and identification of targetable molecular mechanisms in both normal and arrested human lung development.

genomics↗