Biology subjects

Newcomb, D.

Publications and source records attributed to Newcomb, D..

3 recordsLinked to original sources

bioRxiv2025

Quiescence modulates age-related changes in the functional capacity of highly proliferative canine lung mesenchymal stromal cell populations

The functional capacity of highly proliferative cell populations changes with age. Here, we report that the proliferative capacity of canine lung mesenchymal stromal cells (LMSCs) declines with increasing age of the donor. However, other functional changes such as reduced autophagy, reduced migration/wound healing, increased production of reactive oxygen species, and increased senescence are not significantly altered with increasing age. Furthermore, transcriptomic profiling suggests minimal age-related changes. These data suggest that the reduced proliferative capacity of lung LMSCs isolated from aging donors may be associated with reversible cell cycle arrest (quiescence), rather than irreversible cell cycle arrest (senescence). Similar findings have been reported in other systems, including neural and muscle stem cells that are associated with low turnover-rate tissues.

developmental biology↗

bioRxiv2024

Impact of early-life respiratory syncytial virus infection on cell type-specific airway DNA methylation

RationaleInfection with respiratory syncytial virus (RSV) in early-life is associated with subsequent childhood respiratory disorders, but the mechanism for this association is unknown. We hypothesized that RSV-mediated alteration in airway DNA methylation (DNAm) may play a role. ObjectivesInvestigate the impact of early-life RSV infection on airway DNAm. MethodsOur study population consisted of children from the INSPIRE population-based birth cohort. Early-life infection with RSV was defined as infection not requiring clinical illness before age one year, ascertained through active and passive surveillance. Methylation was measured in DNA from nasal airway epithelial cells (NAECs) at ages two years (n=88) and six years (n=539). Bulk gene expression in NAECs was available in a subset of participants at age two years (n=54). In silico cell type deconvolution was used to infer cell type-specific associations in suprabasal, ciliated, and "other" cell types. Measurements and Main ResultsWe identified 164 CpGs in ciliated cells and seven CpGs in suprabasal cells whose cell type-specific DNAm at age two years was associated with early-life RSV infection. The seven associations in suprabasal cells were still present at age six years and the directions of association replicated in in vitro infection of epithelial cells with RSV in air liquid interface cultures. DNAm levels at four of the seven CpGs identified in suprabasal cells correlated with the expression of their nearest genes in suprabasal cells, which included genes previously implicated in asthma-related diseases. The DNAm levels of these four CpGs and the expression of their nearest genes in suprabasal cells at age two years were also associated with recurrent wheezing at age four years. ConclusionsWe demonstrate epigenetic changes in airway progenitor cells of children who have had RSV infection in the first year of life are conserved over time, associated with subsequent wheeze, have functional relevance, and replicate in in vitro infection in ALI cultures. Our study is the first to show that early-life RSV infection, as opposed to severe illness, alters DNAm levels at functionally and clinically relevant loci.

genomics↗

bioRxiv2023

Low Gut Microbial Diversity Augments Estrogen-driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease

Although profibrotic cytokines such as IL-17A and TGF-{beta}1 have been implicated in interstitial lung disease (ILD) pathogenesis, interactions between gut dysbiosis, gonadotrophic hormones and molecular mediators of profibrotic cytokine expression, such as phosphorylation of STAT3, have not been defined. Here we show by chromatin immunoprecipitation sequencing (ChIP-seq) analysis of primary human CD4+ T cells that regions within the STAT3 locus are significantly enriched for binding by the transcription factor estrogen receptor alpha (ERa). Using the murine model of bleomycin-induced pulmonary fibrosis, we found significantly increased regulatory T cells compared to Th17 cells in the female lung. Genetic absence of ESR1 or ovariectomy in mice significantly increased pSTAT3 and IL-17A expression in pulmonary CD4+ T cells, which was reduced after repletion of female hormones. Remarkably, there was no significant reduction in lung fibrosis under either condition, suggesting that factors outside of ovarian hormones also contribute. Assessment of lung fibrosis among menstruating females in different rearing environments revealed that environments favoring gut dysbiosis augment fibrosis. Furthermore, hormone repletion following ovariectomy further augmented lung fibrosis, suggesting pathologic interactions between gonadal hormones and gut microbiota on lung fibrosis severity. Analysis in female sarcoidosis patients revealed a significant reduction in pSTAT3 and IL-17A levels and a concomitant increase in TGF-{beta}1 levels in CD4+ T cells, compared to male sarcoidosis patients. These studies reveal that estrogen is profibrotic in females and that gut dysbiosis in menstruating females augments lung fibrosis severity, supporting a critical interaction between gonadal hormones and gut flora in lung fibrosis pathogenesis.

immunology↗