Biology subjects

Schaefer, S. E.

Publications and source records attributed to Schaefer, S. E..

4 recordsLinked to original sources

bioRxiv2026

Cytoskeletal-nuclear control of alveolar fibroblast identity directs lung regeneration

Respiratory mechanics direct cell fate in the lung, but the mechanisms by which these mechanical signals are sensed and transmitted to the nucleus to control cell state remain unclear. We paired in vivo perturbations of respiratory mechanics with single-cell genomics and found that alveolar fibroblasts are highly sensitive to physical changes in their microenvironment, exhibiting persistent shifts in their transcriptional identity after injury. Surprisingly, transmission of these signals through the nuclear envelope was not essential for maintaining transcriptional or epigenetic stability during homeostasis. However, severing mechanical-nuclear signaling promoted the normalization of alveolar fibroblast identity after acute injury, resulting in improved epithelial regeneration and reduced dysplastic remodeling. These studies reveal the importance of mechanical-nuclear signaling in the regulation of alveolar cell identity and function and reveal that targeting this complex can enhance tissue regeneration.

cell biology↗

bioRxiv2026

A postnatal human lung developmental atlas reveals windows of genetic vulnerability to chronic lung disease

At birth, the lungs undergo an abrupt physiologic change, as the function of gas exchange transitions from the placenta to the lung. Subsequent postnatal development of the lungs is marked by a rapid and profound increase in the growth of the distal airways and alveolar gas exchange compartment. Insults during this period increase the risk of developing lung disease later in life, though how early-life events affect adult disease onset remains unclear. We generated a single-cell atlas of postnatal human lung development from birth through adulthood and mapped temporally regulated gene expression changes in each cell lineage. Using this atlas, we identified disease risk-associated genes with developmentally regulated expression. These analyses reveal cell type-specific and temporally restricted expression of genes associated with adult lung disease risk, including COPD. Heritability enrichment analysis demonstrated that COPD genetic risk is enriched in genes active during early postnatal endothelial development, linking early-life vascular maturation to adult disease susceptibility. These findings characterize the early window of susceptibility for adult chronic lung diseases and establish a framework to guide mechanistic studies of disease-associated genes.

developmental biology↗

bioRxiv2025

Mechanical force-mediated cellular crosstalk maintains the integrity of the lung gas exchange niche

Respiratory motion imposes a constant mechanical strain that has important but poorly defined impact on tissue niches in the lung. We developed a reversible bronchial ligation model to induce and reverse unilateral blockade of lung mechanical motion in vivo and show that this leads to transcriptomic changes in multiple cell lineages that are not normalized upon reinitiation of respiratory motion. Perturbation of mechanosignaling specifically in alveolar epithelial type I (AT1) cells alters the transcriptomic state and fate of their niche neighbors, demonstrating that AT1 cells act as a node that propagates a mechanical cascade throughout the lung alveolus. Mechanically perturbed AT1 cells induce a distinct capillary endothelial cell state that persists after reactivation of respiratory motion, which is mediated by an integrin/TGF-{beta} network within the alveolus that is vulnerable to pharmacological intervention. Importantly, AT1 mechanosignaling and intercellular communication are altered in chronic human lung diseases, highlighting the critical role of an AT1-driven mechanosensing network in lung disease biology. Thus, mechanosensing cells propagate biophysical signals that regulate tissue function and program tissue responses in disease.

cell biology↗

bioRxiv2024

An injury-induced tissue niche shaped by mesenchymal plasticity coordinates the regenerative and disease response in the lung

Severe lung injury causes basal stem cells to migrate and outcompete alveolar stem cells resulting in dysplastic repair and a loss of gas exchange function. This "stem cell collision" is part of a multistep process that is now revealed to generate an injury-induced tissue niche (iTCH) containing Keratin 5+ epithelial cells and plastic Pdgfra+ mesenchymal cells. Temporal and spatial single cell analysis reveals that iTCHs are governed by mesenchymal proliferation and Notch signaling, which suppresses Wnt and Fgf signaling in iTCHs. Conversely, loss of Notch in iTCHs rewires alveolar signaling patterns to promote euplastic regeneration and gas exchange. The signaling patterns of iTCHs can differentially phenotype fibrotic from degenerative human lung diseases, through apposing flows of FGF and WNT signaling. These data reveal the emergence of an injury and disease associated iTCH in the lung and the ability of using iTCH specific signaling patterns to discriminate human lung disease phenotypes.

cell biology↗