Biology subjects

Speth, J.

Publications and source records attributed to Speth, J..

3 recordsLinked to original sources

bioRxiv2026

Longitudinal Single-Cell RNA-seq Profiling of Lung Cell Phenotypes, Signaling, and Cross-talk During Fibrosis Resolution

Resolution of fibrosis following lung injury is distinguished from persistent/progressive parenchymal scarring through the timely clearance of aberrant cell types, removal of excess collagens, and regeneration of alveolar structure. The requisite signaling pathways, cellular cross-talk, and phenotypic shifts associated with, and required for, resolution of established lung fibrosis have not been well characterized. To address this critical knowledge gap, we performed longitudinal single-cell RNA sequencing of whole mouse lung digests obtained during spontaneously resolving fibrosis. We observed a putatively pro-fibrotic macrophage population emerge during peak fibrosis and undergo partial clearance during resolution. Our study also revealed conspicuous shifts in well-established pathways associated with tissue repair and fibrosis among immune, mesenchymal, and epithelial cells during spontaneous resolution. In addition to a decline in pro-fibrotic driver pathways, the putative anti-fibrotic pathways cAMP, HGF/MET, and TWEAK were enriched in several cell types during spontaneous resolution. CellChat analysis was used to predict the cellular senders and recipients of each pathway and characterize their longitudinal changes. Our characterization of the cellular and molecular dynamics in whole lungs during spontaneous fibrosis resolution provides a foundation for the identification of endogenous pathways that might be leveraged to treat pulmonary fibrosis.

cell biology↗

bioRxiv2023

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

cancer biology↗

bioRxiv2021

Bortezomib inhibits lung fibrosis and fibroblast activation without proteasome inhibition

The FDA-approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential anti-fibrotic actions. However, neither its in vivo efficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. Herein, we identify that therapeutic administration of BTZ in a mouse model of pulmonary fibrosis diminished the severity of fibrosis without reducing proteasome activity in the lung. Under conditions designed to mimic this lack of proteasome inhibition in vitro, it reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted de-differentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing expression of dual-specificity phosphatase 1 or DUSP1, and knockdown of DUSP1 abolished its anti-fibrotic actions in fibroblasts. Our findings identify a novel proteasome-independent mechanism of anti-fibrotic actions for BTZ and support its therapeutic repurposing for pulmonary fibrosis.

molecular biology↗