Biology subjects

Gote-Schniering, J.

Publications and source records attributed to Gote-Schniering, J..

4 recordsLinked to original sources

bioRxiv2025

Targeting p16INK4a reverses alveolar epithelial cell dysfunction and induces lung regeneration in emphysema

Pulmonary emphysema involves impaired regenerative capacity of alveolar type 2 epithelial cells (AT2), the main progenitor cells in alveoli. However, the mechanisms underlying dysfunctional epithelial repair remain unclear. In a mouse model of elastase-induced emphysema, we observed an accumulation of activated AT2s in the lung, associated with an overexpression of p16INK4a (p16), a cell cycle inhibitor known to influence stem cell fate. Deletion of p16 promoted the transition of AT2 into alveolar type 1 (AT1) cells, resulting in tissue regeneration in both mice and alveolar organoids. Pharmacological targeting of the p16 pathway using senolytic agents recapitulate this regenerative effect, further supporting the role of p16 as a key brake on epithelial plasticity. These findings demonstrate that alveolar epithelial cell dysfunction can be reversed by p16 deletion or by eliminating p16+ cells, thereby reactivating the AT2-to-AT1 transition and promoting endogenous alveolar regeneration. This work identifies the p16 pathway as a promising therapeutic target for restoring damaged alveoli in emphysema.

cell biology↗

bioRxiv2025

Single cell decomposition of multicellular aging programs associated with impaired lung regeneration

Aging impairs the regenerative capacity of mammalian organs and is a major risk factor for organ fibrosis. Mechanisms underlying persistent fibrosis after lung injury in old individuals remain unclear. We used longitudinal single-cell RNA-seq after lung injury and dissected aging effects computationally and experimentally at baseline and during repair. In old mice, sustained fibroblast activation in the resolution phase of fibrosis was associated with prolonged epithelial senescence and persistent epithelial-mesenchymal crosstalk. Single-cell interpretable tensor decomposition analysis revealed that aging most strongly affected T/B-lymphocytes and macrophages. Notably, we identified a Granzyme K-high CD8+ T cell state that was unique to aged mice, co-localized with epithelial progenitors, and its co-culture or Gzmk treatments in lung organoids impaired progenitor function by inducing stem cell senescence. In summary, our study highlights the effects of immune aging on epithelial progenitor function and provides a time-resolved high resolution map of lung regeneration in the context of aging.

cell biology↗

bioRxiv2024

Radioproteomics stratifies molecular response to antifibrotic treatment in pulmonary fibrosis

Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we used an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed two distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing ILD patients, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a non-invasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.

molecular biology↗

bioRxiv2023

Ex vivo tissue perturbations coupled to single cell RNA-seq reveal multi-lineage cell circuit dynamics in human lung fibrogenesis

Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with scRNAseq and induced a multi-lineage circuit of fibrogenic cell states in hPCLS, which we show to be highly similar to the in vivo cell circuit in a multi-cohort lung cell atlas from pulmonary fibrosis patients. Using micro-CT staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the ex vivo hPCLS model provides evidence that the basaloid cell state was derived from alveolar type-2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in the hPCLS model and anti-fibrotic drug treatments showed highly cell type specific effects. Our work provides an experimental framework for perturbational single cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration and pathology. We further demonstrate that hPCLS offers novel avenues for scalable, high-resolution drug testing to accelerate anti-fibrotic drug development and translation.

cell biology↗