Biology subjects

Landsberger, T.

Publications and source records attributed to Landsberger, T..

3 recordsLinked to original sources

bioRxiv2023

Longitudinal single-cell data informs deterministic modelling of inflammatory bowel disease

Single-cell mRNA sequencing (scRNA-seq) allows deep molecular and cellular profiling of immunological processes. Longitudinal scRNA-seq datasets can be used for deterministic ordinary differential equation (ODE)-based modelling to mechanistically describe immune dynamics. Here, we derived longitudinal changes in the abundance of six colonic cell types during inflammatory bowel disease (IBD) from scRNA-seq data of a mouse model of colitis using ODE-based models. We then predicted the immune dynamics of a different mouse colitis protocol and confirmed these scRNA-seq-based predictions with our previously published single-cell-based flow cytometry data. We further hypothesised that the estimated model parameters reflect biological processes. We validated this prediction of cellular turnover rates with KI-67 staining and with gene expression information from the scRNA-seq data not used for model fitting. Finally, we tested the translational relevance of the model simulations by predicting genes indicative of treatment response in human IBD patients. The predictive power of IBD deterministic modelling from scRNA-seq data highlights its potential to advance our understanding of immune dynamics in health and disease.

systems biology↗

bioRxiv2023

p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

The accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.

cell biology↗

bioRxiv2022

Chronic inflammation partially recapitulates the gene expression signature of aging

Understanding the mechanism of rejuvenation is central to aging research. No study has compared the effects of the four major rejuvenation strategies: senolytics, caloric restriction, in vivo partial cellular reprogramming and young/old blood factor exchange, which operate via different modalities. We use mice transcriptional data to compare them to each other and to normal aging. We find a shared gene expression program common to all rejuvenation strategies, in which inflammation declines and metabolism, especially of fatty acids, increases. An inverse signature occurs in normal aging. To test whether inflammation is upstream of the metabolic signature, we studied chronic inflammation in three different organs in young mice. Chronic inflammation was associated with a similar decline in metabolism, suggesting that inflammation is upstream of the metabolic signature. We find that inflammation may also underlie human transcriptional age calculator. We conclude that a core mechanism of rejuvenation acts through reduction of inflammation with downstream effects that enhance metabolism, attenuating the most robust age-related changes. This supports a notion of directly targeting genes associated with these pathways to mitigate age-related deterioration.

bioinformatics↗