Investigating the role of senescence in the lineage relationships of renal mesenchymal cells during injury.

• Applicant: Isaac Shaw, Ph.D.
• Subject Area: Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 509022179

Chronic kidney disease (CKD) affects over 10% of the global population and kidney fibrosis is the hallmark of CKD. Renal mesenchymal cells are the fibrosis causing cells and considered a therapeutic target. Recent advances have identified multiple transcriptionally distinct cell types within these renal mesenchymal cells, some of which arise in response to injury. Understanding lineage relationships between these populations is key to enable their external manipulation to reduce fibrosis and aid recovery. In parallel, little is known of how ageing affects these mesenchymal cell types, a conspicuous omission given the prevalence of renal disease in the elderly. Aged kidneys contain an altered complement of mesenchymal cells, skewed towards profibrotic disease states. Understanding the role of senescence in driving these changes should enable interventions to counteract them as a therapeutic strategy.This project will use two complimentary state-of-the-art tools to determine how ageing and age-related factors like cellular senescence affect the lineage relationships of mesenchymal cell types. Firstly, genetic barcoding of transcribable elements using CARLIN mice, in combination with single cell RNA sequencing (scRNAseq), will allow direct detection of lineage relationships between mesenchymal cell types. Secondly, spatial transcriptomic methods used in conjunction with mosaic reporter mice driven by mesenchyme-specific Cre lines will facilitate investigation of spatial and microenviroenmental aspects of cell lineage choices. These tools will be used in conjunction with renal injury models, artificial induction of senescence and aged mice to detect the effects of ageing and senescence on injury-induced renal mesenchymal lineage decisions. Furthermore, integrating tools such as ATAC-seq (Assay for Transposase-Accessible Chromatin) will help dissect out likely regulatory pathways driving cellular metamorphoses. By determining how senescence impairs the dynamics of mesenchymal cell populations, we can identify the essential elements that must be targeted to relieve the burden of renal disease in the aged human population.

• DFG Programme: WBP Position