Pancreatic stellate cells have adipogenic and fibrogenic potentials but only show increased pro-fibrogenic propensity upon aging

Abstract

Steatosis and fibrosis are two key pathological features of the aging pancreas that contribute to inflammation, metabolic dysfunction and degenerative changes of the tissue. Pancreatic stellate cells (SCs) are thought to be the main cellular source of ectopic adipocytes and fibrotic structures. SCs are fibroblast-like mesenchymal cells that reside in various microanatomies of the tissue and whose task under healthy, homeostatic conditions is to generate extracellular matrix (ECM) and maintenance signals to ensure tissue integrity and function. To examine pathological changes of the aging pancreas, we conducted single cell RNA-sequencing to analyze murine pancreatic cell heterogeneity and examined morphological changes of the aging exocrine pancreas, comparing young adult and aged wildtype mice. We specifically focused our analyses on SCs and their cellular interaction partners and mechanisms of paracrine crosstalk. Age-dependent transcriptional differences in these cell types occur on the level of ECM-related and pro-fibrotic expression signatures mediated through transforming growth factor (TGF) and platelet-derived growth factor (PDGF) signaling pathways. SCs can be divided into distinct subsets of activated (aSCs) and quiescent stellate cells (qSCs), based on distinct expression signatures and transcript levels of Pdgfra and Pdgfrb, which encode for the PDGF receptor alpha and -beta paralogs. Activated SCs, which display PDGF receptor alpha (PDGFRα) on their surface, exhibited subsets that appeared to be either pro-adipogenic or pro-fibrogenic at the transcriptomic level and aging promoted a pro-fibrogenic switch in aSCs. We conclude that pancreatic SCs are contributors to the age-related decline of the exocrine pancreas through an increased contribution of a pro-fibrotic microenvironment.