Pancreas homeostasis maintenance in health and disfunction [snRNA-seq]

Local inflammation in the pancreas is transient but imprints a durable epigenetic memory on epithelial cells, making them more amenable to oncogenic transformation. However, it is unclear whether epithelial cell heterogeneity is impacted by acute pancreatitis (AP) or whether population dynamics during regeneration contributes to the establishment of inflammation memory. To tackle those questions, we deployed experimental pancreatitis in mice and performed paired sequencing of transcriptomic and chromatin accessibility profiles at single nucleus resolution. We documented cell type abundance but also applied integrative analyses to infer phenotypically-distinct clusters of mesenchymal and exocrine cells. We found that AP perturbs a subset of “idling” acinar cells, which separate from more canonical “secretory” acini based on a more diversified proteome, which include elevated expression of signal transduction receptors. We linked acinar cell heterogeneity to epigenetic differences that also endow idling cells with superior plasticity. These constitute about 40% of acinar cells but can proliferate and skew their phenotype in response to AP. This leads to a remarkable recovery of pancreas histology and function, but also to the dissemination of idling-like features across the exocrine parenchyma. Mechanistically, idling acinar cells are characterized by enhanced transcriptional activity and protein synthesis. After recovery from pancreatitis, acini show elevation of both and establishment of chronic Unfolded Protein Response (UPR). We finally demonstrated that AP-primed pancreata show signs of elevated UPR and that ER stress promotes acinar cell metaplasia. Our data interrogate phenotypical dynamics during tissue regeneration to identify cell states amenable to epigenetic imprinting. They also suggest that UPR-alleviating strategies might curtail the risk of developing pancreatic cancer for individuals who experiences AP. Overall design: Mice were subjected to 8 hourly injection/die over two subsequent days. Control mice were injected with saline solution, and sacrificed after 28 days. Cerulein-treated mice were injected with 50mg/kg of cerulein dissolved in saline solution at every injection, and sacrificed either at 7 days post injection (7days samples) or at 28 days post injection (28days samples).