The role of lysosomal cholesterol accumulation in pancreatic regeneration: possible link between acetyl-CoA metabolism and mTORC1

While cellular identity is generally stably defined, several cell types retain the ability to adapt their characteristics in response to diverse stimuli, both physiological and pathological. A pivotal example of this capability, which is termed cellular plasticity, occurs in the pancreatic tissue throughout acinar-to-ductal metaplasia (ADM); during this process, post-mitotic acinar cells dedifferentiate to a progenitor-like ductal state, which in turn can proliferate and grow. ADM is a physiological and reversible process that supports tissue repair after inflammation or damage; after injury resolution, this course is reverted, leading to histological and functional normalcy. While the ADM macroscopical features have been extensively described and characterized, not much is known regarding the molecular mechanisms underlying this transformation. This project aims to explore the metabolic alterations that support ADM, focusing on the rewiring of acetyl-CoA metabolism and its consequences for cholesterol homeostasis and lysosomal accumulation. This study uncovers a novel mechanism that regulates mTORC1 activation during pancreatic regeneration, which is proposed as a possible mechanism to sustain pancreatic acinar cell plasticity.