Single cell analysis uncovers clonal heterogeneity inthe adult exocrine pancreas

Abstract

The pancreas is a dual organ, performing endocrine and exocrine functions. The exocrine pancreas harbours duct, centroacinar and acinar cells in charge of production, secretion, and transport of digestive enzymes. Acinar cells are producing large amounts of proteins and account for the majority of all cells in the pancreas. The acinar cell pool is believed to be a population of equipotent cells, which are equal in form and function. However, by examining acinar cells on the single cell level, we find that acinar cells represent a heterogeneous pool of morphologically, functionally and molecularly distinct cells. Long-term, multicolour lineage tracing reveals the existence of previously neglected progenitor-like acinar cells with the ability to persistently generate acinar cells for at least one year. In a complementary in vitro approach, we find that only a subpopulation of acinar cells is able to form organoids, if in direct contact with a supporting acinar cell. We demonstrate that binuclear acinar cells are proliferation deficient and uncover their existence in the human pancreas. Chemically induced pancreatitis transiently activates a population of acinar cells, distinct from the proliferating acinar cells that maintain homeostasis. Furthermore, single cell mRNA sequencing of acinar cells confirms their functional heterogeneity on the molecular level. Altogether, our study transforms our understanding of the acinar cell compartment as a pool of equipotent secretory cells and provides a framework to further disentangle the cellular complexity within the exocrine pancreas in the future.