Single-Cell Analysis Uncovers Clonal Acinar Cell Heterogeneity in the Adult Pancreas

Acinar cells make up the majority of all cells in the pancreas, yet the source of new acinar cells during homeostasis remains unknown. Using multicolor lineage-tracing and organoid-formation assays, we identified the presence of a progenitor-like acinar cell subpopulation. These cells have long-term self-renewal capacity, albeit in a unipotent fashion. We further demonstrate that binuclear acinar cells are terminally differentiated acinar cells. Transcriptome analysis of single acinar cells revealed the existence of a minor population of cells expressing progenitor markers. Interestingly, a gain of the identified markers accompanied by a transient gain of proliferation was observed following chemically induced pancreatitis. Altogether, our study identifies a functionally and molecularly distinct acinar subpopulation and thus transforms our understanding of the acinar cell compartment as a pool of equipotent secretory cells. [Display omitted] •Pancreatic acinar cells are heterogeneous in proliferative activity•Only a minor subset of acinar cells retains proliferative activity long term•By single-cell RNA-seq, STMN1 marks a proliferative acinar subpopulation•Injury transiently activates proliferation and STMN1 expression in quiescent cells Wollny et al. show that acinar cells within the adult exocrine pancreas are heterogeneous. Most acinar cells exhibit a limited proliferative capacity or are binuclear and unable to divide. Assays by multicolor lineage tracing, organoid formation, and single-cell RNA-seq identify a minor subset of cells that retain proliferative activity long term.