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Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury


Ma ZZhibo , Lytle NKNikki K , Chen BBob , Jyotsana NNidhi , Novak SWSammy Weiser , Cho CJCharles J , Caplan LLeah , Ben-Levy OOlivia , Neininger ACAbigail C , Burnette DTDylan T , Trinh VQVincent Q , Tan MCBMarcus C B , Patterson EAEmilee A , Arrojo E Drigo RRafael , Giraddi RRRajshekhar R , Ramos CCynthia , Means ALAnna L , Matsumoto IIchiro , Manor UUri , Mills JCJason C , Goldenring JRJames R , Lau KSKen S , Wahl GMGeoffrey M , DelGiorno KEKathleen E . Gastroenterology. 2021 10 23; 162(2). 604-620.e20


BACKGROUND & AIMS: Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression.

METHODS: Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, Kras-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Kras was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining.

RESULTS: scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with Kras-induced ADM identifies populations associated with disease progression. Activation of Kras expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype.

CONCLUSIONS: Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. Kras expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.