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

Gastroenterology. 2022 Feb;162(2):604-620.e20. doi: 10.1053/j.gastro.2021.10.027. Epub 2021 Oct 23.


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, KrasG12D-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. KrasG12D 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 KrasG12D-induced ADM identifies populations associated with disease progression. Activation of KrasG12D 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. KrasG12D 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.

Keywords: ADM; Enteroendocrine Cells; Paligenosis; Plasticity; Tuft Cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acinar Cells / cytology
  • Acinar Cells / metabolism*
  • Carcinoma, Pancreatic Ductal / genetics*
  • Cell Plasticity / genetics
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / metabolism
  • Gene Expression Profiling
  • Humans
  • Metaplasia / genetics*
  • Metaplasia / metabolism
  • Mucin 5AC / genetics
  • Pancreas / cytology
  • Pancreas / metabolism
  • Pancreatic Ducts / cytology
  • Pancreatic Ducts / metabolism*
  • Pancreatic Neoplasms / genetics*
  • Pancreatitis / genetics
  • Pancreatitis / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Single-Cell Analysis


  • KRAS protein, human
  • MUC5AC protein, human
  • Mucin 5AC
  • Proto-Oncogene Proteins p21(ras)