| First Author | Ma Z | Year | 2022 |
| Journal | Gastroenterology | Volume | 162 |
| Issue | 2 | Pages | 604-620.e20 |
| PubMed ID | 34695382 | Mgi Jnum | J:318689 |
| Mgi Id | MGI:6861688 | Doi | 10.1053/j.gastro.2021.10.027 |
| Citation | Ma Z, et al. (2022) Single-Cell Transcriptomics Reveals a Conserved Metaplasia Program in Pancreatic Injury. Gastroenterology 162(2):604-620.e20 |
| abstractText | 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(G12D)-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Kras(G12D) 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(G12D)-induced ADM identifies populations associated with disease progression. Activation of Kras(G12D) 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(G12D) 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. |
