Pancreatic ductal cells in development, regeneration, and neoplasia

Abstract

The pancreas is a complex organ comprised of three critical cell lineages: islet (endocrine), acinar, and ductal. This review will focus upon recent insights and advances in the biology of pancreatic ductal cells. In particular, emphasis will be placed upon the regulation of ductal cells by specific transcriptional factors during development as well as the underpinnings of acinar-ductal metaplasia as an important adaptive response during injury and regeneration. We also address the potential contributions of ductal cells to neoplastic transformation, specifically in pancreatic ductal adenocarcinoma.

Figure 1. Anatomical organization of the pancreatic ductal tree.

(A) Centroacinar cells are terminal end duct cells that interface with acini (white arrowhead; scale bar: 10 μm). (B) Terminal ducts or intercalated ducts (dotted line), respectively, are composed of flat epithelia and merge into intralobular ducts (white arrowhead) that are lined by cuboidal epithelia (scale bar: 10 μm). (C) Intralobular ducts merge to form small interlobular ducts surrounded by mesenchyme (scale bar: 10 μm). (D) Larger interlobular ducts are lined by columnar epithelia (scale bar: 10 μm). (E) Some key acinar, ductal, and endocrine cell transcription factors are depicted (see refs. 4, 6).

Figure 2. Role of Hnf1β and Sox9 in pancreatic ductal lineage specification.

(A) Solar et al. (51) performed pulse-chase experiments using the Hnf1bCreER^T2;R26R mouse model. Hnf1β-positive cells give rise to all pancreatic lineages when recombination was induced prior to secondary transition. When pulse labeled between E13.5 and E15.5, progeny cells were found only within the endocrine and ductal compartments. Induced at E18.5, Hnf1β-positive cells are located exclusively within ducts. (B) Furuyama et al. (52) demonstrated with their Sox9^IRESCreERT2;R26R model that Sox9-positive cells give rise to acinar, ductal, and endocrine cells when induced at E16.5 and P1, respectively. Any time after P7, Sox9-positive cells repopulate the acinar and ductal compartment. (C) Kopp et al. (53) labeled Sox9-positive cells with a transgenic approach, using Sox9CreER^T2;R26R mice, and confirmed that Sox9-expressing cells give rise to all pancreatic lineages when induced between E8.5 and E18.5. When analyzing pancreata that were labeling at P5, recombination was observed in ducts and endocrine cells. TM, tamoxifen.

Figure 3. ADM and PanIN — roles of potential pathways.

In the adult mouse pancreas, ADM may be triggered by inflammation and other factors. Known associations with ADM include, but are not limited to, extracellular cues — TGF-α, Hedgehog signaling, Notch signaling — and intracellular alterations mediated by Kras^G12D activation, including induction of Pdx1, induction of TNF-α, and decreased Mist1 expression. Ductal cells or duct-like cells are replaced by healthy acinar cells during recovery from injury. ADM might represent a precursor lesion to PanIN and constitute a cell of origin for PanIN. The cell of origin for PanIN might be a ductal cell or a distinct yet-to-be-identified progenitor cell.