PDGs possess a specific architecture and molecular

PDGs possess a specific architecture and molecular signature that make them distinct from the pancreatic epithelium, instead resembling gastric stem cell glands. PDGs were also found to express and up-regulate TFF genes during injury. In the stomach TFF1 is normally found predominantly in the epithelium of the surface pit of the stomach and TFF2 is primarily present in the neck region of the antral and pyloric glands of the stomach. TFF and mucins are co-expressed in gastric mucosa, such that MUC6/TFF2 are confined to the basal part of the gastric gland (Taupin and Podolsky, 2003; Longman et al., 2000). This distribution of TFF2 and co-expression of MUC6 are also seen in the PDG niche. This molecular signature and the cellular organization and proliferative activity within the PDGs are reminiscent of the GI crypts/glands, most specifically the antral gland of the stomach (Fig. 6). The similarities between the gastric glands and PDGs may also extend to their functional roles in regeneration and repair in response to inflammatory injury. In stomach, the induction of trefoil-gene transcription occurs early after inflammatory injury and is considered to be important in migration of epithelial buy nebivolol hcl (FitzGerald et al., 2004; Greeley et al., 2010). In the PDGs we also see an up-regulation of TFF1 and TFF2. Although the functional role of TFF in the pancreas is still not fully elucidated, our work suggests that TFF1 and TFF2 play an important role in regulating cell migration from the PDG compartment. Stem cell niches in the GI system are also known to contain several different populations of cells, including actively dividing stem cells, transient amplifying cells (TA), and label-retaining cells (LRC). TA cells will actively divide, expanding the epithelial population for a defined period of time, while LRC have a low rate of proliferative activity but become activated during injury to be reverse stem cells (Blanpain et al., 2007; Hoffmann, 2008; Li and Clevers, 2010; Shaker and Rubin, 2010). The experiments described in our study suggest that the PDG compartment is likely composed of two populations of proliferating cells. There appears to be one population of rapidly dividing cells whose presence is demonstrated by the persistence of Ki-67. Thus a proportion of the proliferating cells found in PDGs behave like transient amplifying cells. The second population of cells has a much lower rate of proliferation and will initially tag, retain their BrdU label, and stay within the PDG compartment. These cells are similar to the label-retaining cells (LRC) initially described by Bickenbach in 1981 (Bickenbach, 1981). Given that only 1% of PDG cells were found to be slowly dividing cells, most of the cells tagged by BrdU are short-lived progenitors. Although the exact functional role of these cells remains to be determined, what is clear is that this compartment is composed of cells with differing proliferative potential. Stem cells and cancer share many properties. Mutations or dysregulation of pathways within the stem cell compartment are thought to contribute to the formation of cancer. One example is the Hedgehog (Hh) pathway, which has been shown to play a role in lineage determination, maintenance of stem cell niches, and pancreatic regeneration (Strobel et al., 2010; Fendrich et al., 2008). Its aberrant up-regulation is found in PDAC specifically within the pancreatic cancer stem cells (CSC) (Thayer et al., 2003; Li et al., 2007). It is interesting to note that cells in the PDG progenitor niche and pancreatic cancer stem cells (CSC) share similar features. Our GSEA microarray analysis not only identified this compartment to be enriched for stem cell pathways; it also showed it to be enriched for pathways dysregulated in pancreatic cancer. Although much work needs to be done to determine the role of the PDGs as the site of origin for pancreatic neoplasia, what this work does reveal is that the PDGs are the site of epithelial proliferation from which differentiated progeny migrate to regenerate and renew the pancreatic epithelium in response to inflammatory injury. Thus PDGs are an epithelial progenitor niche important for pancreatic ductal epithelial regeneration.