Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

Abstract

Background & Aims-Acinar cells constitute 90% of the pancreas epithelium, are polarized, and secrete digestive enzymes. These cells play a crucial role in pancreatitis and pancreatic cancer. However, there are no models to study normal acinar cell differentiation in vitro. The aim of this work was to generate and characterize purified populations of pancreatic acinar cells from embryonic stem cells (ES).

Integrated Proteomic Profiling of Cell Line Conditioned Media and Pancreatic Juice for the Identification of Pancreatic Cancer Biomarkers

“…It is an extracellular matrix protein also found in stromal tissue (109). Mutations in this gene play a role in muscular disorders and differential COL6A1 gene expression has been associated with astrocytomas (110,111); however it has not been studied in pancreatic cancer and was found to be significantly increased in our preliminary assessment in plasma. Taken together, the increased levels of these proteins in pancreatic cancer plasma demonstrate the utility of our label-free differential protein quantification approach to identify proteins relevant for study as potential serological biomarkers of pancreatic cancer.…”

“…S2). In the exocrine pancreas, acinar cells are responsible for secretion of enzymes (zymogens) whereas ductal cells secrete primarily an alkaline fluid (114,115). Although the majority of pancreatic cancers are ductal adenocarcinomas with pancreatic ductal cell-like properties, the cell of origin of these cancers is still unclear (116,117).…”

c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis

“…Persistent c-Myc expression in acinar cells severely compromised their postnatal acinar maturation: at P1, a modest reduction in the levels of Ela1, Amy2a and Ctrb1 transcripts was observed, whereas carboxypeptidase 1 (Cpa1) transcripts were unaffected (figure 2B and online supplementary figure S2). Cpa1 is one of the earliest exocrine genes activated during pancreatic development/differentiation and a marker of acinar precursors, suggesting that the early acinar programme is not affected at this stage 2 35. At P11 and 8 weeks, all digestive enzyme transcripts and proteins were markedly reduced (figure 2B and online supplementary figure S2), indicating a severe disruption of the acinar programme.…”

Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis

“…At D5, Cpa1 and Ctrb1 transcript levels remained very low (1.6±0.3% and 1.3±0.3%) but significantly higher than those of Amy2 and Ela1 that were essentially undetectable (0.1%) (figure 1B). Interestingly, Cpa1 and Ctrb1 are markers of pancreatic multipotent progenitors and early acinar differentiation, respectively 23 24. Protein expression was assessed by immunocytochemistry: Cpa and Ctrb were detected in most cells while Amy expression was essentially undetectable at D5 (figure 1D).…”

“…We reach this conclusion using stringent molecular criteria: (1) Pdx1 and Ptf1a are differentially expressed in the endocrine and exocrine adult compartments yet are uniquely co-expressed in embryonic pancreatic progenitors8 and upon culture in suspension, most cells co-express both proteins; and (2) in these cells the aPTF1 complex is replaced by the ePTF1 complex, which is found on bona fide promoters on which it is active in embryonic pancreas 10 11. This is accompanied by the expression of low levels of ‘early’ digestive enzyme transcripts – such as Cpa1 and Ctrb123 24 – and the virtual absence of ‘late’ digestive enzyme transcripts (ie, Amy2 or Ela1). While the detection of transcript or protein might not represent newly synthesised molecular species, the demonstration by ChIP of the occupancy of the Cpa1 promoter by proteins of the ePTF1 complex, but not of the aPTF1 complex, strongly supports our conclusions.…”