Expression of the Notch Signaling Pathway and Effect on Exocrine Cell Proliferation in Adult Rat Pancreas

Abstract

When pancreatic tissue is injured after duct obstruction, acinoductal metaplasia is observed. Similar metaplastic changes occur when exocrine pancreatic cells are isolated and cultured. We demonstrate that under these experimental conditions the exocrine acinar cells lose their differentiated characteristics: expression of the acinar transcription factors p48/ Ptf1␣ and Mist1 is decreased or lost, whereas expression of the embryonic transcription factor Pdx1 is increased. The receptors Notch1 and Notch2, members of the DSL family of Notch ligands, and the target genes in the Notch-signaling pathway Hes1, Hey1, and Hey2 become strongly up-regulated. We noted also reduced expression of Sel1L, a Notch repressor that is normally highly expressed in exocrine pancreas. Stimulation of Notch by its ligand Jagged1 diminished the proliferation of cultured metaplastic exocrine cells. Chemical inhibition of Notch signaling resulted in increased proliferation and induction of the cell-cycle regulator p21Cip1 . This effect seems to be Hes1-independent and mainly coincides with decreased Hey1 and Hey2 mRNA expression. In conclusion , we demonstrate that during acinoductal metaplasia the Notch-signaling pathway is activated concomitantly with changes in transcription factor expression of pancreatic acinar cells. In addition, we show that Notch signaling is implicated in the suppression of proliferation of these metaplastic exocrine cells. The latter may be important in protection from neoplastic transformation.

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

“…The signalling pathways proposed to be activated under these conditions are mediated by Notch and EGF transduction which lead to the transdifferentiation of acinar cells to a ductal lineage (2;3;40). We have not detected clear changes in the activation of the Notch signalling pathway in the culture conditions tested here (not shown) and the expression of Pdx1, which is induced during the acinar-ductal switch, was also not regulated (40). Because acinar cells express much higher levels of digestive enzymes in the adult than during development, it is possible that only when committed cells terminally achieve a mature differentiation program are the protective mechanisms to bypass the lytic potential of their products activated.…”

“…In all cases, acinar-ductal metaplasia/transdifferentiation occurs in association with a rapid loss of functional properties (39)(40)(41)(42). Here, we describe for the first time, the development of immature acinar cells using the ES-EB model which recapitulates many cues and signals required for the exocrine development in vivo.…”

Gene transcription profiles, global DNA methylation and potential transgenerational epigenetic effects related to Zn exposure history in Daphnia magna

“…Interestingly, the gene with homology to sel-1 suppressor of lin-12-like was upregulated. This protein is known as a repressor of the Notch signaling pathway (Rooman et al, 2006). Activation of the Notch pathway was shown to be crucial for hypermethylation of a gene in Drosophila (Ferres-Marco et al, 2006).…”

Hes1: a key role in stemness, metastasis and multidrug resistance

“…[6][7][8][9][10][11] The expression of Hes1 induced by Notch can be detected more than embryo neural stem cells, intestinal crypt progenitor cells, pancreatic stem cells, bone marrow mesenchymal progenitors and quiescent skeletal muscle stem cells. 9,10,[68][69][70][71] Treatment with g-secretase inhibitor (GSI) results in the suppression of Hes1 and the differentiating state of those stem cells, indicating the role of the Notch pathway in Hes1 expression, as well as the essential status of the Notch-Hes1 pathway in facilitating cell fate decisions and regulating differentiation during development.…”