Role of Cadherin-mediated Cell-Cell Adhesion in Pancreatic Exocrine-to-Endocrine Transdifferentiation

Abstract

Although pancreatic exocrine acinar cells have the potential to transdifferentiate into pancreatic endocrine cells, the mechanisms are poorly understood. Here we report that intracellular signaling pathways, including those involving MAPK and phosphatidylinositol 3 (PI3)-kinase, are activated by enzymatic dissociation of pancreatic acinar cells and that spherical cell clusters are formed by cadherin-mediated cell-cell adhesion during transdifferentiation. Inhibition of PI3-kinase by LY294002 prevents spheroid formation by degrading E-cadherin and ␤-catenin, blocking transdifferentiation into insulin-secreting cells. In addition, neutralizing antibody against E-cadherin suppresses the induction of genes characteristic of pancreatic ␤-cells. We also show that loss of cadherin-mediated cell-cell adhesion induces and maintains a dedifferentiated state in isolated pancreatic acinar cells. Thus, disruption and remodeling of cadherin-mediated cell-cell adhesion is critical in pancreatic exocrine-to-endocrine transdifferentiation, in which the PI3-kinase pathway plays an essential role.

Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells

“…2D) and b-catenin mRNA (data not shown) that were involved in cell-cell adhesion. Inhibition of the functional activities of E-cadherin and catenins blocked the formation of pancreatic b-cells (Dahl et al 1996, Minami et al 2008. In this study, we found that single AsPC-1 cell that did not form the cluster produced no glucagon (data not shown), whereas glucagon production was prominent among cluster-forming cells.…”

“…Pancreatic a-cell differentiation is exquisitely regulated by various factors including transcription factor Pax6 (St-Onge et al 1997), Pdx-1 (Wilson et al 2003, Jensen 2004) and ISL1 (Wang & Drucker 1995) as well as PC2 (Vincent et al 2003), while cadherinmediated cell-cell adhesion is also critical in pancreatic islet differentiation (Dahl et al 1996, Minami et al 2008. Accordingly, we examined the expression of these genes during the AsPC-1 cell differentiation by RT-PCR analysis.…”

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

“…Similarly, adult acinar cells genetically labelled with an amylase promoter-driven Cre recombinase gave rise to new insulin-secreting cells following treatment in vitro with EGF and nicotinamide (Minami et al 2005). The mechanisms are not well understood but may A c c e p t e d M a n u s c r i p t involve disruption and remodelling of cadherin-mediated intercellular contacts by phosphatidyl inositol 3-kinase mediated pathways (Minami et al 2008). The physiological relevance of these in vitro studies is unclear since in vivo support has been indirect (Lardon et al 2004), and recent in vivo lineage tracing studies provide strong evidence that pre-existing acinar cells can give rise to acinar cells but not β cells using several models of pancreatic injury in mice (Desai et al 2007).…”

Pancreatic Stem Cells: Unresolved Business

“…More recently, analysis using the Cre/loxPbased tracing system demonstrated that amylase/elastase-expressing acinar cells can give rise to insulin-positive cells in a suspension culture (Minami et al, 2005). However, because clonal assay of these amylase/elastase-expressing cells and their intermediate steps have not been investigated, this study may simply reveal that mouse and rat pancreatic acinar cells are able to transdifferentiate into surrogate insulin-expressing cells (Baeyens et al, 2005;Minami et al, 2008). This possibility was further supported by a recent study which shows that mouse acinar cells can be directly re-programmed in vivo to β-like cells with just three transcription factor genes, namely, Pdx1, Ngn3 and MafA (Zhou et al, 2008).…”