Pancreatic and duodenal homeobox gene 1 induces hepatic dedifferentiation by suppressing the expression of CCAAT/enhancer-binding protein β

Abstract

It is believed that adult tissues in mammals lack the plasticity needed to assume new developmental fates because of the absence of efficient pathways of dedifferentiation. However, the well-documented ability of the transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) to activate pancreatic lineage development and insulin production following ectopic expression in liver suggests a surprising degree of residual plasticity in adult liver cells. This study seeks a mechanistic explanation for the capacity of PDX-1 to endow liver cells with pancreatic characteristics and function. We demonstrate that PDX-1, previously shown to play an essential role in normal pancreatic organogenesis and pancreatic ␤-cell function and to possess the potential to activate multiple pancreatic markers in liver, can also direct hepatic dedifferentiation. PDX-1 represses the adult hepatic repertoire of gene expression and activates the expression of the immature hepatic marker ␣-fetoprotein. We present evidence indicating that PDX-1 triggers hepatic dedifferentiation by repressing the key hepatic transcription factor CCAAT/enhancerbinding protein ␤. Hepatic dedifferentiation is necessary though not sufficient for the activation of the mature pancreatic repertoire in liver. Conclusion: Our study suggests a dual role for PDX-1 in liver: inducing hepatic dedifferentiation and activating the pancreatic lineage. The identification of dedifferentiation signals may promote the capacity to endow mature tissues in mammals with the plasticity needed for acquiring novel developmental fates and functions to be implemented in the field of regenerative medicine. (HEPATOLOGY 2007;46:898-905.)

Wnt/β‐catenin signaling is critical for dedifferentiation of aged epidermal cells in vivo and in vitro

“…Dedifferentiation is often associated with carcinogenesis and has been named 'anaplasia', that is, reversion of cells to an immature or a less-differentiated form. Besides tumors (Helm et al, 2005), these cells are found in muscle tissue (Chen et al, 2005), nervous tissue (Harrisingh et al, 2004;Sunico & Moreno-Lopez, 2010), renal tissue (Lluis et al, 2008), myocardial tissue (Jopling et al, 2010), hepatic tissue (Meivar-Levy et al, 2007), chondrocytes (Gustafson & Smith, 2010;Kiesslich et al, 2010), and others. In epidermal tissue, dedifferentiation-derived epidermal stem cell-like cells were found in spinous and granular layers of (Fu et al, 2001;Li et al, 2007).…”

Exendin-4 Promotes Liver Cell Proliferation and Enhances the PDX-1-induced Liver to Pancreas Transdifferentiation Process

“…The isolation of human liver cells was performed as described (3,5). The cells were cultured in Dulbecco's minimal essential medium (1 g/liter of glucose) supplemented with 10% fetal calf serum, exendin-4 (5 nM; Sigma), epidermal growth factor (20 ng/ml; Cytolab, Ltd.), and nicotinamide (10 mM; Sigma) and kept at 37°C in a humidified atmosphere of 5% CO 2 and 95% air.…”

“…The adenoviruses used in this study were as follows: Ad-CMV-PDX-1, Ad-RIP-GFP (3,5), Ad-CMV-GFP (Clontech), and Ad-GLUP-RED. Ad-GLUP-RED was prepared by insertion of 350 nucleotides of the 5Ј-flanking region of the rat glucagon promoter (generous gift from A. Manin) in the pACCMV.pLpA plasmid to drive ds-red2-n1 gene expression (KpnI/NotI, Invitrogen).…”

“…Reprogramming liver cells toward the beta cell lineage and function has been extensively studied both in vivo and in vitro (1)(2)(3)(4)(5)(6)(7)(8)(9). An important instructive role for pancreatic transcription factors in dictating the process has been suggested (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

“…An important instructive role for pancreatic transcription factors in dictating the process has been suggested (1)(2)(3)(4)(5)(6)(7)(8)(9). We have previously demonstrated that adult human liver cells can be propagated in vitro and induced to transdifferentiate along the pancreatic endocrine lineage using ectopic expression of PDX-1 (pancreatic and duodenal homeobox gene 1) (3).…”