Pancreatic Duodenal Homeobox-1 de novo expression drives cholangiocyte neuroendocrine-like transdifferentiation.
OBJECTIVE
Reactive cholangiocytes acquire a neuroendocrine-like phenotype, with synthesis and local release of neuropeptides and hormones. The mechanism that drives such phenotypical changes is still undefined. Pancreatic Duodenal Homeobox-1 (PDX-1) is a transcription factor required for pancreatic development, that sustains pancreatic beta-cell response to injury and insulin synthesis. PDX-1 induces neuroendocrine-like transition of pancreatic ductal cells. Cholangiocyte response to injury is modulated by Glucagon-Like Peptide-1 Receptor (GLP-1R), which, in the pancreas, activates PDX-1. We wanted to verify whether PDX-1 plays any role in cholangiocyte neuroendocrine-like transdifferentiation in response to injury.


METHODS
PDX-1 expression was assessed in cholangiocytes from normal and one week bile duct ligated (BDL) rats. Changes in PDX-1 expression and activation upon GLP-1R activation were then assayed. The effects of the lack of PDX-1 in cholangiocytes were studied in vitro by siRNA and in vivo by the employment of PDX-1-deficient (+/-) mice.


RESULTS
BDL but not normal cholangiocytes express PDX-1. GLP-1R activation elicits, in a PI3K-dependent fashion, PDX-1 expression, together with its nuclear translocation. In vitro, GLP-1R-induced increases in VEGF and IGF-1 mRNA expression were blunted in cells with PDX-1 siRNA. In vivo, the VEGF and IGF-1 mRNA expression in the liver after one week BDL was markedly reduced in PDX-1-deficient mice, together with reduced bile duct mass.


CONCLUSIONS
In response to injury, reactive cholangiocytes de novo express PDX-1, the activation of which allows cholangiocytes to synthesize IGF-1 and VEGF. These findings suggest that PDX-1 drives the acquisition of the neuroendocrine-like phenotype by cholangiocytes in response to cholestatic injury.
Marzioni
Marco
M
Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy. m.marzioni@univpm.it
Saccomanno
Stefania
S
Candelaresi
Cinzia
C
Rychlicki
Chiara
C
Agostinelli
Laura
L
Shanmukhappa
Kumar
K
Trozzi
Luciano
L
Pierantonelli
Irene
I
De Minicis
Samuele
S
Benedetti
Antonio
A
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D051381:Rats; D015534:Trans-Activators / Q000235:genetics*
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein