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Aberrant Hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish

 In Hye Jung  ;  Dawoon E. Jung  ;  Young Nyun Park  ;  Si Young Song  ;  Seung Woo Park 
 PLOS ONE, Vol.6(12) : e27941, 2011 
Journal Title
Issue Date
Animals ; Animals, Genetically Modified ; Cell Differentiation ; DNA Primers/genetics ; Fibroblasts/cytology* ; Fibrosis/pathology* ; Green Fluorescent Proteins/metabolism ; Hedgehog Proteins/biosynthesis ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism* ; Immunohistochemistry/methods ; In Situ Hybridization ; Ligands ; Pancreas/pathology* ; Phenotype ; Transgenes ; Zebrafish ; Zebrafish Proteins/biosynthesis ; Zebrafish Proteins/genetics
Hedgehog (Hh) signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP) to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1), Smoothened (Smo), and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs), especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1) only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4). Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of MMPs and TGFß1 by Hh signaling expands on the current understanding of how Hh signaling affects fibrosis and tumorigenesis. These transgenic models will be a valuable platform in exploring the mechanism of fibrogenic pancreatic diseases which are induced by Hh signaling activation.
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1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Institute of Gastroenterology (소화기병연구소) > 1. Journal Papers
Yonsei Authors
Park, Seung Woo(박승우) ORCID logo https://orcid.org/0000-0001-8230-964X
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Song, Si Young(송시영) ORCID logo https://orcid.org/0000-0002-1417-4314
Jung, Dawoon E.(정다운)
Jung, In Hye(정인혜)
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