Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.
OBJECTIVE
Factors released during liver injury, such as platelet derived growth factor-BB (PDGF), promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth.


METHODS
Primary rat hepatic stellate cells (HSC) were treated without or with PDGF, a pharmacologic inhibitor of PDGF-regulated kinases, adenovirus expressing activated or dominant negative AKT, or Hh signaling inhibitors. Shh production, expression of Hh inhibitors and target genes, and HSC growth were assessed.


RESULTS
HSC expressed Shh, Hh pathway components, and the Hh inhibitor, Hip. During culture Hip expression fell, Shh production increased, and Hh target gene expression was induced. Neutralizing Shh antibodies promoted apoptosis. Adding PDGF increased Shh expression and MFB growth. Both processes followed activation of AKT and were abrogated by AKT inhibitors. Adenoviral delivery of activated AKT up-regulated Shh expression, demonstrating a direct role for AKT in regulating Shh expression. Shh-neutralizing antibodies and other Hh pathway inhibitors blocked the mitogenic effects of PDGF.


CONCLUSIONS
These results identify Shh as an autocrine growth factor for MFB and suggest a role for Hh signaling in the pathogenesis of cirrhosis.
Yang
Liu
L
Gastroenterology and Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Wang
Ying
Y
Mao
Hua
H
Fleig
Susanne
S
Omenetti
Alessia
A
Brown
Kevin D
KD
Sicklick
Jason K
JK
Li
Yin-Xiong
YX
Diehl
Anna Mae
AM
D000256:Adenoviridae; D000818:Animals; D000963:Antimetabolites; D019898:Autocrine Communication / Q000502:physiology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D053148:Caspase 3 / Q000096:biosynthesis; D053179:Caspase 7 / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D005347:Fibroblasts / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics*; D022781:Hepatocytes / Q000473:pathology*; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000502:physiology; D020286:Pericytes / Q000187:drug effects / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014162:Transfection
D000963:Antimetabolites; D053823:Hedgehog Proteins; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D051058:Oncogene Protein v-akt; D053148:Caspase 3; D053179:Caspase 7; D001973:Bromodeoxyuridine