TY - JOUR
T1 - Role for Hedgehog signaling in hepatic stellate cell activation and viability
AU - Sicklick, Jason K.
AU - Li, Yin Xiong
AU - Choi, Steve S.
AU - Qi, Yi
AU - Chen, Wei
AU - Bustamante, Marcia
AU - Huang, Jiawen
AU - Zdanowicz, Marzena
AU - Camp, Terese
AU - Torbenson, Michael S.
AU - Rojkind, Marcos
AU - Diehl, Anna Mae
N1 - Funding Information:
We thank Dr PA Beachy for the kind gift of adult Ptc-lacZ mice used in these studies, as well as criticisms; Dr SL Friedman for the kind gift of the LX-2 human hepatic stellate cell line; Drs SS Karhadkar and J Kim for technical assistance, criticisms, and discussion; and DF Sandler for assistance with manuscript preparation. This work was supported by the National Institutes of Health grants RO1 AA010154 (AMD), RO1 DK053792 (AMD), RO1 AA012059 (AMD), RO1 AA01541 (MR), and T32 DK007713 (JKS).
PY - 2005/11
Y1 - 2005/11
N2 - Hepatic stellate cells (HSC) have a complex phenotype that includes both neural and myofibroblastic features. The Hedgehog (Hh) pathway has been shown to direct the fate of neural and myofibroblastic cells during embryogenesis and during tissue remodeling in adults. Therefore, we hypothesized that Hh signaling may regulate the fate of HSC in adults. In this study, we find that freshly isolated stellate cells from adult Patched-lacZ transgenic mice exhibit β-galactosidase activity, indicating Hh pathway activity. Transcripts of Hh ligands, the Hh pathway receptor, and Hh-regulated transcription factors are expressed by stellate cells from mice, rats, and humans. Transfection experiments in a cell line using a Hh-inducible luciferase reporter demonstrate constitutive Hh pathway activity. Moreover, neutralizing antibodies to Hh increase apoptosis, while viability is restored by treatment with Hh ligand. In vitro treatment of primary stellate cells with cyclopamine (Cyc), a pharmacologic inhibitor of the Hh pathway, inhibits activation and slightly decreases cell survival, while a single injection of Cyc into healthy adult mice reduces activation of HSC by more than 50% without producing obvious liver damage. Our findings reveal a novel mechanism, namely the Hh pathway, that regulates the activation and viability of HSC.
AB - Hepatic stellate cells (HSC) have a complex phenotype that includes both neural and myofibroblastic features. The Hedgehog (Hh) pathway has been shown to direct the fate of neural and myofibroblastic cells during embryogenesis and during tissue remodeling in adults. Therefore, we hypothesized that Hh signaling may regulate the fate of HSC in adults. In this study, we find that freshly isolated stellate cells from adult Patched-lacZ transgenic mice exhibit β-galactosidase activity, indicating Hh pathway activity. Transcripts of Hh ligands, the Hh pathway receptor, and Hh-regulated transcription factors are expressed by stellate cells from mice, rats, and humans. Transfection experiments in a cell line using a Hh-inducible luciferase reporter demonstrate constitutive Hh pathway activity. Moreover, neutralizing antibodies to Hh increase apoptosis, while viability is restored by treatment with Hh ligand. In vitro treatment of primary stellate cells with cyclopamine (Cyc), a pharmacologic inhibitor of the Hh pathway, inhibits activation and slightly decreases cell survival, while a single injection of Cyc into healthy adult mice reduces activation of HSC by more than 50% without producing obvious liver damage. Our findings reveal a novel mechanism, namely the Hh pathway, that regulates the activation and viability of HSC.
KW - Cirrhosis
KW - Cyclopamine
KW - Liver
KW - Myofibroblast
KW - Neuroendocrine cells
KW - Patched
UR - http://www.scopus.com/inward/record.url?scp=27144554034&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27144554034&partnerID=8YFLogxK
U2 - 10.1038/labinvest.3700349
DO - 10.1038/labinvest.3700349
M3 - Article
C2 - 16170335
AN - SCOPUS:27144554034
SN - 0023-6837
VL - 85
SP - 1368
EP - 1380
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 11
ER -