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Role for Hedgehog signaling in hepatic stellate cell activation and viability
Open accessAbstract
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 beta-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.
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“NKT cells secrete HSC activating ligands sonic hedgehog (Shh) and osteopontin (Opn) in the MCD mouse model of NASH (117–120).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [117]
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Metadata
- Authors
- Sicklick, J. K., Li, Y.-X., Choi, S. S., Qi, Y., Chen, W., Bustamante, M., Huang, J., Zdanowicz, M., Camp, T., Torbenson, M. S., Rojkind, M., & Diehl, A. M.
- Affiliations
- Duke University (US)
- George Washington University (US)
- Johns Hopkins University (US)
- Corresponding author
- Diehl, Anna Mae
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2005-11
- Volume
- 85
- Issue
- 11
- Pages
- 1368-1380
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W1981442583
- Cited by
- 179
- References
- 77
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 9 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 13 · 2018: 10 · 2017: 13 · 2016: 9 · 2015: 9 · 2014: 11 · 2013: 9 · 2012: 11
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (RO1 DK053792, AA010154)
- National Institute on Alcohol Abuse and Alcoholism (R01 AA01541, R01AA012059, R01AA010154)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007713, R01DK053792)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- Hedgehog signaling, hepatic stellate cells, stellate cell activation, cell viability, apoptosis, cyclopamine, Patched1, liver fibrosis, myofibroblast differentiation
- MeSH terms
- Animals, Antibodies, beta-Galactosidase, Cell Survival, Cells, Cultured, Clone Cells, Dose-Response Relationship, Drug, Humans, Ligands, Luciferases, Male, Mice, Inbred C57BL, Mice, Transgenic, Recombinant Proteins, Veratrum Alkaloids, Signal Transduction, Trans-Activators, Apoptosis, Genes, Reporter, Hepatocytes, Mice, Hedgehog Proteins
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