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Cited by 15Liver physiology and pathologyWnt/β-catenin signaling in development and cancerLiver Disease Diagnosis and Treatment

Elimination of Wnt Secretion From Stellate Cells Is Dispensable for Zonation and Development of Liver Fibrosis Following Hepatobiliary Injury

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Zhang, Rong, Kikuchi, Alexander T., Nakao, Toshimasa, Russell, Jacquelyn O., Preziosi, Morgan E., Poddar, Minakshi, Singh, Sucha, Bell, Aaron W. +2 more·2019·Gene Expression
DOI 10.3727/105221618x15373858350141PMC PMC6466178
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Abstract

Alterations in the Wnt signaling pathway including those impacting hepatic stellate cells (HSCs) have been implicated in liver fibrosis. In the current study, we first examined the expression of Wnt genes in human HSC (HHSCs) after treatment with a profibrogenic factor TGF-β1. Next, we generated HSC-specific Wntless (Wls) knockout (KO) using the Lrat-cre and Wls-floxed mice. KO and littermate controls (CON) were characterized for any basal phenotype and subjected to two liver fibrosis protocols. In vitro, TGF-β1 induced expression of Wnt2, 5a and 9a while decreasing Wnt2b, 3a, 4, and 11 in HHSC. In vivo, KO and CON mice were born at normal Mendelian ratio and lacked any overt phenotype. Loss of Wnt secretion from HSCs had no effect on liver weight and did not impact β-catenin activation in the pericentral hepatocytes. After 7 days of bile duct ligation (BDL), KO and CON showed comparable levels of serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin. Comparable histology, Sirius red staining, and immunohistochemistry for α-SMA, desmin, Ki-67, F4/80, and CD45 indicated similar proliferation, inflammation, and portal fibrosis in both groups. Biweekly administration of carbon tetrachloride for 4 or 8 weeks also led to comparable serum biochemistry, inflammation, and fibrosis in KO and CON. Specific Wnt genes were altered in HHSCs in response to TGF-β1; however, eliminating Wnt secretion from HSC did not impact basal β-catenin activation in normal liver nor did it alter the injury‐repair response during development of liver fibrosis.

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  • HSC-secreted WNTs do not mediate the alterations observed in HSC-depleted mice.

    “These findings align with previous studies30 and exclude HSC-secreted WNTs mediating the alterations observed in HSC-depleted mice.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [30]

    The Discussion reports that blocking WNT secretion from HSCs did not change HSC activation or liver fibrosis in the injury models studied. But the Materials and Methods describe mice with HSC-specific Wls deletion, not HSC-depleted mice; the paper therefore does not establish that HSC-secreted WNTs cannot mediate the alterations observed after HSC depletion. (LLM, conf=0.88)

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Authors
Zhang, R., Kikuchi, A. T., Nakao, T., Russell, J. O., Preziosi, M. E., Poddar, M., Singh, S., Bell, A. W., England, S. G., & Monga, S. P.
Affiliations
  • University of Pittsburgh (US)
  • Kyoto Prefectural University (JP)
  • AbbVie (United States) (US)
ORCID
Venue
Gene Expression
Publisher
Xia & He Publishing
Published
2019-04-18
Volume
19
Issue
2
Pages
121-136
ISSN
1052-2166 (ISSN-L)
DOI
10.3727/105221618x15373858350141
PMC
PMC6466178
OpenAlex
W2890344834
Cited by
15
References
49
Citations by year
2026: 1 · 2025: 3 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 1
FWCI
0.78
Type
journal article
Language
en
Open access
Locations
  • Gene Expression (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01CA204586)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100287, R01DK062277)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
Wnt signaling, hepatic stellate cells, Wnt secretion, liver fibrosis, TGF-β1, bile duct ligation, carbon tetrachloride, zonation, β-catenin activation
MeSH terms
Animals, Biliary Tract, Cells, Cultured, Female, Humans, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Mice, Knockout, Wnt Proteins, beta Catenin, Mice, Transforming Growth Factor beta1, Hepatic Stellate Cells, Wnt Signaling Pathway

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