Endothelial Wnts regulate β‐catenin signaling in murine liver zonation and regeneration: A sequel to the Wnt–Wnt situation
Open accessAbstract
β‐Catenin in hepatocytes, under the control of Wnts, regulates pericentral gene expression. It also contributes to liver regeneration (LR) after partial hepatectomy (PH) by regulating cyclin‐D1 gene expression as shown in the β‐catenin and Wnt coreceptors low‐density lipoprotein receptor‐related protein 5/6 conditional knockouts (KO). However, conditional deletion of Wntless (Wls), required for Wnt secretion, in hepatocytes, cholangiocytes, or macrophages lacked any impact on zonation, while Wls deletion in macrophages only marginally affected LR. Here, we address the contribution of hepatic endothelial cells (ECs) in zonation and LR by characterizing EC‐Wls‐KO generated by interbreeding Wls‐floxed and lymphatic vessel endothelial hyaluronan receptor (Lyve1)‐cre mice. These mice were also used to study LR after PH. While Lyve1 expression in adult liver is limited to sinusoidal ECs only, Lyve1‐cre mice bred to ROSA26‐Stop flox/flox ‐enhanced yellow fluorescent protein (EYFP) mice showed EYFP labeling in sinusoidal and central vein ECs. EC‐Wls‐KO mice showed decreased liver weights; lacked glutamine synthetase, cytochrome P450 2e1, and cytochrome P450 1a2; and were resistant to acetaminophen‐induced liver injury. After PH, EC‐Wls‐KO showed quantitative and qualitative differences in cyclin‐D1 expression at 24‐72 hours, which led to a lower hepatocyte proliferation at 40 hours but a rebound increase by 72 hours. ECs and macrophages isolated from regenerating livers at 12 hours showed significant up‐regulation of Wnt2 and Wnt9b messenger RNA; these are the same two Wnts involved in baseline β‐catenin activity in pericentral hepatocytes. Conclusion : At baseline, ECs secrete Wnt proteins essential for β‐catenin activation in pericentral hepatocytes. During LR, sinusoidal and central vein ECs and secondarily macrophages secrete Wnt2, while predominantly central vein ECs and secondarily macrophages are the likely source of Wnt9b. This process spatiotemporally regulates β‐catenin activation in hepatocytes to induce cell proliferation. ( Hepatology Communications 2018;2:845‐860)
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Liver zonation and functions are regulated by a 'ménage à trois' of WNT-secreting ECs, RSPO3-secreting HSCs and hepatocytes expressing the R-spondin receptors LGR4 and LGR5.
“Our data amend the purely angiocrine model of liver zonation29,41,56,57 and suggest that liver zonation and functions are regulated by a ‘ménage à trois’ of WNT-secreting ECs, RSPO3-secreting HSCs and hepatocytes expressing the R-spondin receptors LGR4 and LGR524.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [57]
The Discussion (page not available in our copy) supports the role of endothelial-cell Wnt2 and Wnt9b in activating β-catenin signaling in hepatocytes during liver zonation. It does not establish the claimed three-cell arrangement: the Figure 7 discussion says the role of stellate cells in this signaling during regeneration remains unknown, and the cited passages do not identify RSPO3-secreting HSCs or hepatocyte LGR4/LGR5 receptors. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWNT2, WNT9B and RSPO3 ligands secreted from central vein endothelial cells and adjacent liver sinusoidal endothelial cells, as well as distinct expression patterns of regulatory elements of the WNT/β-catenin pathway along the porto-central axis, result in a centro-portal gradient of WNT/β-catenin signalling.
“WNT2, WNT9B and RSPO3 ligands secreted from central vein endothelial cells and adjacent liver sinusoidal endothelial cells,25,43,45,46,49 as well as distinct expression patterns of regulatory elements of the WNT/β-catenin pathway along the porto-central axis,22,42,44 result in a centro-portal gradient of WNT/β-catenin signalling.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [45]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredOur data suggest a model in which the Wnt ligand is produced by endothelial cells in the central vein, creating a decreasing gradient of Wnt from the central to the portal vein.
“Our data suggests a model (Fig 6) in which the Wnt ligand is produced by endothelial cells in the central vein70, creating a decreasing gradient of Wnt from the central to the portal vein.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [70]
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A Spatial Atlas of Wnt Receptors in Adult Mouse Liver
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Acevedo‐Acevedo, S., Stefkovich, M. L., Kang, S. W. S., Cunningham, R. P., Cultraro, C. M., & Porat‐Shliom, N. (2022) · Hepatology Communications · doi:10.1002/hep4.1942 · Cited by 7 · see citing works
- Authors
- Preziosi, M., Okabe, H., Poddar, M., Singh, S., & Monga, S. P.
- Affiliations
- University of Pittsburgh (US)
- Kumamoto University (JP)
- Corresponding author
- Monga, Satdarshan P.
- Venue
- Hepatology Communications
- Published
- 2018-06-21
- Volume
- 2
- Issue
- 7
- Pages
- 845-860
- ISSN
- 2471-254X (ISSN-L)
- PMC
- PMC6049069
- OpenAlex
- W2809434958
- Cited by
- 135
- References
- 36
- Citations by year
- 2026: 6 · 2025: 21 · 2024: 19 · 2023: 19 · 2022: 15 · 2021: 19 · 2020: 18 · 2019: 13 · 2018: 5
- FWCI
- 8.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Hepatology Communications (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (F31CA216994, 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 › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- β-catenin signaling, liver zonation, liver regeneration, partial hepatectomy, Wntless, Wnt secretion, hepatic endothelial cells, sinusoidal endothelium, macrophages, Wnt2, Wnt9b, cyclin D1, acetaminophen hepatotoxicity, glutamine synthetase
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