Metabolic and non-metabolic liver zonation is established non-synchronously and requires sinusoidal Wnts
Open accessAbstract
The distribution of complementary metabolic functions in hepatocytes along a portocentral axis is called liver zonation. Endothelial secreted Wnt ligands maintain metabolic zonation in the adult murine liver but whether those ligands are necessary to initiate zonation in the immature liver has been only partially explored. Also, numerous non-metabolic proteins display zonated expression in the adult liver but it is not entirely clear if their localization requires endothelial Wnts. Here we used a novel transgenic mouse model to compare the spatial distribution of zonated non-metabolic proteins with that of typical zonated metabolic enzymes during liver maturation and after acute injury induced by carbon tetrachloride (CCl4). We also investigated how preventing Wnt ligand secretion from endothelial cells affects zonation patterns under homeostasis and after acute injury. Our study demonstrates that metabolic and non-metabolic zonation are established non-synchronously during maturation and regeneration and require multiple endothelial Wnt sources.
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WNT2, 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 [43]
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Experimental — accuracy not yet measuredWNT/β-catenin signalling controlled by the RSPO-LGR4/5-ZNRF3/RNF43 module is a major determinant of hepatocyte identity and metabolic function in the liver.
“WNT/β-catenin signalling controlled by the RSPO-LGR4/5-ZNRF3/RNF43 module is a major determinant of hepatocyte identity and metabolic function in the liver.22,[42], [43], [44], [45], [46], [47], [48]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [43]
The Discussion (page unavailable) identifies Wnt/β-catenin signalling as a key regulator of metabolic hepatic zonation and reports that endothelial Wnts also regulate non-metabolic hepatocyte zonation. The Results (page unavailable) show that Rspo3 enhances a Wnt-induced metabolic gene response. The paper does not establish that the full RSPO-LGR4/5-ZNRF3/RNF43 module controls hepatocyte identity; that module appears in the title of a cited work in the References. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThis fate adoption is likely induced by locally confined secretion of WNT and RSPO ligands from the central vein endothelium and neighbouring sinusoidal endothelial cells.
“This fate adoption is likely induced by locally confined secretion of WNT and RSPO ligands from the central vein endothelium and neighbouring sinusoidal endothelial cells.25,43”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [43]
The Results section on LSEC Wnt secretion (Figure 3A; page unavailable) finds Wnt2, Wnt9b and Rspo3 transcripts in central-vein cells and nearby sinusoidal endothelial cells in newborn mice, consistent with a local source of these ligands. But it reports that LSEC Wnt secretion is dispensable for initially establishing hepatic zonation, so the proposed role of neighbouring sinusoidal cells in inducing initial fate adoption is not established; the passage also measures ligand transcripts rather than secretion of both WNT and RSPO. (LLM, conf=0.82)
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Cites
Macrophage plasticity, polarization, and function in health and disease
Shapouri‐Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S., Mardani, F., Seifi, B., Mohammadi, A., Afshari, J. T., & Sahebkar, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26429 · Cited by 4,930 · see citing works
A gene expression atlas of the central nervous system based on bacterial artificial chromosomes
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., et al. (2003) · Nature · doi:10.1038/nature02033 · Cited by 2,108 · see citing works
Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
Wang, B., Zhao, L., Fish, M., Logan, C. Y., & Nusse, R. (2015) · Nature · doi:10.1038/nature14863 · Cited by 674 · see citing works
The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size
Planas-Paz, L., Orsini, V., Boulter, L., Calabrese, D., Pikiolek, M., Nigsch, F., Xie, Y., Roma, G., Donovan, A., Marti, P., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3337 · Cited by 359 · see citing works
Liver zonation: Novel aspects of its regulation and its impact on homeostasis
Gebhardt, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i26.8491 · Cited by 275 · see citing works
Broad Distribution of Hepatocyte Proliferation in Liver Homeostasis and Regeneration
Chen, F., Jimenez, R. J., Sharma, K., Luu, H. Y., Hsu, B. Y., Ravindranathan, A., Stohr, B. A., & Willenbring, H. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.11.001 · Cited by 236 · see citing works
AXIN2+ Pericentral Hepatocytes Have Limited Contributions to Liver Homeostasis and Regeneration
Sun, T., Pikiolek, M., Orsini, V., Bergling, S., Holwerda, S., Morelli, L., Hoppe, P. S., Planas-Paz, L., Yang, Y., Ruffner, H., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.10.011 · Cited by 166 · see citing works
Preziosi, M., Okabe, H., Poddar, M., Singh, S., & Monga, S. P. (2018) · Hepatology Communications · doi:10.1002/hep4.1196 · Cited by 135 · see citing works
Lüdtke, T. H. ‐., Christoffels, V. M., Petry, M., & Kispert, A. (2009) · Hepatology · doi:10.1002/hep.22700 · Cited by 117 · cited 1× · see citing works
“…Cyp2e1– hepatocytes repaired the damaged Zone 2 through proliferation: 1) those cells expressed the regulator of hepatic progenitor proliferation Tbx3 [(Lüdtke et al., 2009; 2) both Cyp2e1+ hepatocytes and Cyp2e1– hepatocytes incorporated EdU in their DNA and retained this label for up to 5 days.”
BackgroundAngiocrine Wnt signaling controls liver growth and metabolic maturation in mice
Leibing, T., Géraud, C., Augustin, I., Boutros, M., Augustin, H. G., Okun, J. G., Langhans, C., Zierow, J., Wohlfeil, S. A., Olsavszky, V., et al. (2018) · Hepatology · doi:10.1002/hep.29613 · Cited by 116 · see citing works
Yeh, T.-H., Krauland, L., Singh, V., Zou, B., Devaraj, P., Stolz, D. B., Franks, J., Monga, S. P. S., Sasatomi, E., & Behari, J. (2010) · Hepatology · doi:10.1002/hep.23801 · Cited by 81 · see citing works
Flagged first, then by citations
Research works printed but not linked: 24
- Benhamouche S Decaens T Godard C Chambrey R Rickman DS Moinard C Vasseur-Cognet M Kuo CJ Kahn A Perret C Colnot S 2006 Apc tumor suppressor gene is the "zonation-keeper" of mouse liver Developmental Cell 10 759 770 10.1016/j.devcel.2006.03.015 16740478 · DOI · Paper page
- Burke ZD Reed KR Phesse TJ Sansom OJ Clarke AR Tosh D 2009 Liver zonation occurs through a beta-catenin-dependent, c-Myc-independent mechanism Gastroenterology 136 2316 2324 10.1053/j.gastro.2009.02.063 19268669 · DOI · Paper page
- Burke ZD Reed KR Yeh SW Meniel V Sansom OJ Clarke AR Tosh D 2018 Spatiotemporal regulation of liver development by the wnt/β-catenin pathway Scientific Reports 8 2735 10.1038/s41598-018-20888-y 29426940 PMC5807466 · DOI
- Carpenter AC Rao S Wells JM Campbell K Lang RA 2010 Generation of mice with a conditional null allele for wntless Genesis 48 554 558 10.1002/dvg.20651 20614471 PMC3689319 · DOI
- Ding BS Nolan DJ Butler JM James D Babazadeh AO Rosenwaks Z Mittal V Kobayashi H Shido K Lyden D Sato TN Rabbany SY Rafii S 2010 Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration Nature 468 310 315 10.1038/nature09493 21068842 PMC3058628 · DOI
- Font-Burgada J Shalapour S Ramaswamy S Hsueh B Rossell D Umemura A Taniguchi K Nakagawa H Valasek MA Ye L Kopp JL Sander M Carter H Deisseroth K Verma IM Karin M 2015 Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer Cell 162 766 779 10.1016/j.cell.2015.07.026 26276631 PMC4545590 · DOI · Paper page
- Gerbal-Chaloin S Dumé AS Briolotti P Klieber S Raulet E Duret C Fabre JM Ramos J Maurel P Daujat-Chavanieu M 2014 The WNT/β-catenin pathway is a transcriptional regulator of CYP2E1, CYP1A2, and aryl hydrocarbon receptor gene expression in primary human hepatocytes Molecular Pharmacology 86 624 634 10.1124/mol.114.094797 25228302 · DOI
- Halpern KB Shenhav R Massalha H Toth B Egozi A Massasa EE Medgalia C David E Giladi A Moor AE Porat Z Amit I Itzkovitz S 2018 Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells Nature Biotechnology 36 962 970 10.1038/nbt.4231 30222169 PMC6546596 · DOI · Paper page
- Hu J Srivastava K Wieland M Runge A Mogler C Besemfelder E Terhardt D Vogel MJ Cao L Korn C Bartels S Thomas M Augustin HG 2014 Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat Science 343 416 419 10.1126/science.1244880 24458641 · DOI
- Jungermann K Katz N 1989 Functional specialization of different hepatocyte populations Physiological Reviews 69 708 764 10.1152/physrev.1989.69.3.708 2664826 · DOI
- Lehwald N Tao GZ Jang KY Sorkin M Knoefel WT Sylvester KG 2011 Wnt-beta-catenin signaling protects against hepatic ischemia and reperfusion injury in mice Gastroenterology 718 701 705 10.1053/j.gastro.2011.04.051 PMC4084974 21679710 · DOI
- Matsumoto K Imasato M Yamazaki Y Tanaka H Watanabe M Eguchi H Nagano H Hikita H Tatsumi T Takehara T Tamura A Tsukita S 2014 Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice Gastroenterology 147 1134 1145 10.1053/j.gastro.2014.07.033 25068494 · DOI
- Matsumoto T Wakefield L Tarlow BD Grompe M 2020 In Vivo Lineage Tracing of Polyploid Hepatocytes Reveals Extensive Proliferation during Liver Regeneration Cell Stem Cell 26 34 47 10.1016/j.stem.2019.11.014 31866222 PMC7204404 · DOI · Paper page
- Mouta Carreira C Nasser SM di Tomaso E Padera TP Boucher Y Tomarev SI Jain RK 2001 LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver Cancer and cirrhosis Cancer Research 61 8079 8084 11719431
- Notenboom RG Moorman AF Lamers WH 1997 Developmental appearance of ammonia-metabolizing enzymes in prenatal murine liver Microscopy Research and Technique 39 413 423 10.1002/(SICI)1097-0029(19971201)39:5<413::AID-JEMT4>3.0.CO;2-H 9408908 · DOI
- Pham TH Baluk P Xu Y Grigorova I Bankovich AJ Pappu R Coughlin SR McDonald DM Schwab SR Cyster JG 2010 Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning The Journal of Experimental Medicine 207 17 27 10.1084/jem.20091619 20026661 PMC2812554 · DOI · Paper page
- Pu W Zhang H Huang X Tian X He L Wang Y Zhang L Liu Q Li Y Li Y Zhao H Liu K Lu J Zhou Y Huang P Nie Y Yan Y Hui L Lui KO Zhou B 2016 Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration Nature Communications 7 13369 10.1038/ncomms13369 27857132 PMC5120209 · DOI · Paper page
- Rahner C Mitic LL Anderson JM 2001 Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut Gastroenterology 120 411 422 10.1053/gast.2001.21736 11159882 · DOI
- Rocha AS Vidal V Mertz M Kendall TJ Charlet A Okamoto H Schedl A 2015 The angiocrine factor Rspondin3 is a key determinant of liver zonation Cell Reports 13 1757 1764 10.1016/j.celrep.2015.10.049 26655896 · DOI · Paper page
- Sekine S Lan BY Bedolli M Feng S Hebrok M 2006 Liver-specific loss of beta-catenin blocks glutamine synthesis pathway activity and cytochrome p450 expression in mice Hepatology 43 817 825 10.1002/hep.21131 16557553 · DOI · Paper page
- Tanaka M Miyajima A 2016 Liver regeneration and fibrosis after inflammation Inflammation and Regeneration 36 19 10.1186/s41232-016-0025-2 29259692 PMC5725806 · DOI
- Wang Y Nakayama M Pitulescu ME Schmidt TS Bochenek ML Sakakibara A Adams S Davy A Deutsch U Lüthi U Barberis A Benjamin LE Mäkinen T Nobes CD Adams RH 2010 Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis Nature 465 483 486 10.1038/nature09002 20445537 · DOI
- Yang J Mowry LE Nejak-Bowen KN Okabe H Diegel CR Lang RA Williams BO Monga SP 2014 β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation! Hepatology 60 964 976 10.1002/hep.27082 24700412 PMC4139486 · DOI
- Zhao L Jin Y Donahue K Tsui M Fish M Logan CY Wang B Nusse R 2019 Tissue repair in the mouse liver following acute carbon tetrachloride depends on Injury-Induced wnt/beta-Catenin signaling Hepatology 69 2623 2635 10.1002/hep.30563 30762896 PMC7043939 · DOI · Paper page
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Hu, S., Liu, S., Bian, Y., Poddar, M., Singh, S., Cao, C., McGaughey, J., Bell, A., Blazer, L. L., Adams, J. J., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100754 · Cited by 118 · see citing works
Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions
Kaffe, E., Roulis, M., Zhao, J., Qu, R., Sefik, E., Mirza, H., Zhou, J., Zheng, Y., Charkoftaki, G., Vasiliou, V., et al. (2023) · Cell · doi:10.1016/j.cell.2023.07.017 · Cited by 99 · see citing works
Multi-zonal liver organoids from human pluripotent stem cells
Reza, H. A., Santangelo, C., Iwasawa, K., Reza, A. A., Sekiya, S., Glaser, K., Bondoc, A., Merola, J., & Takebe, T. (2025) · Nature · doi:10.1038/s41586-025-08850-1 · Cited by 71 · see citing works
Role and Regulation of Wnt/β-Catenin in Hepatic Perivenous Zonation and Physiological Homeostasis
Goel, C., Monga, S. P., & Nejak-Bowen, K. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.09.007 · Cited by 53 · see citing works
The RSPO‐LGR4/5‐ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease
Annunziato, S., Sun, T., & Tchorz, J. S. (2022) · Hepatology · doi:10.1002/hep.32328 · Cited by 45 · see citing works
Region-specific cellular and molecular basis of liver regeneration after acute pericentral injury.
Wang, S., Wang, X., Shan, Y., Tan, Z., Su, Y., Cao, Y., Wang, S., Dong, J., Gu, J., & Wang, Y. (2024) · Cell Stem Cell · doi:10.1016/j.stem.2024.01.013 · Cited by 40 · see citing works
Distinct hepatocyte identities in liver homeostasis and regeneration
Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30 · see citing works
Perturbed liver gene zonation in a mouse model of non-alcoholic steatohepatitis
Zhou, Y., Zhao, Y., Carbonaro, M., Chen, H., Germino, M., Adler, C., Ni, M., Zhu, Y. O., Kim, S. Y., Altarejos, J., et al. (2024) · Metabolism · doi:10.1016/j.metabol.2024.155830 · Cited by 24 · see citing works
Angiocrine Signaling in Sinusoidal Health and Disease
Cooper, S. A., Kostallari, E., & Shah, V. H. (2023) · Seminars in Liver Disease · doi:10.1055/a-2128-5907 · Cited by 15 · see citing works
- Authors
- Ma, R., Martínez-Ramírez, A. S., Borders, T. L., Gao, F., & Sosa-Pineda, B.
- Affiliations
- Northwestern University (US)
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-03-10
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7067564
- OpenAlex
- W3012347085
- Cited by
- 97
- References
- 11
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 19 · 2023: 17 · 2022: 24 · 2021: 14 · 2020: 6
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Feinberg School of Medicine (New Faculty Award 10040043-01)
- Consejo Nacional de Ciencia y Tecnología (Postdoctoral Fellowship (ASMR))
- 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
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- liver zonation, Wnt signaling, endothelial cells, sinusoidal endothelium, hepatocyte maturation, liver regeneration, metabolic zonation, transgenic mouse model
- MeSH terms
- Age Factors, Animals, Capillaries, Carbon Tetrachloride, Disease Models, Animal, Energy Metabolism, Fluorescent Antibody Technique, Immunohistochemistry, Ligands, Liver, Mice, Transgenic, Signal Transduction, Biomarkers, Gene Expression, Hepatocytes, Endothelial Cells, Wnt Proteins, Mice, Claudin-2
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