Spatial sorting enables comprehensive characterization of liver zonation
Open accessPublished version of a preprint
Abstract
The mammalian liver is composed of repeating hexagonal units termed lobules. Spatially resolved single-cell transcriptomics revealed that about half of hepatocyte genes are differentially expressed across the lobule, yet technical limitations impeded reconstructing similar global spatial maps of other hepatocyte features. Here, we show how zonated surface markers can be used to sort hepatocytes from defined lobule zones with high spatial resolution. We apply transcriptomics, miRNA array measurements and mass spectrometry proteomics to reconstruct spatial atlases of multiple zonated features. We demonstrate that protein zonation largely overlaps with mRNA zonation, with the periportal HNF4α as an exception. We identify zonation of miRNAs such as miR-122, and inverse zonation of miRNAs and their hepatocyte target genes, highlighting potential regulation of protein levels through zonated mRNA degradation. Among the targets we find the pericentral Wnt receptors Fzd7 and Fzd8 and the periportal Wnt inhibitors Tcf7l1 and Ctnnbip1. Our approach facilitates reconstructing spatial atlases of multiple cellular features in the liver and other structured tissues.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Blood flow from the periportal to the perivenous zones along the lobular axis creates spatial gradients of oxygen, metabolites, and nutrients, which benefit hepatocytes and other cells.
“Blood flow from the periportal to the perivenous zones along the lobular axis creates spatial gradients of oxygen, metabolites, and nutrients, which benefit hepatocytes and other cells (Tsukada et al., 2013;Ben-Moshe and Itzkovitz, 2019).”
From Fast formation and maturation enhancement of human liver organoids using a liver-organoid-on-a-chip (2024) · cites this paper as Ben-Moshe and Itzkovitz, 2019
The Introduction (page not specified) says blood flows from portal nodes toward central veins, generating gradients of oxygen and nutrients, and links the graded environment to hepatocyte zonation. It names hormones rather than metabolites as a blood-flow-generated gradient, and does not say these gradients benefit other cell types. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe liver is a spatially and functionally heterogeneous organ that contains branches of the hepatic portal vein, hepatic artery, and biliary tree across its lobules.
“The liver is a spatially and functionally heterogeneous organ that contains branches of the hepatic portal vein, hepatic artery, and biliary tree across its lobules (Ben-Moshe et al., 2019;Inverso et al., 2021).”
From Fast formation and maturation enhancement of human liver organoids using a liver-organoid-on-a-chip (2024) · cites this paper as Ben-Moshe et al., 2019
The Introduction (page unavailable) describes lobules and spatial heterogeneity in hepatocyte gene expression, while the Discussion describes functional differences between zones. The paper mentions blood flowing from portal nodes but does not describe branches of the hepatic portal vein, hepatic artery, and biliary tree across lobules. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTcf7l1 and Tbx3 expression is zonated in the adult mouse liver.
“while it has been previously reported that Tcf7l1 and Tbx3 expression is zonated in the adult mouse liver43,53”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [43]
The Results section (“Regulation of Wnt signaling components by miRNA”) reports that Tcf7l1 is periportally zonated in hepatocytes, supporting that part of the claim. Our copy does not report zonated Tbx3 expression; a search for “Tbx3” found no passage addressing it. No page number was available in the indexed copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExpression of perivenous markers was significantly elevated close to the outlet where oxygenation is lower.
“In contrast, expression of perivenous markers was significantly elevated close to the outlet where oxygenation is lower.”
From 3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation (2023) · cites this paper as [33]
The Results section ('Spatial sorting enables isolating bulk hepatocyte populations') identifies CD73 as a pericentral marker, and 'Zonation patterns of the hepatocyte proteome' reports significant protein zonation, including pericentrally enriched pathways. The Introduction describes blood flowing from portal nodes toward draining central veins and generating an oxygen gradient, but our copy does not explicitly establish that oxygenation is lower near the outlet or report a significance test for the perivenous markers as a group. Page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredClose to the inlet, where oxygen concentrations are highest, increased levels of the periportal marker proteins ARG1, BAAT, PYGL, FBP1 and ASL were observed.
“Close to the inlet, where oxygen concentrations are highest, we observed increased levels of the periportal marker proteins ARG1, BAAT, PYGL, FBP1 and ASL ( Fig. 6 a).”
From 3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation (2023) · cites this paper as [33]
The Results section on hepatocyte proteome zonation reports periportally enriched proteins and pathways, supporting the general periportal-marker context. Our copy does not identify ARG1, BAAT, PYGL, FBP1 and ASL as a set of periportal protein markers; the citing authors’ observation of increased levels near the inlet is their own finding, not one established by this source. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Hepatic zonation along the portal-central axis is important for optimal liver function.
“Spatial and functional hepatic zonation, established by the heterogeneous tissue along the portal-central axis of the liver, is important for ensuring optimal liver function.”
From Fast formation and maturation enhancement of human liver organoids using a liver-organoid-on-a-chip (2024) · cites this paper as Ben-Moshe and Itzkovitz, 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cytoscape: A software Environment for integrated models of biomolecular interaction networks
Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., & Ideker, T. (2003) · Genome Research · doi:10.1101/gr.1239303 · Cited by 51,888 · see citing works
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Kanehisa, M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.27 · Cited by 37,077 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232 · see citing works
Cox, J., & Mann, M. (2008) · Nature Biotechnology · doi:10.1038/nbt.1511 · Cited by 14,855 · see citing works
Robust enumeration of cell subsets from tissue expression profiles
Newman, A. M., Liu, C. L., Green, M. R., Gentles, A. J., Feng, W., Xu, Y., Hoang, C. D., Diehn, M., & Alizadeh, A. A. (2015) · Nature Methods · doi:10.1038/nmeth.3337 · Cited by 12,116 · see citing works
Circulating microRNAs as stable blood-based markers for cancer detection
Mitchell, P. S., Parkin, R. K., Kroh, E. M., Fritz, B. R., Wyman, S. K., Pogosova-Agadjanyan, E. L., Peterson, A., Noteboom, J., O'Briant, K. C., Allen, A., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804549105 · Cited by 7,969 · see citing works
A scaling normalization method for differential expression analysis of RNA-seq data
Robinson, M. D., & Oshlack, A. (2010) · Genome Biology · doi:10.1186/gb-2010-11-3-r25 · Cited by 7,876 · see citing works
Network motifs: simple building blocks of complex networks.
Milo, R., Shen-Orr, S., Itzkovitz, S., Kashtan, N., Chklovskii, D., & Alon, U. (2002) · Science · doi:10.1126/science.298.5594.824 · Cited by 7,368 · see citing works
Self-citationPredicting effective microRNA target sites in mammalian mRNAs
Agarwal, V., Bell, G. W., Nam, J.-W., & Bartel, D. P. (2015) · eLife · doi:10.7554/elife.05005 · Cited by 7,318 · see citing works
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · see citing works
Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq
Dominissini, D., Moshitch-Moshkovitz, S., Schwartz, S., Salmon-Divon, M., Ungar, L., Osenberg, S., Cesarkas, K., Jacob-Hirsch, J., Amariglio, N., Kupiec, M., et al. (2012) · Nature · doi:10.1038/nature11112 · Cited by 4,884 · see citing works
miRBase: annotating high confidence microRNAs using deep sequencing data
Kozomara, A., & Griffiths-Jones, S. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1181 · Cited by 4,629 · see citing works
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities
Nusse, R., & Clevers, H. (2017) · Cell · doi:10.1016/j.cell.2017.05.016 · Cited by 4,342 · see citing works
Silencing of microRNAs in vivo with ‘antagomirs’
Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K. G., Tuschl, T., Manoharan, M., & Stoffel, M. (2005) · Nature · doi:10.1038/nature04303 · Cited by 3,949 · see citing works
Mammalian microRNAs predominantly act to decrease target mRNA levels
Guo, H., Ingolia, N. T., Weissman, J. S., & Bartel, D. P. (2010) · Nature · doi:10.1038/nature09267 · Cited by 3,886 · see citing works
Identification of tissue-specific microRNAs from mouse
Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W., & Tuschl, T. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00809-6 · Cited by 2,859 · see citing works
Modulation of Hepatitis C Virus RNA Abundance by a Liver-Specific MicroRNA
Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M., & Sarnow, P. (2005) · Science · doi:10.1126/science.1113329 · Cited by 2,503 · see citing works
Single-cell chromatin accessibility reveals principles of regulatory variation
Buenrostro, J. D., Wu, B., Litzenburger, U. M., Ruff, D., Gonzales, M. L., Snyder, M. P., Chang, H. Y., & Greenleaf, W. J. (2015) · Nature · doi:10.1038/nature14590 · Cited by 2,308 · see citing works
Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model
Kota, J., Chivukula, R. R., O’Donnell, K. A., Wentzel, E. A., Montgomery, C. L., Hwang, H., Chang, T.-C., Vivekanandan, P., Torbenson, M. S., Clark, K. R., et al. (2009) · Cell · doi:10.1016/j.cell.2009.04.021 · Cited by 1,711 · see citing works
Genetic landscape and biomarkers of hepatocellular carcinoma
Zucman-Rossi, J., Villanueva, A., Nault, J.-C., & Llovet, J. M. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.05.061 · Cited by 1,325 · see citing works
Control of Pancreas and Liver Gene Expression by HNF Transcription Factors
Odom, D. T., Zizlsperger, N., Gordon, D. B., Bell, G. W., Rinaldi, N. J., Murray, H. L., Volkert, T. L., Schreiber, J., Rolfe, A., Gifford, D. K., et al. (2004) · Science · doi:10.1126/science.1089769 · Cited by 1,312 · see citing works
Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280 · see citing works
Circulating microRNAs, potential biomarkers for drug-induced liver injury
Wang, K., Zhang, S., Marzolf, B., Troisch, P., Brightman, A., Hu, Z., Hood, L. E., & Galas, D. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813371106 · Cited by 1,149 · see citing works
Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease
Park, J., Shrestha, R., Qiu, C., Kondo, A., Huang, S., Werth, M., Li, M., Barasch, J., & Suszták, K. (2018) · Science · doi:10.1126/science.aar2131 · Cited by 1,065 · see citing works
Single-cell spatial reconstruction reveals global division of labour in the mammalian liver
Halpern, K. B., Shenhav, R., Matcovitch-Natan, O., Tóth, B., Lemze, D., Golan, M., Massasa, E. E., Baydatch, S., Landen, S., Moor, A. E., et al. (2017) · Nature · doi:10.1038/nature21065 · Cited by 1,059 · see citing works
Self-citationMicroRNAs 103 and 107 regulate insulin sensitivity
Trajkovski, M., Hausser, J., Soutschek, J., Bhat, B., Akin, A., Zavolan, M., Heim, M. H., & Stoffel, M. (2011) · Nature · doi:10.1038/nature10112 · Cited by 1,000 · see citing works
Hirayama, A., Kami, K., Sugimoto, M., Sugawara, M., Toki, N., Onozuka, H., Kinoshitá, T., Saito, N., Ochiai, A., Tomita, M., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4806 · Cited by 959 · see citing works
Budnik, B., Levy, E., Harmange, G., & Slavov, N. (2018) · Genome Biology · doi:10.1186/s13059-018-1547-5 · Cited by 832 · see citing works
MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis
Tsai, W.-C., Hsu, S., Hsu, C.-S., Lai, T., Chen, S.-J., Shen, R., Huang, Y., Chen, H., Lee, C.-H., Tsai, T., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63455 · Cited by 815 · see citing works
Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis
Roderburg, C., Urban, G.-W., Bettermann, K., Vucur, M., Zimmermann, H. W., Schmidt, S., Janssen, J., Koppe, C., Knolle, P. A., Castoldi, M., et al. (2010) · Hepatology · doi:10.1002/hep.23922 · Cited by 802 · 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
Metabolic zonation of the liver: Regulation and implications for liver function
Gebhardt, R. (1992) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(92)90055-5 · Cited by 607 · see citing works
Zonation of parenchymal and nonparenchymal metabolism in liver.
Jungermann, K., & Keitzmann, T. (1996) · Annual Review of Nutrition · doi:10.1146/annurev.nu.16.070196.001143 · Cited by 589 · see citing works
MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression
Ivanovska, I., Ball, A. S., Diaz, R. L., Magnus, J. F., Kibukawa, M., Schelter, J. M., Kobayashi, S. V., Lim, L., Burchard, J., Jackson, A. L., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01977-07 · Cited by 561 · see citing works
Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver
Benhamouche, S., Decaens, T., Godard, C., Chambrey, R., Rickman, D. S., Moinard, C., Vasseur-Cognet, M., Kuo, C. J., Kahn, A., Perret, C., et al. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.03.015 · Cited by 543 · see citing works
High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers
Mederacke, I., Dapito, D. H., Affò, S., Uchinami, H., & Schwabe, R. F. (2015) · Nature Protocols · doi:10.1038/nprot.2015.017 · Cited by 541 · see citing works
Enzyme distribution along the nephron
Guder, W., & Ross, B. D. (1984) · Kidney International · doi:10.1038/ki.1984.143 · Cited by 510 · see citing works
Spatial heterogeneity in the mammalian liver
Ben-Moshe, S., & Itzkovitz, S. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0134-x · Cited by 485 · see citing works
Self-citationMoor, A. E., Harnik, Y., Ben-Moshe, S., Massasa, E. E., Rozenberg, M., Eilam, R., Bahar Halpern, K., & Itzkovitz, S. (2018) · Cell · doi:10.1016/j.cell.2018.08.063 · Cited by 480 · see citing works
Self-citationWNT/β‐catenin signaling in liver health and disease
Thompson, M. D., & Monga, S. P. (2007) · Hepatology · doi:10.1002/hep.21651 · Cited by 472 · see citing works
Visual account of protein investment in cellular functions
Liebermeister, W., Noor, Ε., Flamholz, A. I., Davidi, D., Bernhardt, J., & Milo, R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314810111 · Cited by 408 · see citing works
Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells
Halpern, K. B., Shenhav, R., Massalha, H., Toth, B., Egozi, A., Massasa, E. E., Medgalia, C., David, E., Giladi, A., Moor, A. E., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4231 · Cited by 368 · see citing works
Self-citationThe 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
zUMIs - A fast and flexible pipeline to process RNA sequencing data with UMIs
Parekh, S., Ziegenhain, C., Vieth, B., Enard, W., & Hellmann, I. (2018) · GigaScience · doi:10.1093/gigascience/giy059 · Cited by 349 · see citing works
Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b
Kornfeld, J., Baitzel, C., Könner, A. C., Nicholls, H. T., Vogt, M. C., Herrmanns, K., Scheja, L., Haumaître, C., Wolf, A. M., Knippschild, U., et al. (2013) · Nature · doi:10.1038/nature11793 · Cited by 347 · see citing works
Hoehme, S., Brulport, M., Bauer, A., Bedawy, E., Schormann, W., Hermes, M., Puppe, V., Gebhardt, R., Zellmer, S., Schwarz, M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909374107 · Cited by 340 · see citing works
Inhibition of Wnt signaling by ICAT, a novel β-catenin-interacting proteinPreprint
Tago, K.-I., Nakamura, T., Nishita, M., Hyodo‐Miura, J., Nagai, S.-I., Murata, Y., Adachi, S., Ohwada, S., Morishita, Y., Shibuyà, H., et al. (2000) · Genes & Development · doi:10.1101/gad.14.14.1741 · Cited by 338 · see citing works
Target mRNA abundance dilutes microRNA and siRNA activity
Arvey, A. J., Larsson, E., Sander, C., Leslie, C. S., & Marks, D. S. (2010) · Molecular Systems Biology · doi:10.1038/msb.2010.24 · Cited by 330 · see citing works
Xu, H. M., He, J., Xiao, Z., Zhang, Q.-Q., Chen, Y.-Q., Zhou, H., & Qu, L. (2010) · Hepatology · doi:10.1002/hep.23818 · Cited by 267 · see citing works
Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!
Yang, J., Mowry, L. E., Nejak‐Bowen, K. N., Okabe, H., Diegel, C. R., Lang, R. A., Williams, B. O., & Monga, S. P. (2014) · Hepatology · doi:10.1002/hep.27082 · Cited by 244 · see citing works
Sensitive and powerful single-cell RNA sequencing using mcSCRB-seq
Bagnoli, J., Ziegenhain, C., Janjic, A., Wange, L. E., Vieth, B., Parekh, S., Geuder, J., Hellmann, I., & Enard, W. (2018) · Nature Communications · doi:10.1038/s41467-018-05347-6 · Cited by 242 · see citing works
Farid, W. R. R., Pan, Q., van der Meer, A. J. P., de Ruiter, P. E., Ramakrishnaiah, V., de Jonge, J., Kwekkeboom, J., Janssen, H. L. A., Metselaar, H. J., Tilanus, H. W., et al. (2011) · Liver Transplantation · doi:10.1002/lt.22438 · Cited by 211 · see citing works
Digitonin-collagenase perfusion for efficient separation of periportal or perivenous hepatocytes
Lindros, K. O., & Penttilä, K. E. (1985) · Biochemical Journal · doi:10.1042/bj2280757 · Cited by 208 · see citing works
Absolute quantification of microRNAs by using a universal reference
Bissels, U., Wild, S., Tomiuk, S., Holste, A. S., Hafner, M., Tuschl, T., & Bosio, A. (2009) · RNA · doi:10.1261/rna.1754109 · Cited by 205 · see citing works
The Angiocrine Factor Rspondin3 Is a Key Determinant of Liver Zonation
Rocha, A. S., Vidal, V., Mertz, M., Kendall, T. J., Charlet, A., Okamoto, H., & Schedl, A. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.049 · Cited by 194 · see citing works
Systems-wide temporal proteomic profiling in glucose-starved Bacillus subtilis
Otto, A., Bernhardt, J., Meyer, H., Schaffer, M., Herbst, F., Siebourg‐Polster, J., Mäder, U., Lalk, M., Hecker, M., & Becher, D. (2010) · Nature Communications · doi:10.1038/ncomms1137 · Cited by 182 · see citing works
Cell-Type-Resolved Quantitative Proteomics of Murine Liver
Azimifar, S. B., Nagaraj, N., Cox, J., & Mann, M. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.11.002 · Cited by 173 · see citing works
Sorting cells alters their redox state and cellular metabolome
Llufrio, E. M., Wang, L., Naser, F. J., & Patti, G. J. (2018) · Redox Biology · doi:10.1016/j.redox.2018.03.004 · Cited by 172 · see citing works
Large-scale profiling of microRNAs for The Cancer Genome Atlas
Chu, A., Robertson, G., Brooks, D., Mungall, A. J. J., Birol, İ., Coope, R., Ma, Y. P., Jones, S. J. M., & Marra, M. A. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv808 · Cited by 165 · see citing works
Convergence of Wnt Signaling on the HNF4α-Driven Transcription in Controlling Liver Zonation
Colletti, M., Cicchini, C., Conigliaro, A., Santangelo, L., Alonzi, T., Pasquini, E., Tripodi, M., & Amicone, L. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.05.038 · Cited by 145 · 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
Shy, B. R., Wu, C.-I., Khramtsova, G. F., Zhang, J. Y., Olopade, O. I., Goss, K. H., & Merrill, B. J. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.06.001 · Cited by 124 · see citing works
Holloway, M. G., Miles, G. D., Dombkowski, A. A., & Waxman, D. J. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0564 · Cited by 108 · see citing works
The virtual liver: a multidisciplinary, multilevel challenge for systems biology
Holzhütter, H., Drasdo, D., Preußer, T., Lippert, J., & HENNEY, A. M. (2012) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1158 · Cited by 104 · see citing works
Gebhardt, R., & Hovhannisyan, A. (2009) · Developmental Dynamics · doi:10.1002/dvdy.22041 · Cited by 101 · see citing works
Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control
Brosch, M., Kattler, K., Herrmann, A., von Schönfels, W., Nordström, K., Seehofer, D., Damm, G., Becker, T., Zeissig, S., Nehring, S., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06611-5 · Cited by 98 · see citing works
Molecular Determinants of Liver Zonation
Torre, C., Perret, C., & Colnot, S. (2010) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-385233-5.00005-2 · Cited by 97 · see citing works
Li, W., Dai, H., Ou, Q., Zuo, G., & Liu, C. (2015) · Tumor Biology · doi:10.1007/s13277-015-4456-1 · Cited by 94 · see citing works
Manco, R., Clerbaux, L.-A., Verhulst, S., Bou Nader, M., Sempoux, C., Ambroise, J., Bearzatto, B., Gala, J. L., Horsmans, Y., van Grunsven, L., et al. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.02.003 · Cited by 92 · see citing works
Self-citationDicer is required for proper liver zonation
Sekine, S., Ogawa, R., McManus, M. T., Kanai, Y., & Hebrok, M. (2009) · The Journal of Pathology · doi:10.1002/path.2606 · Cited by 85 · see citing works
Stanulović, V. S., Kyrmizi, I., Julio, M. K., Hoogenkamp, M., Vermeulen, J. L. M., Ruijter, J. M., Talianidis, I., Hakvoort, T. B. M., & Lamers, W. H. (2007) · Hepatology · doi:10.1002/hep.21456 · Cited by 80 · see citing works
Quistorff, B., Grunnet, N., & Cornell, N. W. (1985) · Biochemical Journal · doi:10.1042/bj2260289 · Cited by 77 · see citing works
Dynamic zonation of liver polyploidy
Tanami, S., Ben-Moshe, S., Elkayam, A., Mayo, A., Bahar Halpern, K., & Itzkovitz, S. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2427-5 · Cited by 77 · see citing works
Self-citationThe Wnt/β-catenin pathway: master regulator of liver zonation?
Burke, Z. D., & Tosh, D. (2006) · BioEssays · doi:10.1002/bies.20485 · Cited by 66 · see citing works
Adult Mouse Liver Contains Two Distinct Populations of Cholangiocytes
Li, B., Dorrell, C., Canaday, P. S., Pelz, C., Haft, A., Finegold, M. J., & Grompe, M. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.06.003 · Cited by 66 · see citing works
Orchestrating Wnt signalling for metabolic liver zonation
Birchmeier, W. (2016) · Nature Cell Biology · doi:10.1038/ncb3349 · Cited by 61 · see citing works
Visualizing Gene Expression Data via Voronoi Treemaps
Bernhardt, J., Funke, S., Hecker, M., & Siebourg‐Polster, J. (2009) · International Symposium on Voronoi Diagrams in Science and Engineering · doi:10.1109/isvd.2009.33 · Cited by 57 · see citing works
Colnot, S., & Perret, C. (2010) · Molecular pathology library · doi:10.1007/978-1-4419-7107-4_2 · Cited by 50 · see citing works
Budnik, B., Levy, E., Harmange, G., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/102681 · Cited by 43 · see citing works
Development of complementary expression patterns of E‐ and N‐cadherin in the mouse liver
Doi, Y., Tamura, S., Nammo, T., Fukui, K., Kiso, S., & Nagafuchi, A. (2007) · Hepatology Research · doi:10.1111/j.1872-034x.2007.00028.x · Cited by 34 · see citing works
Berndt, N., Horger, M., Bulik, S., & Holzhütter, H. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006005 · Cited by 34 · see citing works
Abstract 4628: PBISe, an iNOS/Akt inhibitor for colon cancer chemoprevention
Desai, D. H., Irby, R., Aliaga, C. A., & Amin, S. (2011) · Cancer Research · doi:10.1158/1538-7445.am2011-4628 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Integrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics
Longo, S. K., Guo, M. G., Ji, A. L., & Khavari, P. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00370-8 · Cited by 1,059 · see citing works
Spatial heterogeneity in the mammalian liver
Ben-Moshe, S., & Itzkovitz, S. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0134-x · Cited by 485 · see citing works
Self-citationLiver homeostasis is maintained by midlobular zone 2 hepatocytes
Wei, Y., Wang, Y. G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., et al. (2021) · Science · doi:10.1126/science.abb1625 · Cited by 292 · see citing works
Saviano, A., Henderson, N. C., & Baumert, T. F. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.06.004 · Cited by 269 · see citing works
Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis
Ramachandran, P., Matchett, K. P., Dobie, R., Wilson-Kanamori, J. R., & Henderson, N. C. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0304-x · Cited by 253 · see citing works
The spatiotemporal program of zonal liver regeneration following acute injury
Ben-Moshe, S., Veg, T., Manco, R., Dan, S., Papinutti, D., Lifshitz, A., Kolodziejczyk, A. A., Bahar Halpern, K., Elinav, E., & Itzkovitz, S. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.04.008 · Cited by 224 · see citing works
Self-citationSpatial single-cell mass spectrometry defines zonation of the hepatocyte proteome
Rosenberger, F. A., Thielert, M., Strauss, M. T., Schweizer, L., Ammar, C., Mädler, S. C., Metousis, A., Skowronek, P., Wahle, M., Madden, K., et al. (2023) · Nature Methods · doi:10.1038/s41592-023-02007-6 · Cited by 176 · see citing works
A single cell atlas of the human liver tumor microenvironment
Massalha, H., Halpern, K. B., Abu‐Gazala, S., Jana, T., Massasa, E. E., Moor, A. E., Buchauer, L., Rozenberg, M., Pikarsky, E., Amit, I., et al. (2020) · Molecular Systems Biology · doi:10.15252/msb.20209682 · Cited by 164 · see citing works
Self-citationAmino acid metabolism, transport and signalling in the liver revisited.
Paulusma, C., Lamers, W., Bröer, S., & van de Graaf, S. V. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115074 · Cited by 162 · see citing works
Paris, J., & Henderson, N. C. (2022) · Hepatology · doi:10.1002/hep.32408 · Cited by 167 · see citing works
Liver Zonation – Revisiting Old Questions With New Technologies
Cunningham, R. P., & Porat‐Shliom, N. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.732929 · Cited by 166 · see citing works
Metabolism drives macrophage heterogeneity in the tumor microenvironment
Li, S., Yu, J., Huber, A. K., Kryczek, I., Wang, Z., Jiang, L., Li, X., Du, W., Li, G., Wei, S., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110609 · Cited by 166 · see citing works
Strategies for monitoring cell–cell interactions
Bechtel, T. J., Robles, T. R., Fadeyi, O., & Oslund, R. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00790-x · Cited by 152 · see citing works
Space-time logic of liver gene expression at sub-lobular scale
Droin, C., Kholtei, J. E., Bahar Halpern, K., Hurni, C., Rozenberg, M., Muvkadi, S., Itzkovitz, S., & Naef, F. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00323-1 · Cited by 148 · see citing works
Self-citationThe Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease
Bhandari, S., Larsen, A., Mccourt, P., Smedsrød, B., & Sørensen, K. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.757469 · Cited by 121 · see citing works
The Source of Glycolytic Intermediates in Mammalian Tissues
TeSlaa, T. A., Bartman, C., Jankowski, C. S. R., Zhang, Z., Xu, X., Xing, X., Wang, L., Lu, W., Hui, S. T., & Rabinowitz, J. D. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2020.12.020 · Cited by 120 · see citing works
Inverso, D., Shi, J., Lee, K. H., Jakab, M., Ben-Moshe, S., Kulkarni, S. R., Schneider, M., Wang, G., Komeili, M., Vélez, P. A., et al. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.05.001 · Cited by 114 · see citing works
Self-citationUnderstanding the heterogeneity of resident liver macrophages
Blériot, C., & Ginhoux, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02694 · Cited by 107 · see citing works
Dobrowolski, C. N., Paunovska, K., Echeverri, E. S., Loughrey, D., Sanchez, A. J. D. S., Ni, H., Hatit, M. Z. C., Lokugamage, M. P., Kuzminich, Y., Peck, H. E., et al. (2022) · Nature Nanotechnology · doi:10.1038/s41565-022-01146-9 · Cited by 103 · see citing works
Spatial metabolomics and its application in the liver
Santos, A. A., Delgado, T. C., Marques, V., Ramírez-Moncayo, C., Alonso, C., Vidal‐Puig, A., Hall, Z., Martínez‐Chantar, M. L., & Rodrigues, C. M. P. (2023) · Hepatology · doi:10.1097/hep.0000000000000341 · Cited by 100 · see citing works
Lee, S. J., Jeong, W., & Atala, A. (2024) · Advanced Materials · doi:10.1002/adma.202408032 · Cited by 102 · see citing works
Bravo González-Blas, C., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-023-01316-4 · Cited by 85 · see citing works
“The protocol for hepatocyte staining was adapted from a previous study 43 .”
A spatiotemporal atlas of mouse liver homeostasis and regeneration
Xu, J., Guo, P., Hao, S., Shangguan, S., Shi, Q., Volpe, G., Huang, K., Zuo, J., An, J., Yuan, Y., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01709-7 · Cited by 75 · see citing works
Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy
Richter, M. L., Deligiannis, I. K., Yin, K., Danese, A., Lleshi, E., Coupland, P., Vallejos, C. A., Matchett, K. P., Henderson, N. C., Colome-Tatche, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24543-5 · Cited by 75 · see citing works
The elegant complexity of mammalian ecto-5′-nucleotidase (CD73)
Alcedo, K. P., Bowser, J. L., & Snider, N. T. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.05.008 · Cited by 70 · see citing works
Nault, R., Fader, K. A., Bhattacharya, S., & Zacharewski, T. R. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.07.012 · Cited by 69 · see citing works
Nikopoulou, C., Kleinenkuhnen, N., Parekh, S., Sandoval, T., Ziegenhain, C., Schneider, F., Giavalisco, P., Donahue, K.-F., Vesting, A. J., Kirchner, M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00513-y · Cited by 73 · see citing works
Kang, S. W. S., Cunningham, R. P., Miller, C. B., Brown, L. A., Cultraro, C. M., Harned, A., Narayan, K., Hernandez, J. M., Jenkins, L. M. M., Lobanov, A. V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45751-9 · Cited by 61 · see citing works
Choi, W., Ryu, T., Lee, J. H., Shim, Y., Kim, M., Kim, H., Kim, Y. E., Yang, K., Kim, K., Choi, S. E., et al. (2021) · Hepatology · doi:10.1002/hep.31875 · Cited by 60 · see citing works
Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation
Wang, S., Zha, L., Cui, X., Yeh, Y., Liu, R., Jing, J., Shi, H., Chen, W., Hanover, J. A., Yin, J., et al. (2023) · Advanced Science · doi:10.1002/advs.202206068 · Cited by 59 · see citing works
Spatial discordances between mRNAs and proteins in the intestinal epithelium
Harnik, Y., Buchauer, L., Ben‐Moshe, S., Averbukh, I., Levin, Y., Savidor, A., Eilam, R., Moor, A. E., & Itzkovitz, S. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00504-6 · Cited by 56 · see citing works
Self-citationLocally sourced: site-specific immune barriers to metastasis
Correia, A. L. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00836-2 · Cited by 58 · see citing works
Qian, J., Shao, X., Bao, H., Yin, F., Guo, W., Li, C., Li, A., Hua, H., & Fan, X. (2025) · Nature Communications · doi:10.1038/s41467-025-57029-9 · Cited by 58 · see citing works
Nguyen, N. T., Umbaugh, D. S., Sánchez-Guerrero, G., Ramachandran, A., & Jaeschke, H. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03183-0 · Cited by 56 · see citing works
Priming and Maintenance of Adaptive Immunity in the Liver
Kawashima, K., Andreata, F., Beccaría, C. G., & Iannacone, M. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090122-041354 · Cited by 55 · see citing works
Functional Consequences of Metabolic Zonation in Murine Livers: Insights for an Old Story
Berndt, N., Kolbe, E., Gajowski, R., Eckstein, J., Ott, F., Meierhofer, D., Holzhütter, H., & Matz‐Soja, M. (2020) · Hepatology · doi:10.1002/hep.31274 · Cited by 54 · see citing works
Macrophages harness hepatocyte glutamate to boost liver regeneration
Rigual, M. D. M., Angulo-Aguado, M., Zagorac, S., Álvarez-Díaz, R., Benítez-Mondéjar, M., Yi, F., Martínez-Garay, C., Santos-de-Frutos, K., Kim, E., Campos-Olivas, R., et al. (2025) · Nature · doi:10.1038/s41586-025-08778-6 · Cited by 53 · see citing works
Spatial Transcriptomics for Tumor Heterogeneity Analysis
Li, Q., Zhang, X., & Ke, R. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.906158 · Cited by 52 · see citing works
Liver macrophages: development, dynamics, and functions
Nusse, Y., & Kubes, P. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01298-3 · Cited by 50 · see citing works
Single-cell and spatially resolved transcriptomics for liver biology
Lin, P., Yan, X., Jing, S., Wu, Y., Shan, Y., Guo, W., Gu, J., Li, Y., Zhang, H., & Li, H. (2023) · Hepatology · doi:10.1097/hep.0000000000000387 · Cited by 53 · see citing works
Mitochondrial heterogeneity and adaptations to cellular needs
Granath-Panelo, M., & Kajimura, S. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01410-1 · Cited by 49 · see citing works
The liver as an immunological barrier redefined by single‐cell analysis
Stamataki, Z., & Swadling, L. (2020) · Immunology · doi:10.1111/imm.13193 · Cited by 48 · see citing works
Goldfarb, C. N., Karri, K., Pyatkov, M., & Waxman, D. J. (2022) · Endocrinology · doi:10.1210/endocr/bqac059 · Cited by 46 · see citing works
Parlakgül, G., Pang, S., Artico, L. L., Min, N., Cagampan, E., Villa, R., Gonçalves, R. L. S., Lee, G. Y., Xu, C. S., Hotamışlıgil, G. S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48272-7 · Cited by 46 · see citing works
Trinh, V. Q.-H., Lee, T.-F., Lemoinne, S., Ray, K. C., Ybanez, M. D., Tsuchida, T., Carter, J. K., Agudo, J., Brown, B. D., Akat, K. M., et al. (2023) · Science Signaling · doi:10.1126/scisignal.adf6696 · Cited by 45 · see citing works
Khanal, S., Liu, Y., Bamidele, A. O., Wixom, A. Q., Washington, A. M., Jalan-Sakrikar, N., Cooper, S. A., Vuckovic, I., Zhang, S., Zhong, J., et al. (2024) · Science Advances · doi:10.1126/sciadv.adn5228 · Cited by 41 · see citing works
Matz‐Soja, M., Berg, T., & Kietzmann, T. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.08.007 · Cited by 49 · see citing works
Umbaugh, D. S., Ramachandran, A., & Jaeschke, H. (2021) · Toxicological Sciences · doi:10.1093/toxsci/kfab052 · Cited by 41 · see citing works
Spatial metabolic gradients in the liver and small intestine
Samarah, L. Z., Zheng, C., Xing, X., Lee, W. D., Afriat, A., Chitra, U., MacArthur, M. R., Lu, W., Jankowski, C. S. R., Ma, C., et al. (2025) · Nature · doi:10.1038/s41586-025-09616-5 · Cited by 40 · see citing works
A Single‐Cell Perspective of the Mammalian Liver in Health and Disease
Xiong, X., Kuang, H., Liu, T., & Lin, J. D. (2020) · Hepatology · doi:10.1002/hep.31149 · Cited by 40 · see citing works
SOTIP is a versatile method for microenvironment modeling with spatial omics data
Yuan, Z., Li, Y., Shi, M., Yang, F., Gao, J. T., Yao, J., & Zhang, M. Q. (2022) · Nature Communications · doi:10.1038/s41467-022-34867-5 · Cited by 39 · see citing works
Wesseler, M. F., Taebnia, N., Harrison, S., Youhanna, S., Preiss, L. C., Kemas, A. M., Vegvari, A., Mokry, J., Sullivan, G. J., Lauschke, V. M., et al. (2023) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.09.022 · Cited by 39 · see citing works
Liver sinusoidal endothelial cells induce BMP6 expression in response to non–transferrin-bound iron
Charlebois, E., Fillebeen, C., Presley, J., Cagnone, G., Lisi, V., Lavallée, V., Joyal, J., & Pantopoulos, K. (2022) · Blood · doi:10.1182/blood.2022016987 · Cited by 37 · see citing works
Scheidecker, B., Shinohara, M., Sugimoto, M., Danoy, M., Nishikawa, M., & Sakai, Y. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00524 · Cited by 36 · see citing works
Harnessing metabolism of hepatic macrophages to aid liver regeneration
Liu, R., Scimeca, M., Sun, Q., Melino, G., Mauriello, A., Shao, C., Bernassola, F., Bove, P., Candi, E., Valentina, R., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06066-7 · Cited by 37 · see citing works
An immunohistochemical atlas of necroptotic pathway expression
Chiou, S., Al‐Ani, A., Pan, Y., Patel, K. M., Kong, I. Y., Whitehead, L. W., Light, A., Young, S. N., Barrios, M. H., Sargeant, C. J., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00074-6 · Cited by 36 · see citing works
Dall, M., Hassing, A. S., Niu, L., Nielsen, T. S., Ingerslev, L. R., Sulek, K., Trammell, S. A. J., Gillum, M. P., Barrès, R., Larsen, S., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101388 · Cited by 37 · see citing works
Sardo, U., Perrier, P., Cormier, K., Sotin, M., Personnaz, J., Medjbeur, T., Desquesnes, A., Cannizzo, L., Ruíz-Martínez, M., Thevenin, J., et al. (2024) · Blood · doi:10.1182/blood.2023022724 · Cited by 34 · see citing works
Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis
Li, H., Perino, A., Huang, Q. D., von Alvensleben, G., Banaei‐Esfahani, A., Velázquez‐Villegas, L. A., Gariani, K., Korbelius, M., Sleiman, M. S. B., Imbach, J., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.08.015 · Cited by 32 · see citing works
Graphene Oxide Causes Disordered Zonation Due to Differential Intralobular Localization in the Liver
Wu, Y., Feng, W., Liu, R., Xia, T., & Liu, S. (2019) · ACS Nano · doi:10.1021/acsnano.9b08127 · Cited by 33 · see citing works
Thomann, S., Weiler, S. M. E., Wei, T., Sticht, C., Torre, C. D. L., Tóth, M., Rose, F., Tang, Y., Ritz, T., Ball, C. R., et al. (2021) · Liver International · doi:10.1111/liv.15048 · Cited by 33 · see citing works
Zonal human hepatocytes are differentially permissive to Plasmodium falciparum malaria parasites
Yang, A., van Waardenburg, Y. M., van de Vegte‐Bolmer, M., van Gemert, G., Graumans, W., de Wilt, J. H. W., & Sauerwein, R. W. (2021) · The EMBO Journal · doi:10.15252/embj.2020106583 · Cited by 31 · 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
Determination of key events in mouse hepatocyte maturation at the single-cell level
Li, Y., Wang, X., Zheng, J., Xu, Z., Li, L., Xiong, Y., Zhou, B.-C., Gao, J., & Xu, C. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.07.006 · Cited by 30 · see citing works
Spatial transcriptomics analysis of zone-dependent hepatic ischemia-reperfusion injury murine model
Xin, J., Yang, T., Wu, X., Wu, Y., Liu, Y. F., Liu, X., Jiang, M., & Gao, W. (2023) · Communications Biology · doi:10.1038/s42003-023-04564-0 · Cited by 29 · see citing works
Seubnooch, P., Montani, M., Tsouka, S., Claude, E., Rafiqi, U., Perren, A. A., Dufour, J., & Masoodi, M. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100725 · Cited by 29 · see citing works
Spatial transcriptome profiling of normal human liver
Yu, S., Wang, H., Yang, L., Yan, Y., Cai, Q., Ma, D., Jiang, L., Gao, Z., Yu, Z., & Xia, Z. (2022) · Scientific Data · doi:10.1038/s41597-022-01676-w · Cited by 28 · see citing works
Ren, L., Huang, D., Liu, H., Lin, N., Cai, P., Yu, X., Zhang, Y., Luo, N., Lin, H., Su, J., et al. (2024) · Oncology Letters · doi:10.3892/ol.2024.14285 · Cited by 27 · see citing works
Albadry, M., Küttner, J., Grzegorzewski, J., Dirsch, O., Kindler, E. M., Klopfleisch, R., Liška, V., Moulisová, V., Nickel, S., Pálek, R., et al. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1404938 · Cited by 26 · see citing works
Kim, H., Choi, S. E., & Jeong, W. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0152 · Cited by 26 · see citing works
The origin of hepatocellular carcinoma depends on metabolic zonation
Guo, J., Liang, R., Chung, A., Li, Z., Li, B., Chen, E., Li, L., Wang, J., Hsieh, M.-H., Fang, I. X., et al. (2026) · Science · doi:10.1126/science.adv7129 · Cited by 24 · see citing works
Pek, N. M. Q., Liu, K. J., Nichane, M., & Ang, L. T. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.016 · Cited by 25 · see citing works
Hepatic adaptation to chronic metabolic stress primes tumorigenesis
Tzouanas, C. N., Shay, J. E. S., Sherman, M. S., Rubin, A. J., Mead, B. E., Dao, T. T., Tao, J., Lehrich, B. M., Eng, G. M., Patterson-Fortin, J., et al. (2025) · Cell · doi:10.1016/j.cell.2025.11.031 · Cited by 24 · see citing works
Metabolic landscape of disseminated cancer dormancy
Drápela, S., Garcia, B. M., Gomes, A. P., & Correia, A. L. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.10.005 · Cited by 22 · see citing works
Kupffer cells in liver homeostasis and disease: from immune sentinels to metabolic gatekeepers
David, B. A., Andreata, F., Blériot, C., Ginhoux, F., Kubes, P., & Iannacone, M. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01288-0 · Cited by 22 · see citing works
A spatial atlas of the healthy human liver from live donors
Yakubovsky, O., Halpern, K. B., Shir, S., Novoselsky, R., Afriat, A., Egozi, A., Barkai, T., Harnik, Y., Hoefflin, R., Kohanim, Y. K., et al. (2026) · Nature · doi:10.1038/s41586-026-10377-y · Cited by 23 · see citing works
Self-citationHepatocyte size fractionation allows dissection of human liver zonation
Ölander, M., Wegler, C., Flörkemeier, I., Treyer, A., Handin, N., Pedersen, J. M., Vildhede, A. M., Mateus, A., LeCluyse, E. L., Urdzik, J., et al. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30273 · Cited by 21 · see citing works
Advances in liver and pancreas organoids: how far we have come and where we go next
Sljukic, A., Jenkinson, J. G., Niksic, A., Prior, N., & Huch, M. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01116-1 · Cited by 23 · see citing works
Weiss, C. A. M., Brown, L. A., Miranda, L., Pellizzoni, P., Steigerwald, S., Remmert, K., Hernandez, J. M., Borgwardt, K. M., Kleiner, D. E., Ben‐Moshe, S., et al. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01459-2 · Cited by 21 · see citing works
Self-citationDecoding liver fibrogenesis with single-cell technologies
Zhou, T., Musunuru, K., Lui, K. O., & Ding, Q. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac040 · Cited by 21 · see citing works
Zhang, J., Li, D., Zhang, R., Peng, R., & Li, J. (2021) · Experimental Biology and Medicine · doi:10.1177/15353702211035689 · Cited by 20 · see citing works
Multiple Facets of Cellular Homeostasis and Regeneration of the Mammalian Liver
Huppert, S. S., & Schwartz, R. E. (2022) · Annual Review of Physiology · doi:10.1146/annurev-physiol-032822-094134 · Cited by 19 · see citing works
Brumer, R. P., Corrêa-Velloso, J. C., Thomas, S. J., Sandiford, O. A., Thomas, A. P., & Bartlett, P. J. (2023) · The Journal of Physiology · doi:10.1113/jp283691 · Cited by 18 · see citing works
CD73 Maintains Hepatocyte Metabolic Integrity and Mouse Liver Homeostasis in a Sex-Dependent Manner
Alcedo, K. P., Rouse, M. A., Jung, G. S., Fu, D., Minor, M., Willcockson, H. H., Greene, K. G., & Snider, N. T. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.01.016 · Cited by 18 · see citing works
Social Bonds Retain Oxytocin-Mediated Brain-Liver Axis to Retard Atherosclerosis
Ko, S., Anzai, A., Liu, X., Kinouchi, K., Yamanoi, K., Torimitsu, T., Ichihara, G., Kitakata, H., Shirakawa, K., Katsumata, Y., et al. (2024) · Circulation Research · doi:10.1161/circresaha.124.324638 · Cited by 19 · see citing works
Magdy, A., Kim, H., Go, H., Lee, J. M., Sohn, H. A., Haam, K., Jung, H.-J., Park, J., Yoo, T., Kwon, E., et al. (2024) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0229 · Cited by 17 · see citing works
Okada, J., Landgraf, A., Xiaoli, A. M., Liu, L. P., Horton, M., Schuster, V. L., Yang, F., Sidoli, S., Qiu, Y., Kurland, I. J., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01269-y · Cited by 16 · see citing works
Chen, K.-W., Chen, Y.-S., Chen, P.-J., & Yeh, S.-H. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155269 · Cited by 16 · see citing works
Moore, S. T., Lian, X., Vaidya, A., Chatterjee, S., Santelli, J., Sun, Y., Farbiak, L., Zhu, H., & Siegwart, D. J. (2026) · Nature Communications · doi:10.1038/s41467-025-68103-7 · Cited by 16 · see citing works
In Search of Zonation Markers to Identify Liver Functional Disorders
Yang, Q., Zhang, S., Ma, J., Liu, S., & Chen, S. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/9374896 · Cited by 15 · see citing works
Sanchez-Quant, E., Richter, M. L., Colomé‐Tatché, M., & Martinez‐Jimenez, C. P. (2023) · Genome biology · doi:10.1186/s13059-023-03075-9 · Cited by 14 · see citing works
A time- and space-resolved nuclear receptor atlas in mouse liver
Zummo, F. P., Berthier, A., Gheeraert, C., Vinod, M., Bobowski, M., Molendi‐Coste, O., Pineau, L., Jung, M., Guille, L., Dubois‐Chevalier, J., et al. (2023) · Journal of Molecular Endocrinology · doi:10.1530/jme-23-0017 · Cited by 15 · see citing works
Voilquin, L., Liu, T., Jung, Y., Taylor, N. P., Zhao, M., Charville, G. W., Nissen, S. B., Yki‐Järvinen, H., Altman, R. B., & Svensson, K. J. (2022) · iScience · doi:10.1016/j.isci.2022.105802 · Cited by 15 · see citing works
Karri, K., & Waxman, D. J. (2023) · RNA · doi:10.1261/rna.079580.123 · Cited by 14 · see citing works
Liver in infections: a single-cell and spatial transcriptomics perspective
Zou, J., Li, J., Zhong, X. Y., Tang, D., Fan, X., & Chen, R. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00945-z · Cited by 16 · see citing works
Lambers, L., Waschinsky, N., Schleicher, J., König, M., Tautenhahn, H., Albadry, M., Dahmen, U., & Ricken, T. (2024) · Biomechanics and Modeling in Mechanobiology · doi:10.1007/s10237-023-01797-0 · Cited by 13 · see citing works
Murine breast cancers disorganize the liver transcriptome in a zonated manner
Vandenbon, A., Mizuno, R., Konishi, R., Onishi, M., Masuda, K., Kobayashi, Y., Kawamoto, H., Suzuki, A., He, C., Nakamura, Y., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-04479-w · Cited by 12 · see citing works
Fast formation and maturation enhancement of human liver organoids using a liver-organoid-on-a-chip
Byeon, J. H., Jung, D. J., Han, H.-J., Son, W.-C., & Jeong, G. S. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1452485 · Cited by 12 · see citing works
Significance of Liver Zonation in Hepatocellular Carcinoma
Yu, S., Gao, J., Wang, H., Liu, L., Liu, X., Xu, Y., Shi, J., Guo, W., & Zhang, S. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.806408 · Cited by 12 · see citing works
Unraveling the Complexity of Liver Disease One Cell at a Time
Bader, G. D., McGilvray, I. D., MacParland, S. A., Atif, J., & Thoeni, C. E. (2022) · Seminars in Liver Disease · doi:10.1055/s-0042-1755272 · Cited by 12 · see citing works
- Authors
- Ben-Moshe, S., Shapira, Y., Moor, A. E., Manco, R., Veg, T., Bahar Halpern, K., & Itzkovitz, S.
- Affiliations
- Weizmann Institute of Science (IL)
- University of Zurich (CH)
- Corresponding author
- Itzkovitz, Shalev
- Venue
- Nature Metabolism
- Published
- 2019-09-16
- Volume
- 1
- Issue
- 9
- Pages
- 899-911
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6751089
- OpenAlex
- W2974173934
- Cited by
- 205
- References
- 82
- Citations by year
- 2026: 31 · 2025: 29 · 2024: 42 · 2023: 31 · 2022: 26 · 2021: 26 · 2020: 16 · 2019: 4
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Howard Hughes Medical Institute (55008734)
- Vallee Foundation
- European Commission (2007–2013, FP7 2007-2013, FP7/2007)
- Weizmann Institute of Science
- Israel Science Foundation (FP7/2007-2013, 1486/16, 1796/12)
- Israeli Centers for Research Excellence (1796/12)
- Planning and Budgeting Committee of the Council for Higher Education of Israel
- FP7 Ideas: European Research Council (335122)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- liver zonation, lobules, spatial sorting, HNF4α, miR-122, mRNA degradation, Wnt signaling, FZD7, FZD8, TCF7L1
- MeSH terms
- Animals, Humans, Liver, RNA, Messenger, Gene Expression Profiling, Protein Transport, Hepatocytes, MicroRNAs, Single-Cell Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
