The spatiotemporal program of zonal liver regeneration following acute injury
Open accessAbstract
The liver carries a remarkable ability to regenerate rapidly after acute zonal damage. Single-cell approaches are necessary to study this process, given the spatial heterogeneity of liver cell types. Here, we use spatially resolved single-cell RNA sequencing (scRNA-seq) to study the dynamics of mouse liver regeneration after acute acetaminophen (APAP) intoxication. We find that hepatocytes proliferate throughout the liver lobule, creating the mitotic pressure required to repopulate the necrotic pericentral zone rapidly. A subset of hepatocytes located at the regenerating front transiently upregulate fetal-specific genes, including Afp and Cdh17, as they reprogram to a pericentral state. Zonated endothelial, hepatic stellate cell (HSC), and macrophage populations are differentially involved in immune recruitment, proliferation, and matrix remodeling. We observe massive transient infiltration of myeloid cells, yet stability of lymphoid cell abundance, in accordance with a global decline in antigen presentation. Our study provides a resource for understanding the coordinated programs of zonal liver regeneration.
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Hepatocyte proliferation has previously been considered a major driver of hepatic wound closure following necro-inflammatory liver injury.
“Hepatocyte proliferation has previously been considered a major driver of hepatic wound closure following necro-inflammatory liver injury2,24,25”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [24]
Transient fetal reprogramming of peri-injury hepatocytes, which subsequently adopted a zone 3 fate and contributed to local repair, suggests that hepatocytes in this zone have high plasticity.
“Transient fetal reprogramming of peri-injury hepatocytes, which subsequently adopted a zone 3 fate and contributed to local repair, suggests that hepatocytes in this zone have high plasticity104”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [104]
A recent update to the theory is that hepatocytes transiently undergo reprogramming (EMT, or fetal gene expression) as they proliferate.
“A recent update to this theory is that hepatocytes transiently undergo reprogramming (EMT, or fetal gene expression) as they proliferate.104,108”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [104]
Following ablation of pericentral hepatocytes, neighbouring zone 2 hepatocytes upregulated WNT/β-catenin signalling and acquired zone 3 identity to restore metabolic zonation.
“Following ablation of pericentral hepatocytes, neighbouring zone 2 hepatocytes upregulated WNT/β-catenin signalling and acquired zone 3 identity to restore metabolic zonation.85,104,105”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [104]
Transient changes in hepatocyte identity are required when hepatocytes re-enter the cell cycle in response to injury, while others increase metabolic function to maintain hepatic metabolism.
“Transient changes in hepatocyte identity are required when hepatocytes re-enter the cell cycle in response to injury, while others increase metabolic function to maintain hepatic metabolism.25,104,106,107,134”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [104]
Hepatocyte reprogramming likely occurs in acetaminophen (APAP)-induced pericentral liver injury.
“By analyzing the expression of Sox9 and RRGs in published scRNA-seq data, 39 we found that it was likely that hepatocyte reprogramming might occur in acetaminophen (APAP)-induced pericentral liver injury (Figures S6G and S6H).”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [39]
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Myeloid cells in alcoholic liver diseases: Mechanism and prospect
Xu, W., Wu, M., Chen, B., & Wang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.971346 · Cited by 11 · see citing works
Role of Pyroptosis in Acetaminophen-Induced Hepatotoxicity
Jaeschke, H., Umbaugh, D. S., & Ramachandran, A. (2022) · Livers · doi:10.3390/livers2040032 · Cited by 11 · see citing works
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NIPMAP: niche-phenotype mapping of multiplex histology data by community ecology
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Bioinspired Spatially Ordered Multicellular Lobules for Liver Regeneration
Wang, J., Huang, D., Ren, H., & Zhao, Y. (2025) · Research · doi:10.34133/research.0634 · Cited by 10 · see citing works
Multicellular dynamics of zonal liver regeneration mapped in space and time
Chen, F., & Tchorz, J. S. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.05.008 · Cited by 10 · see citing works
Fragment-sequencing unveils local tissue microenvironments at single-cell resolution
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Unveiling the power of microenvironment in liver regeneration: an in-depth overview
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Development of a hepatic cryoinjury model to study liver regeneration
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PPARα agonist ameliorates cholestatic liver injury by regulating hepatic macrophage homeostasis
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Myeloid cell path to malignancy: insights into liver cancer
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Emerging Roles of Spatial Transcriptomics in Liver Research
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Repopulation of microglia and its implications for CNS disorders: Insights from the single-cell era
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Organ‐Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming
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SETDB1 promotes mammalian liver regeneration by stimulating cytokine CSF3 in hepatocytes
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Hepatocyte regeneration is driven by embryo-like DNA methylation reprogramming
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- Authors
- Ben-Moshe, S., Veg, T., Manco, R., Dan, S., Papinutti, D., Lifshitz, A., Kolodziejczyk, A. A., Bahar Halpern, K., Elinav, E., & Itzkovitz, S.
- Affiliations
- Weizmann Institute of Science (IL)
- German Cancer Research Center (DE)
- Corresponding author
- Itzkovitz, Shalev
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2022-06
- Volume
- 29
- Issue
- 6
- Pages
- 973-989.e10
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W4281664504
- Cited by
- 224
- References
- 98
- Citations by year
- 2026: 56 · 2025: 62 · 2024: 56 · 2023: 36 · 2022: 14
- FWCI
- 25.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Funders
- Israel Science Foundation (1486/16)
- European Research Council (768956)
- Wolfson Family Charitable Trust
- Chan Zuckerberg Initiative (CZF2019-002434)
- Edmond de Rothschild Foundation
- European Commission
- Howard Hughes Medical Institute
- Minerva Foundation
- Horizon 2020 Framework Programme
- Vallee Foundation
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- liver regeneration, acetaminophen hepatotoxicity, hepatocyte proliferation, alpha-fetoprotein, CDH17, hepatic stellate cells, liver endothelial cells, hepatic macrophages, myeloid cell infiltration, immune cell recruitment, extracellular matrix remodeling, antigen presentation, spatial heterogeneity, mouse liver
- MeSH terms
- Acetaminophen, Animals, Liver, Liver Regeneration, Hepatocytes, Mice, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury
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.
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