Cited by 224Liver physiology and pathologyDrug-Induced Hepatotoxicity and ProtectionTissue Engineering and Regenerative Medicine

The spatiotemporal program of zonal liver regeneration following acute injury

Open access
Ben-Moshe, Shani, Veg, Tamar, Manco, Rita, Dan, Stav, Papinutti, Delfina, Lifshitz, Aviezer, Kolodziejczyk, Aleksandra A., Bahar Halpern, Keren +2 more·2022·Cell Stem Cell

Abstract

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.

Integrity signals

Registry

Crossref · 10.1016/j.stem.2022.04.008

Cites

99 of 99 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

  • 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”
  • 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”
  • 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”
  • 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”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
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
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.

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