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Cited by 103Liver physiology and pathologyDrug-Induced Hepatotoxicity and ProtectionOrgan Transplantation Techniques and Outcomes

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Functional compensation precedes recovery of tissue mass following acute liver injury

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Walesky, Chad M., Kolb, Kellie E., Winston, Carolyn L., Henderson, Jake, Kruft, Benjamin, Fleming, Ira, Ko, Sungjin, Monga, Satdarshan P., Mueller, Florian, Apte, Udayan, Shalek, Alex K., Goessling, Wolfram·2020·Nature Communications
DOI 10.1038/s41467-020-19558-3PMC PMC7677389
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Abstract

The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/β-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation.

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  • During two distinct phases of regeneration, macrophage-derived WNT ligands were required for functional compensation and induction of metabolic gene expression, whereas endothelium-derived WNT ligands were more important for inducing hepatocyte proliferation.

    “During two distinct phases of regeneration, macrophage-derived WNT ligands were required for functional compensation and induction of metabolic gene expression, whereas endothelium-derived WNT ligands were more important for inducing hepatocyte proliferation.134”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [134]

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Metadata

Authors
Walesky, C. M., Kolb, K. E., Winston, C. L., Henderson, J., Kruft, B., Fleming, I., Ko, S., Monga, S. P., Mueller, F., Apte, U., Shalek, A. K., & Goessling, W.
Affiliations
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • University of Pittsburgh (US)
  • Centre National de la Recherche Scientifique (FR)
  • University of Kansas Medical Center (US)
Corresponding author
  • Shalek, Alex K.
  • Goessling, Wolfram
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-11-19
Volume
11
Issue
1
Pages
5785-5785
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-19558-3
PMC
PMC7677389
OpenAlex
W3099310641
Cited by
103
References
54
Citations by year
2026: 9 · 2025: 15 · 2024: 16 · 2023: 21 · 2022: 13 · 2021: 22 · 2020: 7
FWCI
9.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Liver Foundation (R01DK105198, R24OD017870, R01DK090311)
  • Cholangiocarcinoma Foundation
  • Searle Scholars Program
  • National Institutes of Health (R24OD017870)
  • National Cancer Institute (R01CA204586)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK090311, R01DK105198, R01DK100287, R01DK098414, F32DK111151, P30DK120531, P30DK034854, R01DK062277)
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 › Organ Transplantation Techniques and Outcomes
Keywords
acute liver injury, liver regeneration, functional compensation, Wnt/β-catenin signaling, hepatic macrophages, transcriptional compensation, non-proliferating cells, liver repair, single-cell RNA sequencing
MeSH terms
Acetaminophen, Animals, Cell Cycle, Disease Models, Animal, Hepatectomy, Liver, Liver Regeneration, Macrophages, Mice, Inbred C57BL, Mice, Knockout, Gene Expression Profiling, Hepatocytes, Cell Proliferation, Wnt Proteins, beta Catenin, Mice, Wnt Signaling Pathway

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