Evidence map›Paper›PMID 26254847›Full record

ArticleJournal of hepatology2016

Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate.

Hiroyuki Nojima, Christopher M Freeman, Rebecca M Schuster, Lukasz Japtok, Burkhard Kleuser, Michael J Edwards, Erich Gulbins, Alex B Lentsch

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of hepatology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 175 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
175citing papers in PubMed, 2 pooled it
9.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

175 citing papers in PubMed, 2 syntheses or guidelines pooled it, 300 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Trial
  4. Review
  5. Article
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  8. Review
  9. 80 years of extracellular vesicles: from discovery to clinical translation.Extracellular vesicles and circulating nucleic acids · 2026
    Review
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  15. Article
  16. Article
  17. Article
  18. Organ Crosstalk: The Role of Spleen.Phenomics (Cham, Switzerland) · 2025
    Review
  19. Article
  20. Review

115 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 2 countries.

Hiroyuki NojimaDepartment of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Christopher M FreemanDepartment of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Rebecca M SchusterDepartment of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Lukasz JaptokInstitute of Nutritional Science, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany.
Burkhard KleuserInstitute of Nutritional Science, University of Potsdam, Arthur-Scheunert Allee 114-116, 14558 Nuthetal, Germany.
Michael J EdwardsDepartment of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Erich GulbinsDepartment of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA; Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Alex B LentschDepartment of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA. Electronic address: alex.lentsch@uc.edu.
University of Cincinnati Medical Center · USUniversity of Potsdam · DE

Funding

Stem Cell/Organoid and Genome Editing CoreP30DK078392 · NIDDK · CINCINNATI CHILDRENS HOSP MED CTR · PI Alexander Miethke · 2007 to 2026
$24.4M
REGULATION OF HEPATIC ISCHEMIA/REPERFUSION INJURYR01DK056029 · NIDDK · UNIVERSITY OF LOUISVILLE · PI LENTSCH, ALEX B. · 2000 to 2018
$6.0M
Age Effects on Liver Inflammation and InjuryR01AG025881 · NIA · UNIVERSITY OF CINCINNATI · PI LENTSCH, ALEX B. · 2005 to 2014
$3.0M
NIA NIH HHS AG025881NIA NIH HHS R01 AG025881NIDDK NIH HHS DK56029NIDDK NIH HHS P30 DK078392NIDDK NIH HHS R01 DK056029
6 · The paper itself

Abstract

BACKGROUND &

aimsExosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury.

methodsExosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo.

resultsHepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases.

conclusionsOur data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease.

Indexed as

Liver RegenerationAnimalsCell ProliferationExosomesHepatocytesLysophospholipidsMaleMiceMice, Inbred C57BLPhosphotransferases (Alcohol Group Acceptor)SphingosineSphingosine KinaseLysophospholipidsPhosphotransferases (Alcohol Group Acceptor)Sphingosinesphingosine 1-phosphateSphingosine Kinasesphingosine kinase 2, mouseIschemia/reperfusionLiver injurySphingolipidsSphingosine kinaseTransplantation

Identifiers

PMID26254847
PMCPMC4843792
OpenAlexW1066172147

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.