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Cited by 62Liver physiology and pathologyTissue Engineering and Regenerative MedicineOrgan Transplantation Techniques and Outcomes

Molecular pathways of liver regeneration: A comprehensive review

Open access
Kiseleva, Yana V, Antonyan, Sevak Z, Zharikova, Tatyana S, Tupikin, Kirill A, Kalinin, Dmitry V, Zharikov, Yuri O·2021·World Journal of Hepatology
DOI 10.4254/wjh.v13.i3.270PMC PMC8006075
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Abstract

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70% of its volume. Although knowledge of this phenomenon dates back to Greek mythology (the story of Prometheus), many aspects of liver regeneration are still not understood. A variety of different factors, including inflammatory cytokines, growth factors, and bile acids, promote liver regeneration and control the final size of the organ during typical regeneration, which is performed by mature hepatocytes, and during alternative regeneration, which is performed by recently identified resident stem cells called "hepatic progenitor cells". Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass, such as in cases of chronic injury or excessive acute injury. In liver maintenance, the body mass ratio is essential for homeostasis because the liver has numerous functions; therefore, a greater understanding of this process will lead to better control of liver injuries, improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases. The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries. Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.

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Crossref · 10.4254/wjh.v13.i3.270

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  • TGF-β is a central regulator of liver regeneration with a dual role: at low concentrations it promotes regeneration, and at high concentrations it induces hepatocyte apoptosis and suppresses regeneration.

    “Transforming growth factor-beta (TGF-β) is one of the central regulators of LR but exhibits a dual role: At low concentrations, it promotes regeneration; at high concentrations, it induces hepatocyte apoptosis and suppresses regeneration.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [60]

    The Termination phase section says TGF-β1 induces cell apoptosis to correct excessive liver mass and describes some TGF-β family members as inhibitors of proliferation. It does not say that low concentrations of TGF-β promote regeneration or that its effects switch at a particular concentration; the Proliferative phase instead names TGF-α as a mitogen. Page numbers are not provided in our copy. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • TGF-β is considered the main termination mechanism of liver regeneration, ensuring that the process ceases when the liver reaches its normal size.

    “TGF-β is considered the main termination mechanism of LR, ensuring that the process ceases when the liver reaches its normal size.”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [60]

    The Termination phase section (page unavailable) says proliferation stops when the needed liver-mass-to-body-mass ratio is reached, and that TGF-β1 helps correct excessive liver mass. It describes TGF-β as one of several inhibitory pathways, however, and does not identify it as the main termination mechanism. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Hedgehog signaling regulates YAP-1 expression, stimulates glutaminolysis, activates hepatic stellate cells, prevents apoptosis of hepatocytes, biliary epithelial cells, and liver progenitor cells, and plays an up-regulatory role in liver regeneration.

    “The Hedgehog (Hh) signaling pathway regulates the expression of YAP-1, which in turn stimulates glutaminolysis and activates hepatic stellate cells (Ito cells). Additionally, Hh signaling prevents apoptosis of hepatocytes, biliary epithelial cells, and liver progenitor cells, playing an up-regulatory role in LR[60].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [60]

  • TGF-β activity is closely linked to portal circulation parameters and shear stress.

    “Notably, its activity is closely linked to portal circulation parameters and shear stress[60].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [60]

    The Termination phase discusses TGF-β1’s role in limiting liver regeneration, while Phases of typical liver regeneration discusses portal pressure changes and mechanically stimulated sinusoidal endothelial cells. Neither section links TGF-β activity to portal circulation parameters or shear stress; searches for those terms found no such link in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Kiseleva, Y. V., Antonyan, S. Z., Zharikova, T. S., Tupikin, K. A., Kalinin, D. V., & Zharikov, Y. O.
Affiliations
  • Sechenov University (RU)
  • Research Institute of Emergency Care (RU)
  • Russian University of Medicine (RU)
  • National Medical Research Center of Surgery named after A. Vishnevsky (RU)
ORCID
Venue
World Journal of Hepatology
Publisher
Baishideng Publishing Group Inc.
Published
2021-03-27
Volume
13
Issue
3
Pages
270-290
ISSN
1948-5182 (ISSN-L)
DOI
10.4254/wjh.v13.i3.270
PMC
PMC8006075
OpenAlex
W3138310216
Cited by
62
References
18
Citations by year
2026: 11 · 2025: 14 · 2024: 16 · 2023: 8 · 2022: 5 · 2021: 8
FWCI
1.21
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • World Journal of Hepatology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
liver regeneration, hepatic progenitor cells, hepatocytes, molecular pathways, inflammatory cytokines, growth factors, bile acids, liver injury, liver homeostasis, liver transplantation, liver disease

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