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  • Review Article
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Liver regeneration: from myth to mechanism

Key Points

  • The unusual ability of the liver to regenerate is a logical evolutionary adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. Regeneration in response to injury, or partial removal of the liver, involves replication of the mature cells of the liver and is not normally mediated by stem cells.

  • The cytokine- and growth-factor-mediated pathways that are involved in liver regeneration are being successfully dissected using molecular and genetic approaches. The main cytokine-mediated pathways include members of the innate immune system, tumour necrosis factor (TNF)α and interleukin (IL)-6, and growth-factor-mediated pathways are regulated by hepatocyte growth factor (HGF) and transforming growth factor (TGF)α.

  • Regulation is partly paracrine, as factors that are secreted by neighbouring cells within the liver or other organs function on hepatocytes, the main functional cells within the liver, to stimulate signal-transduction pathways that lead to cell-cycle transition and DNA replication. Important signal-transduction pathways include those that involve signal transducer and activator of transcription (STAT)3 and mitogen-activated protein kinase (MAPK), although the exact details and the interplay between growth factors and cytokines remain to be elucidated.

  • The same cytokine- and growth-factor-mediated pathways that promote regeneration of the liver protect the liver against apoptotic damage that is caused by toxins and viral infections. IL-6, HGF and insulin-like-growth-factor-binding protein (IGFBP)-1 function to reduce the production of apoptogenic factors like TGFβ, reduce caspase activation and reduce the production of reactive oxygen species.

  • The liver is able to maintain sufficient functional capacity and differentiated function as it regenerates by upregulating genes that are important for differentiated function. Resident hepatic and growth-induced transcription factors interact to amplify the expression of critical hepatic genes.

  • The liver stops regenerating once it has attained the mass that is required for the functional needs of the organism, and critical regulatory pathways that are important for terminating regeneration include TGFβ, activin and suppressor of cytokine signalling (SOCS).

  • The study of liver regeneration in rodents has had a critical effect on medical practice and allowed for the development of new liver-transplant technologies. Because human livers also regenerate it has become possible to use partial livers from living donors for transplantation, thereby increasing the number of organs that are available for transplantation.

Abstract

The unusual regenerative properties of the liver are a logical adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches. So what is known about this process at present and which questions remain?

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Figure 1: Liver regeneration is triggered by partial hepatectomy or liver damage.
Figure 2: Patterns of DNA synthesis and induction of gene expression during rat liver regeneration.
Figure 3: Growth-factor- and cytokine-regulated pathways are activated during liver regeneration.
Figure 4: The interleukin-6–STAT3 signalling pathway.
Figure 5: Protecting the liver against apoptosis.

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Zixuan Zhao, Xinyi Chen, … Hanry Yu

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DATABASES

Swiss-Prot

AKT

C3

C5

EGF

gp130

GRB2

IL-6

IL-6R

insulin

JAK1

Met

pro-HGF

pro-SCF

Raf

SOCS3

STAT3

TGFα

TNFα

uPA

FURTHER INFORMATION

Bulfinch's mythology

Glossary

ACUTE-PHASE RESPONSE

A defence reaction of the organism to toxic or infectious agents that seeks to eliminate the causative agent and restrict organ damage through the production of cytokines such as interleukin (IL)-6 and -1 and tumour necrosis factor (TNF)α. These cytokines upregulate the production of acute-phase proteins, such as complement (C)-reactive protein and serum amyloid protein, which protect against damage in the liver and other organs.

KUPFFER CELL

A macrophage, or monocytic cell, of the liver that is permanently located in the liver within gaps between sinusoidal endothelial cells. Kupffer cells form the largest population of macrophages within the body and can migrate within the liver to sites of injury.

STELLATE CELL

A cell that resides within the space of Disse, in recesses between hepatocytes. They amount to 2–20 per 100 hepatocytes, and their main function lies in the storage of vitamin A. Stellate cells are activated during liver injury and become myofibroblasts that produce extracellular matrix. They are important in the progression of fibrosis and liver disease.

SINUSOID

Hepatic microcirculatory vessel with its base at the perimeter of the classic lobule that includes the portal vein, hepatic artery and apex of the central vein. It is the basic blood-circulatory unit of the liver. A single inlet portal venule serves 19 blood-delivery capillaries or sinusoids that surround the hepatocytes and are lined by fenestrated endothelial cells.

CYTOKINE

A member of a large family of secreted proteins that interact with a cellular receptor. Cytokine production results in the activation of an intracellular-signalling cascade that commonly regulates processes such as immune function and inflammation.

LIVER FIBROSIS AND CIRRHOSIS

A process that leads to the accumulation of extracellular matrix and collagen. These substances are primarily laid down by activated hepatic stellate cells during chronic liver injury, which is caused by hepatotoxins, such as alcohol, or by viral hepatitis. Fibrosis and cirrhosis are part of the same process, cirrhosis being end-stage, generally irreversible, liver fibrosis that is associated with clinical signs such as portal hypertension.

PARTIAL HEPATECTOMY

The removal of specific lobes of the liver, generally by ligation of the blood supply and resection. The procedure normally does not involve a specific incision in a liver lobe.

GROWTH FACTOR

A member of a large family of secreted proteins that interact with a cellular receptor, which leads to a mitogenic response that results in DNA synthesis and progression through the cell cycle. Growth factors commonly interact with receptor tyrosine kinases.

LIVER LOBULE

A microscopic unit of liver parenchyma. This hexagonal unit contains portal tracts at its periphery and a central vein from which one-cell-deep plates of hepatocytes radiate.

PLOIDY

The DNA content of a cell, which is normally diploid (2N) in eukaryotic cells. However, hepatic cells can be polyploid, with the tetraploid (4N) DNA content reflecting the failure of cells to undergo mitosis after DNA replication.

CARBON TETRACHLORIDE

(CCl4). A well-studied hepatotoxin that is metabolized to a highly reactive free radical that causes direct hepatocyte injury by altering the permeability of cellular lysosomal and mitochondrial membranes.

Fas LIGAND

A secreted protein that interacts with Fas, a receptor on the surface of many cells, which results in the activation of the apoptotic cascade. The liver is particularly sensitive to systemic administration of Fas ligand by the subcutaneous route, and death from systemic Fas-ligand administration is due to liver failure.

FIBRONECTIN

An extracellular-matrix protein that functions in the structural integrity of the cell, and that interacts with the cell-surface receptor integrin α5β1, which causes intracellular signalling.

OVAL CELL

A periportal cuboidal cell with an oval-shaped nucleus that is thought to function as a hepatic stem cell. Oval-cell formation can be induced by exposing the liver to chemical hepatocarcinogens, they might also be precursors of hepatocellular carcinoma.

PARABIOSIS

A surgical procedure whereby the circulation of two animals is joined.

IMMEDIATE-EARLY GENE

A gene that is transcribed in the absence of de novo protein synthesis as the result of transcriptional activation by normally latent transcription factors that become active after stimulation. This includes, for example, activation by a growth factor or, in this case, immediately after partial hepatectomy.

MITOGENESIS

The process of stimulating transit through the cell cycle. A 'mitogen' stimulates transit through the cell cycle.

COMPLEMENT SYSTEM

A host defence system that consists of more than 30 plasma and cell-surface proteins, and that is a component of both innate and antibody-mediated immunity. After activation, a chain of reactions ensues, which involves the proteolysis and assembly of complement components, and the generation of C3 and the membrane-attack complex.

ISCHAEMIA

The reduced blood flow and oxygenation of tissues that leads to necrosis, injury and apoptosis.

APOPTOGENIC

Resulting in apoptosis or programmed cell death. In the liver, Fas ligand is a direct apoptogen because it binds its cognate receptor and activates the cell-death cascade. TGFβ is an indirect apoptogen that activates cell-death pathways through as-yet-unknown, indirect mechanisms.

GLUCONEOGENIC

Resulting in the net production of glucose, which is subsequently released into the blood stream. Enzymes of the gluconeogenic pathway in the liver include phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase.

HYPOGLYCAEMIA

A physiological condition that is caused by a low level of glucose in the blood. The liver is an important organ in the control of glucose levels in the blood.

FOLLISTATIN

A single-chain polypeptide that binds activin, a member of the TGFβ family, and neutralizes its biological activities — including its anti-proliferative activities in hepatocytes.

LIVING RELATED-DONOR TRANSPLANT

A liver transplant that is carried out using a lobe of the liver that has been removed from a living donor and transplanted into a family member who is in need of a liver transplant. As a result, liver regeneration must occur in the donor to restore the mass of the liver that was removed.

SMALL-FOR-SIZE TRANSPLANT ORGAN

A portion of a cadaveric liver that can be transplanted into a recipient, allowing one liver to be used for more than one recipient. As the transplanted liver is too small to serve the needs of the recipient, liver hyperplasia must occur in the transplanted liver to increase the liver mass to the necessary size.

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Taub, R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 5, 836–847 (2004). https://doi.org/10.1038/nrm1489

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