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Liver regeneration and inflammation: from fundamental science to clinical applications

Abstract

Liver regeneration is a complex process involving the crosstalk of multiple cell types, including hepatocytes, hepatic stellate cells, endothelial cells and inflammatory cells. The healthy liver is mitotically quiescent, but following toxic damage or resection the cells can rapidly enter the cell cycle to restore liver mass and function. During this process of regeneration, epithelial and non-parenchymal cells respond in a tightly coordinated fashion. Recent studies have described the interaction between inflammatory cells and a number of other cell types in the liver. In particular, macrophages can support biliary regeneration, contribute to fibrosis remodelling by repressing hepatic stellate cell activation and improve liver regeneration by scavenging dead or dying cells in situ. In this Review, we describe the mechanisms of tissue repair following damage, highlighting the close relationship between inflammation and liver regeneration, and discuss how recent findings can help design novel therapeutic approaches.

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Fig. 1: Microscopic liver anatomy.
Fig. 2: Mechanisms of liver regeneration involving non-parenchymal cells.
Fig. 3: Roles of parenchymal cells in liver regeneration.
Fig. 4: Crosstalk between parenchymal and non-parenchymal cells during liver injury and regeneration.
Fig. 5: Populations of macrophages during liver damage and repair.
Fig. 6: Aims of cell therapy for chronic liver disease.

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Acknowledgements

The authors thank R. Aird and B. Dwyer for helpful discussions regarding the draft manuscript.

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Contributions

L.C. and H.E. wrote the first draft of the manuscript. S.F. and M.H. reviewed the first draft and added to the manuscript.

Corresponding author

Correspondence to Stuart Forbes.

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Competing interests

S.F. has patents pending entitled “Macrophage-based therapy” in national territories of the USA, Europe, Japan, China and Australia. These patents have been derived from PCT/GB2017/052769 filed in 18 September 2017 and claim priority from UK application 1615923.8 filed on 19 September 2016. Both of the original patents have now been abandoned because the original UK patent and PCT patent are no longer live and have now been replaced by the national patents. L.C. is a co-founder and current employee of Resolution Therapeutic Ltd.

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Nature Reviews Molecular Cell Biology thanks Frank Tacke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Cirrhosis

Terminal stage of liver fibrosis, when the scarring of the liver is hardly or not reversible. It is associated with high morbidity and mortality and may lead to the development of liver cancer.

Hepatocellular carcinoma

Most common type of liver cancer, develops in people with chronic liver diseases of various causes. It is caused by an uncontrolled hyperproliferation of hepatocytes.

Orthotopic liver transplantation

Surgical replacement of a non-functional liver with a healthy liver from a living or deceased donor. ‘Orthotopic’ refers to the donor liver being placed in the same anatomical position as the host liver.

Necrosis

Premature and non-regulated form of cell death, which results in autolysis of the cell, with subsequent dissemination of the intracellular components in the extracellular space and inflammation.

Apoptosis

A form of programmed cell death characterized by blebbing of the cellular membranes, condensation of chromatin and retention of membrane integrity, thereby preventing the triggering of inflammatory responses.

Zonation

Definition of three distinct metabolic zones for hepatocytes along the sinusoids, depending on the oxygen gradient (higher near the hepatic artery and progressively lower closer to the central vein).

Cellular senescence

A state of permanent cell cycle arrest in which cells exit the G1 phase and enter irreversibly the G0 phase. Senescent cells secrete factors in the microenvironment, triggering a senescence-associated secretory phenotype.

Matrix metalloproteases

(MMPs). Zinc-dependent enzymes (endopeptidases) that hydrolyse peptide bonds in extracellular matrix molecules, thereby promoting their degradation. They are usually stored as proenzymes, and are converted into their active form when needed.

Danger-associated molecular patterns

Molecules that are normally intracellular and that are passively released into the extracellular space when a cell dies following a pathway that does not preserve membrane integrity, such as necrosis.

Phagocytosis

Engulfment of a cargo by a living cells. The cargo can be either a pathogen or a dead or dying cell. In mammalians, professional phagocytes such as macrophages perform high-rate phagocytosis in the case of infection or tissue damage.

Pathogen-associated molecular patterns

Molecules that derive from pathogens and that allow the innate immune system to categorize which type of threat it has to fight thanks to the engagement of specific receptors on innate immune cells that recognize one specific type of molecule only.

GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway

Pathway of the innate immune system that detects the presence of cytosolic DNA (usually indicating a viral infection or tumorigenesis) and responds by triggering the expression of inflammatory genes, such as those encoding interferon-β, which drives antiviral responses.

Fatty liver disease

A form of liver injury where the parenchymal cells are progressively replaced by adipocytes with subsequent loss of function of the liver.

TH1 adaptive immune response

A branch of the adaptive immune response. T helper 1 (TH1) cells normally develop following antigenic stimulation and co-stimulation of the naive T cell in the presence of interferon-γ and are involved in the killing of infected or tumoural cells.

TH2 adaptive immune response

A branch of the adaptive immune response. T helper 2 (TH2) cells normally develop following antigenic stimulation and co-stimulation of the naive T cell in the presence of IL-4 and IL-13, and they support type II immune responses, including the B cell response.

Unconventional T cells

T cells expressing a γδ T cell receptor. They have a barrier function against invading pathogens, and they are active in local cancer immunosurveillance.

TH17 adaptive immune responses

A branch of the adaptive immune response. T helper 17 (TH17) cells secrete cytokines belonging to the IL-17 family, particularly IL-17A, IL-17F, IL-22 and TNF. They are involved in host defence, attacking pathogens such as extracellular bacteria and fungi.

Regulatory T cells

(Treg cells). Treg cells normally develop following antigenic stimulation and co-stimulation of the naive T cell in the presence of TGFβ and IL-2. They secrete cytokines such as IL-10, TGFβ and IL-35. They are involved in repression of T cell responses.

TNF-related weak inducer of apoptosis

(TWEAK). Cytokine belonging to the TNF superfamily that acts in a pleiotropic fashion through interaction with its receptor, FN14. It has been implicated in processes such as cell proliferation, angiogenesis and control of inflammation.

Haematopoietic stem cells

Stem cells that self-renew and give rise to other progenitor cells that in turn produce all of the cell lineages of the blood. They reside in the red bone marrow of most bones.

Immunosuppression

In this instance, a therapeutic regime aimed at suppressing the host immune system to prevent rejection of the transplanted organ.

Mesenchymal stromal cells

(MSCs). Stem/progenitor cells that can give rise to tissue of embryonic mesenchymal origin such as cartilage (chondrocytes), bone (osteoblasts), muscle (myocytes) and adipose tissue (adipocytes).

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Campana, L., Esser, H., Huch, M. et al. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00373-7

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