Liver regeneration: biological and pathological mechanisms and implications

Michalopoulos, George K.; Bhushan, Bharat

doi:10.1038/s41575-020-0342-4

Cited by 573 publications

(574 citation statements)

References 195 publications

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“…One of the characteristics of the liver is its high regenerative capacity, which is demonstrated when it is damaged by liver diseases or partial hepatectomy. Recent studies have shown that the dedifferentiation of bile duct epithelial cells and mature hepatocytes plays an important role in liver regeneration [8][9][10][11][12]. Specifically, it has been shown that hepatocytes and bile duct epithelial cells decidualize into highly proliferative hepatic progenitors in injured mouse livers, which are characterized by (1) a phenotype that is positive for both hepatocyte and bile duct epithelial markers, (2) characteristic cell morphology, and (3) high proliferative capacity [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Drug metabolic activity is a critical cell-intrinsic determinant for selection of hepatocytes during long-term culture

Akiyama

Saku

Miyata

et al. 2021

Preprint

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The liver plays many important roles in homeostasis, including drug detoxification, metabolism, and bile production. Hepatocytes, which are the main constituent cells of the liver, play an important role in the pathogenesis of liver diseases, identification of candidate compounds in drug discovery research, pharmacokinetic studies, and toxicity evaluation. Human hepatocytes are, however, difficult to grow in normal in vitro culture systems, making it difficult to secure cell numbers. As an alternative, evaluation systems using animal models and hepatocellular carcinoma cells have been established, but interspecies and interracial differences and low hepatic function have been pointed out as problems. Therefore, there is still a need for a highly stable method to prepare human hepatocytes with sufficient functionality. In this study, we aimed to establish an in vitro long-term culture system that enables stable proliferation and maintenance of the functionality of human hepatocytes to stably supply human hepatocytes. In the established culture system, the stable proliferation of human hepatocytes was achieved by co-culturing hepatocytes with mouse fetal fibroblasts to dedifferentiate them into hepatic progenitor-like cells. Furthermore, we succeeded in purifying human hepatocytes by puromycin with a rapid cytocidal effect and proliferating them to over 30 population doublings for more than 200 days. Hepatocytes with high expression of cytochrome P450 genes survived after exposure to cytotoxic antibiotics because of enhanced drug-metabolizing activity. These results show that the above culture system enables simple and efficient hepatocyte proliferation, and is considered to be an effective method for stable supply of hepatocytes and significant cost reduction in drug discovery research.

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Section: Introductionmentioning

confidence: 99%

Drug metabolic activity is a critical cell-intrinsic determinant for selection of hepatocytes during long-term culture

Akiyama

Saku

Miyata

et al. 2021

Preprint

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“…All vertebrates also share a highly conserved evolution of the hepatic portalliver system (Subbotin, 2017). A fact is that the liver is the only parenchymal organ that regenerates up to the proper ratio with respect to body size, in contrast with other organs, which only partially regenerate (Michalopoulous and Bhushan, 2021).…”

Section: Factors Contributing To the High Regenerative Capacity Of Thmentioning

confidence: 99%

Liver regeneration observed across the different classes of vertebrates from an evolutionary perspective

Delgado–Coello

2021

Heliyon

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The liver is a key organ that performs diverse functions such as metabolic processing of nutrients or disposal of dangerous substances (xenobiotics). Accordingly, it seems to be protected by several mechanisms throughout the life of organisms, one of which is compensatory hyperplasia, also known as liver regeneration. This review is a recapitulation of the scientific reports describing the different ways in which the various classes of vertebrates deal with liver injuries, where since mammals have an improved molecular toolkit, exhibit optimized regeneration of the liver compared to lower vertebrates. The main molecules involved in the compensatory process, such as proinflammatory and inhibitory cytokines, are analyzed across vertebrates with an evolutionary perspective. In addition, the possible significance of this mechanism is discussed in the context of the long life span of vertebrates, especially in the case of mammals.

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“…The regenerative capacity of the liver is a central aspect of its functionality. Not only can small functional lesions be easily repaired by newly proliferating tissue, but it also allows for simultaneous surgical resections of multiple lobes of the liver without permanent impairments [99]. To this day, multiple studies depict IL-22 as an important player in mediating wound healing and tissue regeneration [22].…”

Section: Liver Regenerationmentioning

confidence: 99%

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

et al. 2021

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The human liver fulfills several vital tasks daily and possesses an impressive ability to self-regenerate. However, the capacity of this self-healing process can be exhausted by a variety of different liver diseases, such as alcoholic liver damage, viral hepatitis, or hepatocellular carcinoma. Over time, all these diseases generally lead to progressive liver failure that can become fatal if left untreated. Thus, a great effort has been directed towards the development of innovative therapies. The most recently discovered therapies often involve modifying the patient’s immune system to enhance a beneficial immune response. Current data suggest that, among others, the cytokine IL-22 might be a promising therapeutical candidate. IL-22 and its endogenous antagonist, IL-22BP, have been under thorough scientific investigation for nearly 20 years. While IL-22 is mainly produced by TH22 cells, ILC3s, NKT cells, or γδ T cells, sources of IL-22BP include dendritic cells, eosinophils, and CD4+ cells. In many settings, IL-22 was shown to promote regenerative potential and, thus, could protect tissues from pathogens and damage. However, the effects of IL-22 during carcinogenesis are more ambiguous and depend on the tumor entity and microenvironment. In line with its capabilities of neutralizing IL-22 in vivo, IL-22BP possesses often, but not always, an inverse expression pattern compared to its ligand. In this comprehensive review, we will summarize past and current findings regarding the roles of IL-22 and IL-22BP in liver diseases with a particular focus on the leading causes of advanced liver failure, namely, liver infections, liver damage, and liver malignancies.

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Liver regeneration: biological and pathological mechanisms and implications

Cited by 573 publications

References 195 publications

Drug metabolic activity is a critical cell-intrinsic determinant for selection of hepatocytes during long-term culture

Drug metabolic activity is a critical cell-intrinsic determinant for selection of hepatocytes during long-term culture

Liver regeneration observed across the different classes of vertebrates from an evolutionary perspective

The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies

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