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Journal of Hepatology 2000The liver can precisely regulate its growth and mass. Surgical resection of hepatic lobes or hepatocyte loss caused by viral or chemical injury triggers hepatocyte... (Review)
Review
The liver can precisely regulate its growth and mass. Surgical resection of hepatic lobes or hepatocyte loss caused by viral or chemical injury triggers hepatocyte replication while enlarged liver mass is corrected by apoptosis. Hepatocytes have a great replicative capacity and are capable of repopulating the liver. However, "stem-like" cells proliferate when hepatocyte replication is blocked or delayed. Detailed studies of the mechanisms that regulate liver growth have been done in animals subjected to partial hepatectomy or chemical injury. Substantial progress has been achieved using appropriate transgenic and knockout mouse models for this work. Gene expression in the regenerating liver can be divided into several phases, starting with expression of a large number of immediate early genes. Hepatocytes need to be primed before they can fully respond to the growth factors HGF (Hepatocyte Growth Factor), TGFalpha (Transforming Growth Factor Alpha), and EGF (Epidermal Growth Factor) in vitro. Priming requires the cytokines TNF and IL-6 in addition to other agents that prevent cytotoxicity. Reactive Oxygen Species and glutathione content can determine whether the TNF effect on hepatocytes is proliferative or apoptotic. At least four transcription factors, NFkappaB, STAT3 (which are strongly induced by TNF), AP-1 and C/EBPbeta play major roles in the initiation of liver regeneration. In addition, extensive remodeling of the hepatic extracellular matrix occurs shortly after partial hepatectomy. Progression through the cell cycle beyond the initiation phase requires growth factors. The expression of Cyclin D1 probably establishes the stage at which replication becomes growth factor-independent and autonomous. Knowledge about the mechanisms of liver regeneration can now be applied to correct clinical problems caused by deficient liver growth.
Topics: Animals; Cell Cycle; Cell Division; Genes, Immediate-Early; Growth Substances; Humans; Liver; Liver Regeneration; Stem Cells; Transcription Factors
PubMed: 10728791
DOI: 10.1016/s0168-8278(00)80412-2 -
Cells Apr 2020Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries... (Review)
Review
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.
Topics: Endothelium; Humans; Liver Cirrhosis; Liver Regeneration; Signal Transduction
PubMed: 32290100
DOI: 10.3390/cells9040929 -
Aging Aug 2018The regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are... (Review)
Review
The regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are involved in the impairment of liver mass recovery during aging. Among the intracellular factors, age-dependent decrease of BubR1 (budding uninhibited by benzimidazole-related 1), YAP (Yes-associated protein) and SIRT1 (Sirtuin-1) have been associated to dampening of tissue reconstitution and inhibition of cell cycle genes following partial hepatectomy. Extra-cellular factors, such as age-dependent changes in hepatic stellate cells affect liver regeneration through inhibition of progenitor cells and reduction of liver perfusion. Furthermore, chronic release of pro-inflammatory proteins by senescent cells (SASP) affects cell proliferation suggesting that senescent cell clearance might improve tissue regeneration. Accordingly, young plasma restores liver regeneration in aged animals through autophagy re-establishment. This review will discuss how intracellular and extracellular factors cooperate to guarantee a proper liver regeneration and the possible causes of its impairment during aging. The possibility that an improvement of the liver regenerative capacity in elderly might be achieved through elimination of senescent cells autophagy or by administration of direct mitogenic agents devoid of cytotoxicity will also be entertained.
Topics: Aging; Animals; Cellular Senescence; Gene Expression Regulation; Liver; Liver Regeneration; Mice
PubMed: 30157472
DOI: 10.18632/aging.101524 -
JCI Insight Jun 2022Senescent cells have long been associated with deleterious effects in aging-related pathologies, although recent studies have uncovered their beneficial roles in certain...
Senescent cells have long been associated with deleterious effects in aging-related pathologies, although recent studies have uncovered their beneficial roles in certain contexts, such as wound healing. We have found that hepatic stellate cells (HSCs) underwent senescence within 2 days after 2/3 partial hepatectomy (PHx) in young (2-3 months old) mice, and the elimination of these senescent cells by using the senolytic drug ABT263 or by using a genetic mouse model impaired liver regeneration. Senescent HSCs secrete IL-6 and CXCR2 ligands as part of the senescence-associated secretory phenotype, which induces multiple signaling pathways to stimulate liver regeneration. IL-6 activates STAT3, induces Yes-associated protein (YAP) activation through SRC family kinases, and synergizes with CXCL2 to activate ERK1/2 to stimulate hepatocyte proliferation. The administration of either IL-6 or CXCL2 partially restored liver regeneration in mice with senescent cell elimination, and the combination of both fully restored liver weight recovery. Furthermore, the matricellular protein central communication network factor 1 (CCN1, previously called CYR61) was rapidly elevated in response to PHx and induced HSC senescence. Knockin mice expressing a mutant CCN1 unable to bind integrin α6β1 were deficient in senescent cells and liver regeneration after PHx. Thus, HSC senescence, largely induced by CCN1, is a programmed response to PHx and plays a critical role in liver regeneration through signaling pathways activated by IL-6 and ligands of CXCR2.
Topics: Animals; Hepatectomy; Hepatic Stellate Cells; Interleukin-6; Ligands; Liver Regeneration; Mice; Receptors, Interleukin-8B
PubMed: 35708907
DOI: 10.1172/jci.insight.158207 -
Mediators of Inflammation 2017Liver regeneration is a highly organized tissue regrowth process and is the most important reaction of the liver to injury. The overall process of liver regeneration... (Review)
Review
Liver regeneration is a highly organized tissue regrowth process and is the most important reaction of the liver to injury. The overall process of liver regeneration includes three phases: priming stage, proliferative phase, and termination phase. The initial step aims to induce hepatocytes to be sensitive to growth factors with the aid of some cytokines, including TNF- and IL-6. The proliferation phase promotes hepatocytes to re-enter G1 with the stimulation of growth factors. While during the termination stage, hepatocytes will discontinue to proliferate to maintain normal liver mass and function. Except for cytokine- and growth factor-mediated pathways involved in regulating liver regeneration, new substances and technologies emerge to influence the regenerative process. Here, we reviewed novel and important signaling molecules involved in the process of liver regeneration to provide a cue for further research.
Topics: Animals; Hepatocytes; Humans; Interleukin-6; Liver; Liver Regeneration; Tumor Necrosis Factor-alpha
PubMed: 28947857
DOI: 10.1155/2017/4256352 -
Frontiers in Bioscience : a Journal and... Jul 2002Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual... (Review)
Review
Unlike other vital organs, the liver typically regenerates after injury. Indeed, the very factors that cause liver injury initiate a reparative process in the residual liver that includes the induction of cytoprotective mechanisms, deletion of mortally wounded cells, repair of less damaged survivors, liver cell proliferation to replace the cells that died, the deposition of new matrix, and tissue remodeling to restore normal hepatic mass and architecture. During liver regeneration, the liver normally continues to perform vital, liver-specific functions. Unfortunately, the hepatic regenerative response sometimes becomes disrupted--either failing to occur or occurring in a disordered, or incomplete fashion. Abnormal regeneration contributes to the pathogenesis of fulminate liver failure, cirrhosis, and primary liver cancers. Research in the field of regenerative biology has identified several events that are required for liver regeneration. These include injury-induced changes in the hepatic microenvironment, the ability of surviving liver cells and/or their progenitors to proliferate, and a temporary suspension of homeostatic mechanisms that normally couple cell proliferation to programmed cell death. The signals that mediate these complex biologic responses are being detailed. A better understanding of the extra- and intracellular signals that prompt the injured liver to regenerate should suggest treatments to promote liver regeneration in patients with otherwise fatal liver diseases.
Topics: Animals; Humans; Liver Regeneration
PubMed: 12086922
DOI: 10.2741/A925 -
The FEBS Journal Dec 2023The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of... (Review)
Review
The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of hepatocytes, which are the major functional constituents in the liver. In response to liver injury, hepatocytes undergo remarkable alterations, such as reprogramming, wherein they lose their original identity and acquire properties from other cells. This phenomenon of hepatocyte reprogramming, coupled with hepatocyte expansion, plays a central role in liver regeneration, and its underlying mechanisms are complex and multifaceted. Understanding the fate of reprogrammed hepatocytes and the mechanisms of their conversion has significant implications for the development of innovative therapeutics for liver diseases. Herein, we review the plasticity of hepatocytes in response to various forms of liver injury, with a focus on injury-induced hepatocyte reprogramming. We provide a comprehensive summary of current knowledge on the molecular and cellular mechanisms governing hepatocyte reprogramming, specifically in the context of liver regeneration, providing insight into potential applications of this process in the treatment of liver disorders, including chronic liver diseases and liver cancer.
Topics: Animals; Adult; Humans; Liver Regeneration; Hepatocytes; Liver; Stem Cells; Liver Neoplasms; Mammals
PubMed: 37556833
DOI: 10.1111/febs.16930 -
Current Opinion in Genetics &... Aug 2022Cell identity conversion in liver injury is the process that mature cells, specifically hepatocytes or cholangiocytes, convert into cells with other identities, which... (Review)
Review
Cell identity conversion in liver injury is the process that mature cells, specifically hepatocytes or cholangiocytes, convert into cells with other identities, which is found to play a pivotal role in liver regeneration. A better characterization of cell identity conversion will not only facilitate the understanding of liver tissue repair but also the development of novel regenerative therapies. In this review, we discuss the latest advances in cell identity conversion during liver regeneration, including conversions between hepatocytes and cholangiocytes and hepatocyte reprogramming to liver progenitor-like cells. To develop a unified description of cellular states in injury-related liver regeneration, we further propose the quantitative approach to explore cell identity conversion based on the Waddington's landscape.
Topics: Cell Differentiation; Epithelial Cells; Hepatocytes; Liver; Liver Regeneration
PubMed: 35644120
DOI: 10.1016/j.gde.2022.101921 -
Clinical and Molecular Hepatology Jan 2023The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse... (Review)
Review
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
Topics: Humans; Wnt Signaling Pathway; Liver Regeneration; Liver Cirrhosis; Liver Neoplasms; beta Catenin
PubMed: 35785913
DOI: 10.3350/cmh.2022.0058 -
Experimental Biology and Medicine... Aug 2023Chronic liver disease is one of the most common diseases worldwide, and its prevalence is particularly high among adults aged 40-60 years; it takes a toll on... (Review)
Review
Chronic liver disease is one of the most common diseases worldwide, and its prevalence is particularly high among adults aged 40-60 years; it takes a toll on productivity and causes significant economic burden. However, there are still no effective treatments that can fundamentally treat chronic liver disease. Although liver transplantation is considered the only effective treatment for chronic liver disease, it has limitations in that the pool of available donors is vastly insufficient for the number of potential recipients. Even if a patient undergoes liver transplantation, side effects such as immune rejection or bile duct complications could occur. In addition, impaired liver regeneration due to various causes, such as aging and metabolic disorders, may cause liver failure after liver resection, even leading to death. Therefore, further research on the liver regeneration process and therapeutic strategies to improve liver regeneration are needed. In this review, we describe the process of liver regeneration after hepatectomy, focusing on various cytokines and signaling pathways. In addition, we review treatment strategies that have been studied to date to improve liver regeneration, such as promotion of hepatocyte proliferation and metabolism and transplantation of mesenchymal stem cells. This review helps to understand the physiological processes involved in liver regeneration and provides basic knowledge for developing treatments for successful liver regeneration.
Topics: Adult; Humans; Hepatectomy; Liver Regeneration; Liver; Liver Diseases; Liver Transplantation; Cell Proliferation
PubMed: 37786387
DOI: 10.1177/15353702231191195