• cell biology
• metabolic disorders
• reprogramming
• self-renewal

• Humans
• Liver Regeneration/genetics
• Liver/metabolism
• Liver/pathology
• Liver/injuries
• Signal Transduction/genetics
• Animals
• Liver Diseases/therapy
• Liver Diseases/metabolism
• Liver Diseases/genetics
• Liver Diseases/pathology

• 82270643 National Natural Science Foundation of China (National Science Foundation of China)
• 82070644 National Natural Science Foundation of China (National Science Foundation of China)
• 82170621 National Natural Science Foundation of China (National Science Foundation of China)
• The National multidisciplinary collaborative diagnosis and treatment capacity building project for major diseases (TJZ202104)，the Science and Technology Major Program of Sichuan Province (2022ZDZX0019), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC18008, ZYGD22006).

• carcinoma
• cholestasis
• development
• metabolism
• regeneration

• Humans
• Wnt Signaling Pathway/physiology
• Liver/pathology
• Liver/metabolism
• Liver Diseases/metabolism
• Liver Diseases/pathology
• Animals
• beta Catenin/metabolism

• adherens junctions
• desmosomes
• gap junctions
• liver
• tight junctions

• Humans
• Intercellular Junctions/physiology
• Liver
• Cell Communication/physiology
• Liver Diseases/physiopathology
• Liver Diseases/pathology
• Animals
• Hepatocytes/physiology
• Cell Adhesion

• 858014 European Horizon 2020 Future and Emerging Technologies program
• G012318N Research Foundation Flanders-Belgium
• G020018N Research Foundation Flanders-Belgium
• G0F7219N Research Foundation Flanders-Belgium
• the Methusalem program of the Flemish Government
• the University Hospital of the Vrije Universiteit Brussel-Belgium (Scientific Fund Willy Gepts)

• Cell proliferation
• Clinical applications
• Expression profile
• Liver regeneration
• ncRNAs

• Bile salt
• FGF21
• FXR
• Hepatectomy
• Liver resection
• MASH
• MASLD
• PPAR
• Thyroid Hormone
• Transplantation

• Humans
• Liver Regeneration/physiology
• Animals
• Fatty Liver/metabolism

• hepatocyte growth factor
• growth factor signalling

• Animals
• Male
• Mice
• beta Catenin/metabolism
• Cell Polarity
• Cell Proliferation
• Hepatocytes/metabolism
• Liver/metabolism
• Liver/pathology
• Liver Regeneration
• Macrophages/metabolism
• Mice, Inbred C57BL
• Mice, Knockout
• Tripartite Motif Proteins/metabolism
• Tripartite Motif Proteins/genetics
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitin-Protein Ligases/genetics
• Ubiquitination
• Wnt Signaling Pathway

• 82372809 National Natural Science Foundation of China (National Science Foundation of China)
• 81872045 National Natural Science Foundation of China (National Science Foundation of China)

• Anatomy
• Depressions
• Fissure
• Groove
• Liver
• Sulcus
• Variant

• Animals
• Mice
• Humans
• Liver Regeneration/physiology
• Hepatocytes/physiology

• GREB1
• HNF4α
• Hepatoblastoma
• Hepatocellular carcinoma
• Wnt
• β-Catenin

• Humans
• Wnt Signaling Pathway
• Carcinogenesis/pathology
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Liver Neoplasms/genetics
• Animals
• Liver/metabolism
• Liver/pathology
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/genetics
• beta Catenin/metabolism

• 18K06956 Grants-in-Aid for Scientific Research
• 21K07121 Grants-in-Aid for Scientific Research
• 16H06374 Grants-in-Aid for Scientific Research
• 22ama221104h0001 Project for Cancer Research and Therapeutic Evolution (P-PROMOTE)

• G6PD
• NRF2
• SLAM-ITseq
• acute liver failure
• nascent transcription
• pentose phosphate pathway
• regeneration
• zebrafish

• Animals
• Pentose Phosphate Pathway/genetics
• Liver Regeneration/genetics
• NF-E2-Related Factor 2/genetics
• NF-E2-Related Factor 2/metabolism
• Zebrafish/genetics
• Zebrafish/metabolism
• Liver/metabolism

• Wnt pathway
• hepatocellular carcinoma
• mechanism
• progression
• therapy
• therapy resistance
• tumorigenesis

• Biological sciences
• Health sciences

• genes
• hepatic lobule
• liver regeneration
• regenerative microenvironment
• zonation

• cirrhosis
• hepatocellular carcinoma
• hbv
• hcv
• nafld

• regeneration
• proliferation
• metabolism
• zonation
• cholestasis

• beta Catenin/metabolism
• Liver/pathology
• Wnt Signaling Pathway
• Liver Regeneration
• Homeostasis

• R01 DK124412 NIDDK NIH HHS
• R01 DK116993 NIDDK NIH HHS
• R01 CA251155 NCI NIH HHS
• R01 DK062277 NIDDK NIH HHS
• R01 CA204586 NCI NIH HHS
• R01 DK119435 NIDDK NIH HHS
• R01 DK103775 NIDDK NIH HHS
• P30 DK120531 NIDDK NIH HHS

• cholangiocarcinoma
• colorectal liver metastasis
• hepatocellular carcinoma
• liver resection
• liver transplantation
• machine perfusion
• organ preservation

• Chronic liver diseases
• Fatty liver
• Fibrosis
• Oxidative stress
• Steatosis
• Wnt/β-catenin

• Humans
• Non-alcoholic Fatty Liver Disease/pathology
• Carcinoma, Hepatocellular/pathology
• Wnt Signaling Pathway/physiology
• beta Catenin
• Glycogen Synthase Kinase 3 beta/metabolism
• Liver Neoplasms/pathology
• Disease Progression
• Liver/pathology
• Liver Cirrhosis/pathology
• Fibrosis

• Acute liver failure
• Acute on chronic liver failure
• Cytokines
• Growth factors
• Homeostasis
• Partial hepatectomy
• Regeneration
• microRNAs

• Cytochrome P450
• Hepatic progenitor cell
• Hepatocyte
• Liver regeneration
• Pluripotent stem cell

• Humans
• Pluripotent Stem Cells
• Embryonic Stem Cells
• Liver
• Drug Discovery
• Eye Diseases, Hereditary

• aging
• embryogenesis
• hypomagnesemia
• liver disease
• liver regeneration
• magnesium
• nutritional intake

• Humans
• Magnesium
• Longevity
• Nutritional Status
• Liver
• Aging

• partial hepatectomy
• wnt signaling
• pathway redundancy
• liver failure
• hepatocyte proliferation

• Mice
• Animals
• Liver Regeneration/physiology
• beta Catenin/metabolism
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Insulin/metabolism
• Hepatocytes/metabolism
• TOR Serine-Threonine Kinases/metabolism
• Wnt Signaling Pathway/physiology
• Mice, Knockout
• Cell Proliferation
• Sirolimus/pharmacology

• R01 DK116993 NIDDK NIH HHS
• R01 CA251155 NCI NIH HHS
• R01 DK062277 NIDDK NIH HHS
• P30 DK120531 NIDDK NIH HHS
• R01 CA204586 NCI NIH HHS
• R01 CA250227 NCI NIH HHS

• HCC
• cholangiocytes
• cirrhosis
• hepatocytes
• liver regeneration
• liver zonation
• ploidy
• ploidy reversal

• Hepatocellular carcinoma
• Liver diseases
• Liver regeneration
• WNT signaling pathway

As a general model for cell cycle control, repressors keep cells quiescent until growth signals remove the inhibition. For S phase, this is exemplified by the Retinoblastoma (RB) protein and its inactivation. It was unknown whether similar mechanisms operate in the M phase. The Wnt signaling pathway is an important regulator of cell proliferation. Here, we find that Wnt induces expression of the transcription factor Tbx3, which in turn represses mitotic inhibitors E2f7 and E2f8 to permit mitotic progression. Such a cascade of transcriptional repressors may be a general mechanism for cell division control. These findings have implications for tissue homeostasis and disease, as the function for Wnt signaling in mitosis is relevant to its widespread role in stem cells and cancer.

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/β-catenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. The TBX3 protein directly represses transcription of E2f7 and E2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.

• Wnt
• liver
• proliferation

• liver regeneration
• macrophages polarization
• organoids

• biliary tract disease
• liver
• prognostic markers

• Animals
• Chitosan
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/genetics
• Curcumin/pharmacology
• Nanoparticles
• RNA Interference

• oncogenes
• drug regulation
• cancer genetics
• non-coding rnas
• self-renewal

The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.

• Liver
• Liver regeneration potential
• Regeneration biology
• Tumour
• Therapies

• R01 CA251928 NCI NIH HHS
• R01 DK125396 NIDDK NIH HHS

To elucidate the characteristics of different liver regeneration animal models, understand the activation signals and mechanisms related to liver regeneration, and obtain a more comprehensive conception of the entire liver regeneration process.

Liver regeneration is one of the most enigmatic and fascinating phenomena of the human organism. Despite suffering significant injuries, the liver still can continue to perform its complex functions through the regeneration system. Although advanced topics on liver regeneration have been proposed; unfortunately, complete regeneration of the liver has not been achieved until now. Therefore, increasing understanding of the liver regenerative process can help improve our treatment of liver failure. It will provide a new sight for the treatment of patients with liver injury in the clinic.

Literatures on liver regeneration animal models and involved basic research on molecular mechanisms were retrieved to analyze the characteristics of different models and those related to molecular basis.

The process of liver regeneration is complex and intricate, consisting of various and interactive pathways. There is sufficient evidence to demonstrate that liver regeneration is similar between humans and rodents. At the same time, many of the same cytokines, growth factors, and signaling pathways are relevant. There are many gaps in our current knowledge. Understanding of this knowledge will provide more supportive clinical treatment strategies, including small-scale liver transplantation and high-quality regenerative process after surgical resection, and offer possible targets to treat the dysregulation of regeneration that occurs in chronic hepatic diseases and tumors. Current research work, such as the use of animal models as in vivo vectors for high-quality human hepatocytes, represents a unique and significant cutting edge in the field of liver regeneration.

• Liver regeneration
• animal model
• cytokines
• signaling pathways

• aging liver
• hepatic progenitors
• liver repopulation
• redox homeostasis

• Aging
• Animals
• Humans
• Liver/metabolism
• Liver Regeneration

• liver regeneration
• wnt
• β-catenin
• cyclin d1
• proliferation
• metabolism
• endothelial cells
• hepatocytes
• macrophages

• Animals
• Humans
• Liver/metabolism
• Liver/physiology
• Liver Regeneration
• Wnt Signaling Pathway
• beta Catenin/metabolism

• R01 DK116993 NIDDK NIH HHS
• R01 CA251155 NCI NIH HHS
• R01 DK062277 NIDDK NIH HHS
• P30 DK120531 NIDDK NIH HHS
• R01 CA204586 NCI NIH HHS

• Hepatic resection
• Liver metastasis
• Liver regeneration
• Surgical oncology

• Animals
• Hepatectomy/methods
• Humans
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Liver Regeneration
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/surgery

• Wnt pathway
• c-myc
• colorectal liver metastasis
• liver regeneration
• renin-angiotensin system

• APP1181580 National Health and Medical Research Council
• APP1099302 National Health and Medical Research Council
• n/a Royal Australasian College of Surgeons
• n/a Tour de Cure
• n/a Reg Worcester Foundation for Surgery

Liver cancer is a dreadful tumor which has gradually increased in incidence all around the world. One major driver of liver cancer is the Wnt–β-catenin pathway which is active in a subset of these tumors. While this pathway is normally important in liver development, regeneration and homeostasis, it’s excessive activation due to mutations, is detrimental and leads to tumor cell growth, making it an important therapeutic target. There are also some unique characteristics of this pathway activation in liver cancer. It makes the tumor addicted to specific amino acids and in turn to mTOR signaling, which can be treated by certain existing therapies. In addition, activation of the Wnt–β-catenin in liver cancer appears to alter the immune cell landscape making it less likely to respond to the new immuno-oncology treatments. Thus, Wnt–β-catenin active tumors may need to be treated differently than non-Wnt–β-catenin active tumors.

Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, mostly due to stabilizing missense mutations in its downstream effector β-catenin (encoded by CTNNB1) or loss-of-function mutations in AXIN1 (the gene which encodes for Axin-1, an essential protein for β-catenin degradation), are seen in a major subset of HCC. Because of the important role of β-catenin in liver pathobiology, its role in HCC has been extensively investigated. In fact, CTNNB1 mutations have been shown to have a trunk role. β-Catenin has been shown to play an important role in regulating tumor cell proliferation and survival and in tumor angiogenesis, due to a host of target genes regulated by the β-catenin transactivation of its transcriptional factor TCF. Proof-of-concept preclinical studies have shown β-catenin to be a highly relevant therapeutic target in CTNNB1-mutated HCCs. More recently, studies have revealed a unique role of β-catenin activation in regulating both tumor metabolism as well as the tumor immune microenvironment. Both these roles have notable implications for the development of novel therapies for HCC. Thus, β-catenin has a pertinent role in driving HCC development and maintenance of this tumor-type, and could be a highly relevant therapeutic target in a subset of HCC cases.

• molecular therapeutics
• precision medicine
• tumor immunology
• tumor metabolism
• β-catenin mutations

Regeneration is an evolutionarily conserved process in animal kingdoms, however, the regenerative capacities differ from species and organ/tissues. Mammals possess very limited regenerative potential to replace damaged organs, whereas non-mammalian species usually have impressive abilities to regenerate organs. The regeneration process requires proper spatiotemporal regulation from key signaling pathways. The canonical Notch and Wnt signaling pathways, two fundamental signals guiding animal development, have been demonstrated to play significant roles in the regeneration of vertebrates. In recent years, increasing evidence has implicated the cross-talking between Notch and Wnt signals during organ regeneration. In this review, we summarize the roles of Notch signaling and Wnt signaling during several representative organ regenerative events, emphasizing the functions and molecular bases of their interplay in these processes, shedding light on utilizing these two signaling pathways to enhance regeneration in mammals and design legitimate therapeutic strategies.

• Crosstalk
• Notch signaling
• Regeneration
• Wnt signaling

• liver regeneration
• lysosome
• tumorigenesis
• tmem9
• wnt
• β-catenin
• apc
• v-atpase
• hepatocellular carcinoma

• Animals
• Hepatocytes/physiology
• Humans
• Liver/physiology
• Liver/physiopathology
• Liver Diseases/physiopathology
• Liver Regeneration/physiology
• Signal Transduction

The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/β-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation.

The liver possesses the ability to regenerate following sudden injury. Here, the authors use single-cell RNA-sequencing and in situ transcriptional analyses to identify a new phase of liver regeneration in mice aimed at maintaining essential functions throughout the regenerative process.

• hepatectomy
• liver regeneration
• liver transplantation

• Animals
• Fatty Liver/physiopathology
• Hepatectomy/methods
• Humans
• Liver/physiology
• Liver Regeneration/physiology
• Liver Transplantation/methods

Owing to its pronounced regenerative capacity in many tissues and organs, the zebrafish brain represents an ideal platform to understand the endogenous regeneration mechanisms that restore tissue integrity and function upon injury or disease. Although radial glial and neuronal cell populations have been characterized with respect to specific marker genes, comprehensive transcriptomic profiling of the regenerating telencephalon has not been conducted so far. Here, by processing the lesioned and unlesioned hemispheres of the telencephalon separately, we reveal the differentially expressed genes (DEGs) at the early wound healing and early proliferative stages of regeneration, i.e., 20 h post-lesion (hpl) and 3 days post-lesion (dpl), respectively. At 20 hpl, we detect a far higher number of DEGs in the lesioned hemisphere than in the unlesioned half and only 7% of all DEGs in both halves. However, this difference disappears at 3 dpl, where the lesioned and unlesioned hemispheres share 40% of all DEGs. By performing an extensive comparison of the gene expression profiles in these stages, we unravel that the lesioned hemispheres at 20 hpl and 3 dpl exhibit distinct transcriptional profiles. We further unveil a prominent activation of Wnt/β-catenin signaling at 20 hpl, returning to control level in the lesioned site at 3 dpl. Wnt/β-catenin signaling indeed appears to control a large number of genes associated primarily with the p53, apoptosis, forkhead box O (FoxO), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) signaling pathways specifically at 20 hpl. Based on these results, we propose that the lesioned and unlesioned hemispheres react to injury dynamically during telencephalon regeneration and that the activation of Wnt/β-catenin signaling at the early wound healing stage plays a key role in the regulation of cellular and molecular events.

• Wnt/β-catenin pathway
• brain regeneration
• comparative transcriptome analysis
• telencephalon
• wound healing
• zebrafish

The canonical Wnt (Wnt/β-catenin) signalling pathway is highly conserved and plays a critical role in regulating cellular processes both during development and in adult tissue homeostasis. The Wnt/β-catenin signalling pathway is vital for correct body patterning and is involved in fate specification of the gut tube, the primitive precursor of liver. In adults, the Wnt/β-catenin pathway is increasingly recognised as an important regulator of metabolic zonation, homeostatic renewal and regeneration in response to injury throughout the liver. Herein, we review recent developments relating to the key role of the pathway in the patterning and fate specification of the liver, in the directed differentiation of pluripotent stem cells into hepatocytes and in governing proliferation and zonation in the adult liver. We pay particular attention to recent contributions to the controversy surrounding homeostatic renewal and proliferation in response to injury. Furthermore, we discuss how crosstalk between the Wnt/β-catenin and Hedgehog (Hh) and hypoxia inducible factor (HIF) pathways works to maintain liver homeostasis. Advancing our understanding of this pathway will benefit our ability to model disease, screen drugs and generate tissue and organ replacements for regenerative medicine.

• Wnt signalling
• development
• differentiation
• endoderm
• liver
• stem cell
• zonation

• Animals
• Body Patterning
• Cell Differentiation
• Gastrulation
• Hedgehog Proteins/metabolism
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Homeostasis
• Humans
• Liver/cytology
• Liver/embryology
• Liver/metabolism
• Liver/physiology
• Liver Regeneration
• Pluripotent Stem Cells/cytology
• Wnt Proteins/metabolism
• Wnt Signaling Pathway
• beta Catenin/metabolism

• HepaRG cells
• Hippo signaling
• apoptosis
• aryl hydrocarbon receptor
• cell proliferation

• Adaptor Proteins, Signal Transducing/genetics
• Apoptosis/drug effects
• Apoptosis/genetics
• Cell Line
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Gene Expression/drug effects
• Humans
• Liver/drug effects
• Liver/pathology
• Models, Biological
• Polychlorinated Dibenzodioxins/toxicity
• RNA, Small Interfering/genetics
• Receptors, Aryl Hydrocarbon/metabolism
• Signal Transduction
• Stem Cells/drug effects
• Stem Cells/pathology
• Trans-Activators/genetics
• Transcription Factors/genetics
• Transcriptional Coactivator with PDZ-Binding Motif Proteins
• Transfection
• YAP-Signaling Proteins

• alternative splicing analysis
• dedifferentiation
• liver regeneration
• proteomics
• transcription factor motif analysis
• transcriptomics

• Anatomy
• Grooves
• Liver
• Surface
• Surgery
• Variant

• Aged
• Aged, 80 and over
• Anatomic Variation
• Female
• Humans
• Liver/anatomy & histology
• Male
• Middle Aged
• Trinidad and Tobago