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Hepatology (Baltimore, Md.) Aug 2019The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal... (Review)
Review
The liver is both an immunologically complex and a privileged organ. The innate immune system is a central player, in which the complement system emerges as a pivotal part of liver homeostasis, immune responses, and crosstalk with other effector systems in both innate and adaptive immunity. The liver produces the majority of the complement proteins and is the home of important immune cells such as Kupffer cells. Liver immune responses are delicately tuned between tolerance to many antigens flowing in from the alimentary tract, a tolerance that likely makes the liver less prone to rejection than other solid organ transplants, and reaction to local injury, systemic inflammation, and regeneration. Notably, complement is a double-edged sword as activation is detrimental by inducing inflammatory tissue damage in, for example, ischemia-reperfusion injury and transplant rejection yet is beneficial for liver tissue regeneration. Therapeutic complement inhibition is rapidly developing for routine clinical treatment of several diseases. In the liver, targeted inhibition of damaged tissue may be a rational and promising approach to avoid further tissue destruction and simultaneously preserve beneficial effects of complement in areas of proliferation. Here, we argue that complement is a key system to manipulate in the liver in several clinical settings, including liver injury and regeneration after major surgery and preservation of the organ during transplantation.
Topics: Complement System Proteins; Graft Rejection; Humans; Liver; Liver Regeneration; Liver Transplantation; Reperfusion Injury; Treatment Outcome
PubMed: 30653682
DOI: 10.1002/hep.30508 -
International Journal of Molecular... Nov 2020The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed.... (Review)
Review
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
Topics: Animals; Fatty Liver; Hepatectomy; Humans; Liver; Liver Regeneration; Liver Transplantation
PubMed: 33182515
DOI: 10.3390/ijms21218414 -
Annual Review of Pathology Jan 2021Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in and conserved from unicellular... (Review)
Review
Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in and conserved from unicellular organisms to mammals. Genetic studies of mouse and rat livers have revealed that the Hippo pathway is a key regulator of liver size, regeneration, development, metabolism, and homeostasis and that perturbations in the Hippo pathway can lead to the development of common liver diseases, such as fatty liver disease and liver cancer. In turn, pharmacological targeting of the Hippo pathway may be utilized to boost regeneration and to prevent the development and progression of liver diseases. We review current insights provided by the Hippo pathway into liver pathophysiology. Furthermore, we present a path forward for future studies to understand how newly identified components of the Hippo pathway may control liver physiology and how the Hippo pathway is regulated in the liver.
Topics: Animals; Hippo Signaling Pathway; Homeostasis; Humans; Liver; Liver Regeneration; Mice; Protein Serine-Threonine Kinases; Rats; Signal Transduction
PubMed: 33234023
DOI: 10.1146/annurev-pathol-030420-105050 -
Trends in Cell Biology Apr 2020The liver, whose major functional cell type is the hepatocyte, is a peculiar organ with remarkable regenerative capacity. The widely held notion that hepatic progenitor... (Review)
Review
The liver, whose major functional cell type is the hepatocyte, is a peculiar organ with remarkable regenerative capacity. The widely held notion that hepatic progenitor cells contribute to injury-induced liver regeneration has long been debated. However, multiple lines of evidence suggest that the plasticity of differentiated cells is a major mechanism for the cell source in injury-induced liver regeneration. Investigating cell plasticity could potentially expand our understanding of liver physiology and facilitate the development of new therapies for liver diseases. In this review, we summarize the cell sources for hepatocyte regeneration and the clinical relevance of cell plasticity for human liver diseases. We focus on mechanistic insights on the injury-induced cell plasticity of hepatocytes and biliary epithelial cells and discuss future directions for investigation. Specifically, we propose the notion of 'reprogramming competence' to explain the plasticity of differentiated hepatocytes.
Topics: Animals; Cell Plasticity; Epithelial Cells; Hepatocytes; Homeostasis; Humans; Liver Regeneration; Models, Biological
PubMed: 32200807
DOI: 10.1016/j.tcb.2020.01.007 -
Cell Stem Cell Oct 2020Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident... (Review)
Review
Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
Topics: Cell Proliferation; Epithelial Cells; Hepatocytes; Humans; Liver; Liver Diseases; Liver Regeneration
PubMed: 32971004
DOI: 10.1016/j.stem.2020.08.016 -
Hepatology (Baltimore, Md.) Dec 2021The liver is innervated by autonomic and sensory fibers of the sympathetic and parasympathetic nervous systems that regulate liver function, regeneration, and disease.... (Review)
Review
The liver is innervated by autonomic and sensory fibers of the sympathetic and parasympathetic nervous systems that regulate liver function, regeneration, and disease. Although the importance of the hepatic nervous system in maintaining and restoring liver homeostasis is increasingly appreciated, much remains unknown about the specific mechanisms by which hepatic nerves both influence and are influenced by liver diseases. While recent work has begun to illuminate the developmental mechanisms underlying recruitment of nerves to the liver, evolutionary differences contributing to species-specific patterns of hepatic innervation remain elusive. In this review, we summarize current knowledge on the development of the hepatic nervous system and its role in liver regeneration and disease. We also highlight areas in which further investigation would greatly enhance our understanding of the evolution and function of liver innervation.
Topics: Animals; Humans; Liver; Liver Diseases; Liver Regeneration; Mice
PubMed: 34256416
DOI: 10.1002/hep.32055 -
Hepatology (Baltimore, Md.) Jan 2022Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy...
BACKGROUND AND AIMS
Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.
APPROACH AND RESULTS
In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Ppara mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (Ppara ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area.
CONCLUSIONS
This study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
Topics: Animals; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Hepatectomy; Hepatocytes; Hepatomegaly; Humans; Liver; Liver Regeneration; Male; Mice; Mice, Transgenic; PPAR alpha; Pyrimidines; Signal Transduction; TEA Domain Transcription Factors; YAP-Signaling Proteins
PubMed: 34387904
DOI: 10.1002/hep.32105 -
Nature Genetics Apr 2023Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes....
Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes. However, the subset of BECs with such facultative tissue stem cell potential, as well as the mechanisms enabling transdifferentiation, remains elusive. Here we identify a transitional liver progenitor cell (TLPC), which originates from BECs and differentiates into hepatocytes during regeneration from severe liver injury. By applying a dual genetic lineage tracing approach, we specifically labeled TLPCs and found that they are bipotent, as they either differentiate into hepatocytes or re-adopt BEC fate. Mechanistically, Notch and Wnt/β-catenin signaling orchestrate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively. Together, our study provides functional and mechanistic insights into transdifferentiation-assisted liver regeneration.
Topics: Liver Regeneration; Cell Proliferation; Liver; Hepatocytes; Epithelial Cells; Stem Cells; Cell Differentiation
PubMed: 36914834
DOI: 10.1038/s41588-023-01335-9 -
International Journal of Biological... 2020The liver is sensitive to pathogen-induced acute or chronic liver injury, and liver transplantation (LT) is the only effective strategy for end-stage liver diseases.... (Review)
Review
The liver is sensitive to pathogen-induced acute or chronic liver injury, and liver transplantation (LT) is the only effective strategy for end-stage liver diseases. However, the clinical application is limited by a shortage of liver organs, immunological rejection and high cost. Mesenchymal stromal cell (MSC)-based therapy has gradually become a hot topic for promoting liver regeneration and repairing liver injury in various liver diseases, since MSCs are reported to migrate toward injured tissues, undergo hepatogenic differentiation, inhibit inflammatory factor release and enhance the proliferation of liver cells . MSCs exert immunoregulatory effects through cell-cell contact and the secretion of anti-inflammatory factors to inhibit liver inflammation and promote liver regeneration. In addition, MSCs are reported to effectively inhibit the activation of cells of the innate immune system, including macrophages, natural killer (NK) cells, dendritic cells (DCs), monocytes and other immune cells, and inhibit the activation of cells of the adaptive immune system, including T lymphocytes, B lymphocytes and subsets of T cells or B cells. In the current review, we mainly focus on the potential effects and mechanisms of MSCs in inhibiting the activation of immune cells to attenuate liver injury in models or patients with acute liver failure (ALF), nonalcoholic fatty liver disease (NAFLD), and liver fibrosis and in patients or models after LT. We highlight that MSC transplantation may replace general therapies for eliminating acute or chronic liver injury in the near future.
Topics: Animals; Humans; Liver; Liver Regeneration; Liver Transplantation; Mesenchymal Stem Cells
PubMed: 32071558
DOI: 10.7150/ijbs.39725 -
Cell Stem Cell Mar 2023Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal...
Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal injury, mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiate into liver progenitor-like cells (LPLCs) in both mice and humans, which contribute remarkably to regeneration. However, it remains unknown which and how external factors trigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profiling and lineage-specific deletion tools, we uncovered that periportal-specific LPLC formation was initiated by regionally activated Kupffer cells but not peripheral monocyte-derived macrophages. Unexpectedly, using in vivo screening, the proinflammatory factor IL-6 was identified as the niche signal repurposed for RRG induction via STAT3 activation, which drove RRG expression through binding to their pre-accessible enhancers. Notably, RRGs were activated through injury-specific rather than liver embryogenesis-related enhancers. Collectively, these findings depict an injury-specific niche signal and the inflammation-mediated transcription in driving the conversion of hepatocytes into a progenitor phenotype.
Topics: Animals; Humans; Mice; Cell Differentiation; Hepatocytes; Interleukin-6; Kupffer Cells; Liver; Liver Regeneration
PubMed: 36787740
DOI: 10.1016/j.stem.2023.01.009