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Hepatology (Baltimore, Md.) May 2016
Topics: Cues; Humans; Immunologic Factors; Liver; Liver Regeneration
PubMed: 26853091
DOI: 10.1002/hep.28490 -
International Journal of Molecular... May 2019Regeneration of the liver has been an interesting and well-investigated topic for many decades. This etiology and time-dependent mechanism has proven to be extremely... (Review)
Review
Regeneration of the liver has been an interesting and well-investigated topic for many decades. This etiology and time-dependent mechanism has proven to be extremely challenging to investigate, certainly in human diseases. A reason for this challenge is found in the numerous interactions of different cell components, of which some are even only temporarily present (e.g., inflammatory cells). To orchestrate regeneration of the epithelial cells, their interaction with the non-epithelial components is of utmost importance. Hepatocytes, cholangiocytes, liver progenitor cells, and peribiliary glands have proven to be compartments of regeneration. The ductular reaction is a common denominator in virtually all liver diseases; however, it is predominantly found in late-stage hepatic and biliary diseases. Ductular reaction is an intriguing example of interplay between epithelial and non-epithelial cells and encompasses bipotential liver progenitor cells which are able to compensate for the loss of the exhausted hepatocytes and cholangiocytes in biliary and hepatocytic liver diseases. In this manuscript, we focus on the etiology-specific damage that is observed in different human diseases and how the liver regulates the regenerative response in an acute and chronic setting. Furthermore, we describe the importance of morphological keynotes in different etiologies and how spatial information is of relevance for every basic and translational research of liver regeneration.
Topics: Biliary Tract; Carcinogenesis; Hepatectomy; Hepatocytes; Humans; Liver Diseases; Liver Regeneration
PubMed: 31083462
DOI: 10.3390/ijms20092332 -
Annual Review of Physiology Feb 2023Liver regeneration occurs in response to diverse injuries and is capable of functionally reestablishing the lost parenchyma. This phenomenon has been known since... (Review)
Review
Liver regeneration occurs in response to diverse injuries and is capable of functionally reestablishing the lost parenchyma. This phenomenon has been known since antiquity, encapsulated in the Greek myth where Prometheus was to be punished by Zeus for sharing the gift of fire with humanity by having an eagle eat his liver daily, only to have the liver regrow back, thus ensuring eternal suffering and punishment. Today, this process is actively leveraged clinically during living donor liver transplantation whereby up to a two-thirds hepatectomy (resection or removal of part of the liver) on a donor is used for transplant to a recipient. The donor liver rapidly regenerates to recover the lost parenchymal mass to form a functional tissue. This astonishing regenerative process and unique capacity of the liver are examined in further detail in this review.
Topics: Animals; Humans; Liver Transplantation; Living Donors; Liver; Hepatectomy; Liver Regeneration; Homeostasis; Mammals
PubMed: 36270290
DOI: 10.1146/annurev-physiol-032822-094134 -
Oxidative Medicine and Cellular... 2022The regenerative capacity of the liver decreases with increase in age. In recent years, studies in mice have found that the regenerative capacity of the liver is... (Review)
Review
The regenerative capacity of the liver decreases with increase in age. In recent years, studies in mice have found that the regenerative capacity of the liver is associated with changes in the immune system of the liver, cytokines in the body, aging-related epigenetic modifications in the cell, and intracellular signaling pathways. In the immune system of the aging liver, monocytes and macrophages play an important role in tissue repair. During tissue repair, monocytes and macrophages undergo a series of functional and phenotypic changes to initiate and maintain tissue repair. Studies have discovered that knocking out macrophages in the liver during the repair phase results in significant impairment of liver regeneration. Furthermore, as the body ages, the secretion and function of cytokines undergo a series of changes. For example, the levels of interleukin-6, transforming growth factor-alpha, hepatocyte growth factor, and vascular endothelial growth factor undergo changes that alter hepatocyte regulation, thereby affecting its proliferation. In addition, body aging is accompanied by cellular aging, which leads to changes in gene expression and epigenetic modifications. Additionally, this in turn causes alterations in cell function, morphology, and division and affects the regenerative capacity of the liver. As the body ages, the activity of associated functional proteins, such as CCAAT-enhancer-binding proteins, p53, and switch/sucrose nonfermentable complex, changes in the liver, leading to alterations in several signaling pathways, such as the Hippo, PI3K-Akt, mTOR, and STAT3 pathways. Therefore, in recent years, research on aging and liver regeneration has primarily focused on the immune system, signaling pathways, epigenetic changes of senescent cells, and cytokine secretion in the liver. Hence, this review details the roles of these influencing factors in liver regeneration and impact of aging-related factors.
Topics: Animals; Cytokines; Epigenesis, Genetic; Liver Regeneration; Macrophages; Mice; Oxidative Stress; Phosphatidylinositol 3-Kinases; Vascular Endothelial Growth Factor A
PubMed: 35936214
DOI: 10.1155/2022/9018811 -
Cell Reports Mar 2024Liver injury stimulates hepatocyte replication and hepatic stellate cell (HSC) activation, thereby driving liver regeneration. Aberrant HSC activation induces liver...
Liver injury stimulates hepatocyte replication and hepatic stellate cell (HSC) activation, thereby driving liver regeneration. Aberrant HSC activation induces liver fibrosis. However, mechanisms underlying liver regeneration and fibrosis remain poorly understood. Here, we identify hepatic Snai1 and Snai2 as important transcriptional regulators for liver regeneration and fibrosis. Partial hepatectomy or CCl4 treatment increases occupancies of Snai1 and Snai2 on cyclin A2 and D1 promoters in the liver. Snai1 and Snai2 in turn increase promoter H3K27 acetylation and cyclin A2/D1 expressions. Hepatocyte-specific deletion of both Snai1 and Snai2, but not one alone, suppresses liver cyclin A2/D1 expression and regenerative hepatocyte proliferation after hepatectomy or CCl4 treatments but augments CCl4-stimulated HSC activation and liver fibrosis. Conversely, Snai2 overexpression in the liver enhances hepatocyte replication and suppresses liver fibrosis after CCl4 treatment. These results suggest that hepatic Snai1 and Snai2 directly promote, via histone modifications, reparative hepatocyte replication and indirectly inhibit liver fibrosis.
Topics: Animals; Mice; Cyclin A2; Hepatectomy; Liver; Liver Cirrhosis; Liver Regeneration
PubMed: 38451818
DOI: 10.1016/j.celrep.2024.113875 -
Aging Oct 2019
Topics: Animals; Epithelial Cells; Humans; Liver Regeneration
PubMed: 31645478
DOI: 10.18632/aging.102386 -
World Journal of Gastroenterology Sep 2019Gradual alterations of cell's physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells. Once... (Review)
Review
Gradual alterations of cell's physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells. Once becoming senescent, the cell stops dividing permanently but remains metabolically active. Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers, such as, morphological changes, expression of cell cycle inhibitors, senescence associated β-galactosidase activity, and changes in nuclear membrane. When cells in an organ become senescent, the entire organism can be affected. This may occur through the senescence-associated secretory phenotype (SASP). SASP may exert beneficial or harmful effects on the microenvironment of tissues. Research on senescence has become a very exciting field in cell biology since the link between age-related diseases, including cancer, and senescence has been established. The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence. The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes. Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration. This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.
Topics: Aging; Bile Ducts, Intrahepatic; Cellular Senescence; Hepatocytes; Humans; Liver; Liver Diseases; Liver Regeneration
PubMed: 31558857
DOI: 10.3748/wjg.v25.i34.5069 -
Biochemical and Biophysical Research... Oct 2022In-depth knowledge of liver regeneration could facilitate the development of therapies for liver injury and liver failure. As a member of the homeobox superfamily,...
In-depth knowledge of liver regeneration could facilitate the development of therapies for liver injury and liver failure. As a member of the homeobox superfamily, HOXA13 plays an important role in regulating tumorigenesis and development. However, the exact role of HOXA13 in liver regeneration remains unclear. In this study, we confirmed that HOXA13 promotes hepatocyte proliferation both in vivo and in vitro. HOXA13 was upregulated during liver regeneration, and its overexpression further accelerated hepatocyte proliferation and liver function recovery during liver regeneration. Furthermore, we found that HOXA13 promoted hepatocyte proliferation and liver regeneration by upregulating bone morphogenetic protein-7 (BMP-7) mRNA. These findings provide a new potential target for the treatment of liver failure.
Topics: Bone Morphogenetic Protein 7; Cell Proliferation; Homeodomain Proteins; Humans; Liver Failure; Liver Regeneration
PubMed: 35868069
DOI: 10.1016/j.bbrc.2022.07.018 -
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 -
Cells Jun 2020Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not...
Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers ( and ). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation ( and ) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (, and ). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.
Topics: Adult; Cell Differentiation; Female; Humans; Liver Regeneration; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Regenerative Medicine; Young Adult
PubMed: 32580448
DOI: 10.3390/cells9061521