Hepatostat: Liver regeneration and normal liver tissue maintenance.

doi:10.1002/HEP.28988

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Hepatostat: Liver regeneration and normal liver tissue maintenance.

Journal Article•DOI•

Hepatostat: Liver regeneration and normal liver tissue maintenance.

George K. Michalopoulos¹•Institutions (1)

University of Pittsburgh¹

01 Apr 2017-Hepatology (Hepatology)-Vol. 65, Iss: 4, pp 1384-1392

TL;DR: Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood.

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About: This article is published in Hepatology.The article was published on 2017-04-01 and is currently open access. It has received 315 citations till now. The article focuses on the topics: Liver regeneration & Liver injury.

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Journal Article•DOI•

Liver regeneration: biological and pathological mechanisms and implications

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George K. Michalopoulos¹, Bharat Bhushan¹•Institutions (1)

University of Pittsburgh¹

01 Jan 2021-Nature Reviews Gastroenterology & Hepatology

TL;DR: The regenerative mechanisms employed by hepatic cells after liver injury as well as the experimental models used to investigate these mechanisms are described and the clinical implications are discussed.

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Abstract: The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this ‘hepatostat’ will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver. The liver has a broad range of regenerative capacities. In this Review, Michalopoulos and Bhushan describe the regenerative mechanisms employed by hepatic cells after liver injury as well as the experimental models used to investigate these mechanisms and discuss the clinical implications.

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331 citations

Journal Article•DOI•

Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture

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Weng Chuan Peng¹, Catriona Y. Logan¹, Matt Fish¹, Teni Anbarchian¹, Francis Aguisanda¹, Adrián Álvarez-Varela¹, Peng Wu¹, Yinhua Jin¹, Junjie Zhu¹, Bin Li², Markus Grompe², Bruce Wang³, Roel Nusse¹ - Show less +9 more•Institutions (3)

Stanford University¹, Oregon Health & Science University², University of California, San Francisco³

29 Nov 2018-Cell

TL;DR: In vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah-/- mice, it is shown that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months.

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176 citations

Cites background from "Hepatostat: Liver regeneration and ..."

...The signals driving the in vivo proliferation of transplanted hepatocytes remain to be determined but may include inflammatory signals that drive regeneration in other types of injury models, such as partial hepatectomy (Michalopoulos and DeFrances, 1997; Michalopoulos, 2017)....
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Journal Article•DOI•

Hallmarks of Aging in the Liver.

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Nicholas J. Hunt¹, Nicholas J. Hunt², Sun Woo Sophie Kang¹, Sun Woo Sophie Kang², Glen P Lockwood², Glen P Lockwood¹, David G. Le Couteur¹, David G. Le Couteur², Victoria C. Cogger¹, Victoria C. Cogger² - Show less +6 more•Institutions (2)

Concord Repatriation General Hospital¹, University of Sydney²

01 Jan 2019-Computational and structural biotechnology journal

TL;DR: Age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease.

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Abstract: While the liver demonstrates remarkable resilience during aging, there is growing evidence that it undergoes all the cellular hallmarks of aging, which increases the risk of liver and systemic disease. The aging process in the liver is driven by alterations of the genome and epigenome that contribute to dysregulation of mitochondrial function and nutrient sensing pathways, leading to cellular senescence and low-grade inflammation. These changes promote multiple phenotypic changes in all liver cells (hepatocytes, liver sinusoidal endothelial, hepatic stellate and Kupffer cells) and impairment of hepatic function. In particular, age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease.

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154 citations

Cites background from "Hepatostat: Liver regeneration and ..."

...Liver regeneration and repair is driven by a complex network of mitogenic growth factors, non-mitogenic cytokines, paracrine mediators and transcription factors [47]....
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Journal Article•DOI•

Development of the liver: Insights into organ and tissue morphogenesis

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Elke A. Ober¹, Frédéric P. Lemaigre²•Institutions (2)

University of Copenhagen¹, Université catholique de Louvain²

01 May 2018-Journal of Hepatology

TL;DR: The key morphogenetic steps during liver development, from the prehepatic endoderm stage to the postnatal period, are reviewed, and several model organisms are considered while focussing on the mammalian liver.

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146 citations

Journal Article•DOI•

Supramolecular Adhesive Hydrogels for Tissue Engineering Applications.

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Yue Zhao, Shanliang Song, Xiangzhong Ren, Junmin Zhang, Quan Lin, Yanli Zhao - Show less +2 more

13 Jan 2022-Chemical Reviews

TL;DR: This review is expected to offer comparative views and critical insights to inspire more advanced studies on supramolecular adhesive hydrogels and pave the way for different fields even beyond tissue engineering applications.

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Abstract: Tissue engineering is a promising and revolutionary strategy to treat patients who suffer the loss or failure of an organ or tissue, with the aim to restore the dysfunctional tissues and enhance life expectancy. Supramolecular adhesive hydrogels are emerging as appealing materials for tissue engineering applications owing to their favorable attributes such as tailorable structure, inherent flexibility, excellent biocompatibility, near-physiological environment, dynamic mechanical strength, and particularly attractive self-adhesiveness. In this review, the key design principles and various supramolecular strategies to construct adhesive hydrogels are comprehensively summarized. Thereafter, the recent research progress regarding their tissue engineering applications, including primarily dermal tissue repair, muscle tissue repair, bone tissue repair, neural tissue repair, vascular tissue repair, oral tissue repair, corneal tissue repair, cardiac tissue repair, fetal membrane repair, hepatic tissue repair, and gastric tissue repair, is systematically highlighted. Finally, the scientific challenges and the remaining opportunities are underlined to show a full picture of the supramolecular adhesive hydrogels. This review is expected to offer comparative views and critical insights to inspire more advanced studies on supramolecular adhesive hydrogels and pave the way for different fields even beyond tissue engineering applications.

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124 citations

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References

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Journal Article•

Liver regeneration : Frontiers in medicine: Regeneration

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G. K. Michalopoulos, M. C. Defrances

01 Jan 1997-Science

TL;DR: This review attempts to integrate the findings of the last three decades and looks toward clues as to the nature of the causes that trigger this fascinating organ and cellular response.

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Abstract: Liver regeneration after the loss of hepatic tissue is a fundamental parameter of liver response to injury. Recognized as a phenomenon from mythological times, it is now defined as an orchestrated response induced by specific external stimuli and involving sequential changes in gene expression, growth factor production, and morphologic structure. Many growth factors and cytokines, most notably hepatocyte growth factor, epidermal growth factor, transforming growth factor-α, interleukin-6, tumor necrosis factor-α insulin, and norepinephrine, appear to play important roles in this process. This review attempts to integrate the findings of the last three decades and looks toward clues as to the nature of the causes that trigger this fascinating organ and cellular response.

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2,338 citations

Journal Article•DOI•

Hepatology SnapshotLiver regeneration

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Nelson Fausto¹, Jean S. Campbell¹, Kimberly J. Riehle¹•Institutions (1)

University of Washington¹

01 Sep 2012-Journal of Hepatology

TL;DR: A fresh look at the fundamentals of liver regeneration in light of recent technical innovations is taken, and it is demonstrated that there are three peaks of DNA synthesis after PH, initially in zone 1, then in the mid-lobule, and 15% of pre-existing hepatocytes never divide after PH.

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1,533 citations

"Hepatostat: Liver regeneration and ..." refers background in this paper

...norepinephrine, TNF, IL6, serotonin, and bile acids (1, 3-7)....
[...]
...There are several reviews on liver regeneration, providing detail coverage of the cellular kinetics, histological changes and signaling pathways associated with this process (1-7)....
[...]
...For more extensive analysis see references (1, 3, 5, 6)...
[...]
...(1,3,5,6) TNF and its effects were extensively characterized by Fausto et al.(5) TNFR1–/– mice have delayed regeneration attributed to inefficient activation of NFjB. IL6 is associated with proper activation of STAT3....
[...]
...Prior to DNA synthesis there is activation and migration to nucleus of transcription factors STAT3, C/EBPβ and NFkB (3), and enhanced expression of p21,p53, c-fos, c-jun, c-Myc,TGFβ (5), Oct4 and Nanog, the latter two under the control of MET/HGF and EGFR (18)....
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Journal Article•DOI•

Liver regeneration: from myth to mechanism

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Rebecca Taub¹, Rebecca Taub²•Institutions (2)

Hoffmann-La Roche¹, University of Pennsylvania²

01 Oct 2004-Nature Reviews Molecular Cell Biology

TL;DR: The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches.

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Abstract: The unusual regenerative properties of the liver are a logical adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. The numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches. So what is known about this process at present and which questions remain?

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1,447 citations

"Hepatostat: Liver regeneration and ..." refers background in this paper

...There are several reviews on liver regeneration, providing detail coverage of the cellular kinetics, histological changes and signaling pathways associated with this process (1-7)....
[...]
...For more extensive analysis see references (1, 3, 5, 6)...
[...]
...norepinephrine, TNF, IL6, serotonin, and bile acids (1, 3-7)....
[...]

Journal Article•DOI•

The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal

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Bin Zhao¹, Karen Tumaneng², Kun-Liang Guan²•Institutions (2)

Life Sciences Institute¹, University of California, San Diego²

01 Aug 2011-Nature Cell Biology

TL;DR: Current understanding of the composition and regulation of the Hippo pathway is summarized, and how cell polarity and cell adhesion proteins inform the role of this pathway in organ size control and regeneration is discussed.

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Abstract: Precise control of organ size is crucial during animal development and regeneration. In Drosophila and mammals, studies over the past decade have uncovered a critical role for the Hippo tumour-suppressor pathway in the regulation of organ size. Dysregulation of this pathway leads to massive overgrowth of tissue. The Hippo signalling pathway is highly conserved and limits organ size by phosphorylating and inhibiting the transcription co-activators YAP and TAZ in mammals and Yki in Drosophila, key regulators of proliferation and apoptosis. The Hippo pathway also has a critical role in the self-renewal and expansion of stem cells and tissue-specific progenitor cells, and has important functions in tissue regeneration. Emerging evidence shows that the Hippo pathway is regulated by cell polarity, cell adhesion and cell junction proteins. In this review we summarize current understanding of the composition and regulation of the Hippo pathway, and discuss how cell polarity and cell adhesion proteins inform the role of this pathway in organ size control and regeneration.

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1,039 citations

"Hepatostat: Liver regeneration and ..." refers background in this paper

...Protein) controlled by the Hippo pathway, involving the core kinases MST1/2 and LATS1/2 (62, 63)....
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...related to cell proliferation and cell size (62, 63)....
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Journal Article•DOI•

Hippo signaling: growth control and beyond

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Georg Halder¹, Randy L. Johnson•Institutions (1)

University of Texas MD Anderson Cancer Center¹

01 Jan 2011-Development

TL;DR: Recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development are reviewed and exciting new insights are provided into the elusive mechanisms that regulate organ growth and regeneration.

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Abstract: The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration.

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953 citations

"Hepatostat: Liver regeneration and ..." refers background in this paper

...It is reasonable to speculate that the functional significance of Hippo/Yap as a regulator of liver size probably depends on the fact that many growth regulatory signals affect it; this allows the pathway to function as an “integrator” of multiple competing growth regulatory signals and regulate liver size with precision determined by the balance of positive and negative signal regulation (69)....
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...The paradigm from Drosophila indicates that Hippo pathway is affected by multiple stimuli, including cell adhesion, polarity, and a protocadherin known as Fat (69)....
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...(68) The paradigm from Drosophila indicates that the Hippo pathway is affected by multiple stimuli, including cell adhesion, polarity, and a protocadherin known as Fat....
[...]