A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice

Mitchell, Claudia; Willenbring, Holger

doi:10.1038/nprot.2008.80

Cited by 480 publications

(477 citation statements)

References 23 publications

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“…19 For sham operation, mice were anesthetized and then subject to laparotomy, followed by brief manipulation of the intestines, but not the liver, with cotton swabs before wound closure. The animals were sacrificed at the indicated times following surgery.…”

Section: Partial Hepatectomy Modelmentioning

confidence: 99%

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Yin

Wang

Park

et al. 2011

The American Journal of Pathology

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Emerging evidence suggests that proinflammatory cytokines, including tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6), play a critical role in the initiation and progression of liver regeneration; however, relatively little is known about the role of antiinflammatory cytokine IL-10 in liver regeneration after partial hepatectomy (PHx). Here, we examined the role of IL-10 in liver regeneration using a model of PHx in several strains of genetically modified mice. After PHx, expression of IL-10 mRNA in the liver and spleen was significantly elevated. Such elevation was diminished in TLR4 mutant mice. Compared with wild-type mice, IL-10 ؊/؊ mice had higher levels of expression of proinflammatory cytokines (IL-6, TNF-␣, and IFN-␥) and inflammatory markers (CCR2 and F4/80) in the liver, as well as higher serum levels of proinflammatory cytokines after PHx. The number of neutrophils and macrophages was also higher in the livers of IL-10 ؊/؊ mice than in wild-type mice after PHx. Liver regeneration as determined by BrdU incorporation after PHx was higher in IL-10 ؊/؊ mice than in wild-type mice, which was associated with higher levels of activation of IL-6 downstream signal STAT3 in the liver. An additional deletion of STAT3 in hepatocytes significantly reduced liver regeneration in IL-10 ؊/؊ mice after PHx. Collectively, IL-10 plays an important role in negatively regulating liver regeneration via limiting inflammatory response and subsequently tempering hepatic STAT3 activation.

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Section: Partial Hepatectomy Modelmentioning

confidence: 99%

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Yin

Wang

Park

et al. 2011

The American Journal of Pathology

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“…Two-thirds PHX was performed as described (48). The removed liver tissue was snap-frozen in liquid nitrogen and used for analyses as 0-h control samples.…”

Section: Methodsmentioning

confidence: 99%

Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB ₁ ) receptors in the regenerating liver

Mukhopadhyay¹,

Çınar²,

Yin³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB 1 R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB 1 R in the control of liver regeneration. Here we report that mice lacking CB 1 R globally or in hepatocytes only and wild-type mice treated with a CB 1 R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB 1 R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hydrolase. In wild-type but not CB 1 R −/− mice, PHX induces robust upregulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB 1 R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.T he mammalian liver has a unique ability to regenerate fully after tissue loss or injury, thus ensuring that the critical functions of the liver are maintained. Liver regeneration is tightly regulated by multiple growth factors, cytokines, and hormones that induce quiescent hepatocytes to enter the cell cycle and undergo limited replication to restore liver mass (1, 2). Loss of liver tissue can occur in response to toxic chemicals, such as alcohol or CCl 4 , or viral infection, in which case the regenerative process is superimposed on an inflammatory response aimed at removing dead cells or the infectious agent. There is no inflammatory response during the regenerative response triggered by surgical removal of part of the liver, as in the case of liver tumors or liver transplantation. Two-thirds partial hepatectomy (PHX) is an experimental model for liver regeneration uncomplicated by an inflammatory response that frequently is used to gain insight into humoral factors that modulate hepatocyte proliferation. In mice, the peak proliferative response occurs 40 h after PHX.Endocannabinoids, such as arachidonoyl ethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), are lipid mediators that promote neural progenitor cell proliferation via activation of cannabinoid type 1 receptors (CB 1 R) in the brain (3, 4). CB 1 R and endocannabinoids also are present in the liver (5) where they promote de novo lipogenesis (5-7...

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“…Two-thirds PH surgery was performed as described (33). Briefly, adult mice (2-3 mo old) were injected with poly(I:C) to induce DDB1 deletion in the liver.…”

Section: Methodsmentioning

confidence: 99%

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Yamaji

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Etiologic risk factors for hepatocellular carcinoma can be involved in the transformation process by directly targeting intracellular signaling pathways or by indirectly stimulating chronic cycles of hepatocyte destruction and regeneration. However, the contribution of these two routes to hepatocarcinogenesis has not been determined, partly because of the difficulty in distinguishing damaged and regenerated hepatocytes. Here we report that induced deletion of the damaged DNA binding protein 1 (DDB1) abrogates the self-renewing capacity of hepatocytes, resulting in compensatory proliferation of DDB1-expressing hepatocytes. Constitutive stimulation of this regeneration process leads to development of hepatocellular carcinoma, which surprisingly contains no disruption of the DDB1 gene, indicating a cell-nonautonomous role of DDB1 inactivation in tumor initiation. Our results suggest that viruses and hepatoxins may cause liver tumors by simply driving hepatocyte turnover without directly targeting cancer cells. of all primary liver cancers, is the fifth most common cancer and the third leading cause of cancer death worldwide (1). HCC development follows a multistep progression from hepatic dysplasia to neoplasia, with accumulation of somatic mutations and chromosomal alterations (2). Conventionally, these genetic alterations are identified in human liver tumor samples by gene expression profiling, genomic and proteomic analysis, and direct sequencing. Candidate genes are subsequently validated in cell cultures and animals. This methodology has led to the identification of oncogenes and tumor suppressor genes important for liver tumor development, such as those regulating Wnt/β-catenin, p53, EGFR receptor tyrosine kinases, and MET/HGF pathways (3).Alternatively, interactions between host factors and HCC-associated pathogens such as hepatitis B virus (HBV) and hepatitis C virus (HCV) can be investigated to understand early molecular and cellular alterations leading to HCC initiation. HBV encodes a nonstructural regulatory protein, HBx, that is required for HBV replication and implicated in HBV-associated HCC (4). How HBx contributes to hepatocarcinogenesis is unclear, but is believed to involve its myriad target host proteins, one of which is the damaged DNA binding protein 1 (DDB1) (5). DDB1 is the linker protein for the Cullin 4 (Cul4) E3 ubiquitin ligase (6), which regulates ubiquitination and proteasomal degradation of proteins essential for nucleotide excision repair [DDB2 (7) and CSB (8)], cell cycle progression [p21 (9, 10), p27 (11), and Myc (12)], DNA replication [Cdt1 (13) and POLH-1 (14)], and cell growth [c-Jun (15) and TSC2 (16)]. Other substrates of the E3 ligase, including XPC (7), histones H3 and H4 (17), and histone H2A (18), are modified without degradation to facilitate DNA damage repair. Several viral regulatory proteins such as the HIV Vpr protein (19) and the simian virus 5 V protein (20) can hijack the E3 ligase to target undesired host factors and benefit the respective viral life cycle.In this...

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A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice

Cited by 480 publications

References 23 publications

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB ₁ ) receptors in the regenerating liver

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

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A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice

Cited by 480 publications

References 23 publications

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Enhanced Liver Regeneration in IL-10–Deficient Mice after Partial Hepatectomy via Stimulating Inflammatory Response and Activating Hepatocyte STAT3

Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB 1 ) receptors in the regenerating liver

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

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Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB ₁ ) receptors in the regenerating liver