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Loss of Integrin ?v?8 in Murine Hepatocytes Accelerates Liver Regeneration.

ABSTRACT: Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes after liver injury. In other systems, integrin ?v?8 has a major role in activating transforming growth factor (TGF)-?, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin ?v?8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte ?v?8, after partial hepatectomy, hepatocyte proliferation and liver-to-body weight ratio were significantly increased in Itgb8flox/flox;Alb-Cre mice compared with control mice. Antibody-mediated blockade of hepatocyte ?v?8 in vitro, with assessment of TGF-? signaling pathways by real-time quantitative PCR array, supported the hypothesis that integrin ?v?8 inhibition alters hepatocyte TGF-? signaling toward a pro-regenerative phenotype. A diethylnitrosamine-induced model of hepatocellular carcinoma, used to examine the possibility that this pro-proliferative phenotype might be oncogenic, revealed no difference in either tumor number or size between Itgb8flox/flox;Alb-Cre and control mice. Immunohistochemistry for integrin ?v?8 in healthy and injured human liver demonstrated that human hepatocytes express integrin ?v?8. Depletion of hepatocyte integrin ?v?8 results in increased hepatocyte proliferation and accelerated liver regeneration after partial hepatectomy in mice. These data demonstrate that targeting integrin ?v?8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases.

SUBMITTER: Greenhalgh SN

PROVIDER: S-EPMC6360354 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Loss of Integrin αvβ8 in Murine Hepatocytes Accelerates Liver Regeneration.

Greenhalgh Stephen N SN Matchett Kylie P KP Taylor Richard S RS Huang Katherine K Li John T JT Saeteurn Koy K Donnelly Mhairi C MC Simpson Eilidh E M EEM Pollack Joshua L JL Atakilit Amha A Simpson Kenneth J KJ Maher Jacquelyn J JJ Iredale John P JP Sheppard Dean D Henderson Neil C NC

The American journal of pathology 20181116 2

Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes after liver injury. In other systems, integrin αvβ8 has a major role in activating transforming growth factor (TGF)-β, a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin αvβ8 would increase hepatocyte proliferation and accelerate liver regeneration after injury. Using Itgb8<sup>flox/flox</sup>;Alb-Cre mice to ...[more]

PMID: 30448409

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Project description:Background & aimsLiver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration.MethodsHepatocyte proliferation was studied in vitro in hepatoma cell lines and ex vivo in precision-cut human liver slices. Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL-/-) and specifically invalidated in hepatocytes (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGLMye-/- mice.ResultsPrecision-cut human liver slices from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice.ConclusionsOur data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming.Impact and implicationsBy using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.

Project description:Liver is a unique organ in displaying a reparative and regenerative response after acute/chronic damage or partial hepatectomy, when all the cell types must proliferate to re-establish the liver mass. The NADPH oxidase NOX4 mediates Transforming Growth Factor-beta (TGF-?) actions, including apoptosis in hepatocytes and activation of stellate cells to myofibroblasts. Aim of this work was to analyze the impact of NOX4 in liver regeneration by using two mouse models where Nox4 was deleted: 1) general deletion of Nox4 (NOX4-/-) and 2) hepatocyte-specific deletion of Nox4 (NOX4hepKO). Liver regeneration was analyzed after 2/3 partial hepatectomy (PH). Results indicated an earlier recovery of the liver-to-body weight ratio in both NOX4-/- and NOX4hepKO mice and an increased survival, when compared to corresponding WT mice. The regenerative hepatocellular fat accumulation and the parenchyma organization recovered faster in NOX4 deleted livers. Hepatocyte proliferation, analyzed by Ki67 and phospho-Histone3 immunohistochemistry, was accelerated and increased in NOX4 deleted mice, coincident with an earlier and increased Myc expression. Primary hepatocytes isolated from NOX4 deleted mice showed higher proliferative capacity and increased expression of Myc and different cyclins in response to serum. Transcriptomic analysis through RNA-seq revealed significant changes after PH in NOX4-/- mice and support a relevant role for Myc in a node of regulation of proliferation-related genes. Interestingly, RNA-seq also revealed changes in the expression of genes related to activation of the TGF-? pathway. In fact, levels of active TGF-?1, phosphorylation of Smads and levels of its target p21 were lower at 24?h in NOX4 deleted mice. Nox4 did not appear to be essential for the termination of liver regeneration in vivo, neither for the in vitro hepatocyte response to TGF-?1 in terms of growth inhibition, which suggest its potential as therapeutic target to improve liver regeneration, without adverse effects.

Dataset Information

Loss of Integrin ?v?8 in Murine Hepatocytes Accelerates Liver Regeneration.

Publications

Loss of Integrin αvβ8 in Murine Hepatocytes Accelerates Liver Regeneration.

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