Hippo Pathway Activity Influences Liver Cell Fate

Yimlamai, Dean; Christodoulou, Constantina; Galli, Giorgio; Yanger, Kilangsungla; Pepe-Mooney, Brian; Gurung, Basanta; Shrestha, Kriti; Cahan, Patrick; Stanger, Ben Z.; Camargo, Fernando D.

doi:10.1016/j.cell.2014.03.060

Cited by 709 publications

(874 citation statements)

References 48 publications

(68 reference statements)

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“…In mature hepatocytes YAP is expressed at very low levels, whereas it is highly expressed in the progenitor cell compartments18. High levels of YAP indicate a HPC phenotype resulting in differentiation into hepatocytes and liver growth30. The present results indicated a higher expression of YAP after ALPPS compared with that following PVL and LLL, and YAP reached maximum levels on days 3–7 in ALPPS20 and ALPPS10 groups, inversely correlated to FLR size.…”

Section: Discussionsupporting

confidence: 48%

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Experimental evaluation of liver regeneration patterns and liver function following ALPPS

et al. 2017

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BackgroundThe underlying mechanism of liver regeneration after Associating Liver Partition and Portal vein ligation (PVL) for Staged hepatectomy (ALPPS) is still unclear. The aim of this study was to evaluate the relationship between future liver remnant (FLR) volume, liver regeneration characteristics and restoration of function in an experimental model of ALPPS.MethodsAn ALPPS model in rats was developed with selective PVL, parenchymal transection and partial hepatectomy (step 1), followed by resection of the liver (step 2). Three different ALPPS groups with FLR sizes of 30, 20 and 10 per cent of total liver volume were compared with sham‐operated controls and animals undergoing resection of left lateral lobe and 90 per cent PVL with respect to morbidity, mortality, liver regeneration and function.ResultsThree of 15 animals that had ALPPS with 10 per cent FLR (ALPPS10) died after step 1. Ascites developed in two of five rats that had ALPPS with 20 per cent FLR and in three of four animals in the ALPPS10 group after step 2. Although the relative increments in FLR size and growth rates were highest in the ALPPS groups, small FLR size was associated with a sustained increase in levels of serum aminotransferases and bilirubin, a lower albumin concentration, severe sinusoidal injury, increased expression of proliferation markers and increased activation of hepatic progenitor cells after step 2.ConclusionThere is discordance between FLR volume increase and functional restoration after the ALPPS procedure.

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Section: Discussionsupporting

confidence: 48%

“…YAP is a critical regulator of liver size through expansion of undifferentiated HPCs18 30. In mature hepatocytes YAP is expressed at very low levels, whereas it is highly expressed in the progenitor cell compartments18.…”

Section: Discussionmentioning

confidence: 99%

Experimental evaluation of liver regeneration patterns and liver function following ALPPS

et al. 2017

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“…Mice with liver-specific deletion of Nf2 (14), Sav1 (15, 16), or Mst1/2 (17, 18), or mice with transgenic Yap1 expression (19)(20)(21), show not only liver tumors but also hepatocyte dedifferentiation (22), increased liver stem/progenitor cells, and hepatomegaly. However, the precise roles of mammalian Hippo signaling components have been difficult to identify, partly because multiple homologs of each element exist.…”

Section: Significancementioning

confidence: 99%

Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice

Nishio

Sugimachi

Goto

et al. 2015

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

166

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Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial–mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.

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“…In particular, Yap promotes the ability to self-renew and differentiate in embryonic stem cells, 101 satellite muscle cells 102 and liver cells. 103 Increased expression of Yap in the heart induces CM proliferation 5 and protects against MI in mice. 71 Activation of functions in the heart.…”

Section: Hippo Pathway In Heart Regenerationmentioning

confidence: 99%