Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2

Abstract The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the mai...

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Main Authors: Giulio Loforese, Thomas Malinka, Adrian Keogh, Felix Baier, Cedric Simillion, Matteo Montani, Thanos D Halazonetis, Daniel Candinas, Deborah Stroka
Format: Article
Language:English
Published: Springer Nature 2017-01-01
Series:EMBO Molecular Medicine
Subjects:
Online Access:https://doi.org/10.15252/emmm.201506089
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author Giulio Loforese
Thomas Malinka
Adrian Keogh
Felix Baier
Cedric Simillion
Matteo Montani
Thanos D Halazonetis
Daniel Candinas
Deborah Stroka
author_facet Giulio Loforese
Thomas Malinka
Adrian Keogh
Felix Baier
Cedric Simillion
Matteo Montani
Thanos D Halazonetis
Daniel Candinas
Deborah Stroka
author_sort Giulio Loforese
collection DOAJ
description Abstract The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two‐thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non‐regenerating livers. We provide pre‐clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non‐regenerative disorders.
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spelling doaj.art-bb867698978741b1a93c15961be0af982024-03-03T07:05:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-01-0191466010.15252/emmm.201506089Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2Giulio Loforese0Thomas Malinka1Adrian Keogh2Felix Baier3Cedric Simillion4Matteo Montani5Thanos D Halazonetis6Daniel Candinas7Deborah Stroka8Department of Clinical Research, Visceral Surgery and Medicine University of Bern Bern SwitzerlandDepartment of Clinical Research, Visceral Surgery and Medicine University of Bern Bern SwitzerlandDepartment of Clinical Research, Visceral Surgery and Medicine University of Bern Bern SwitzerlandDepartment of Clinical Research, Visceral Surgery and Medicine University of Bern Bern SwitzerlandInterfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics University of Bern Bern SwitzerlandInstitute of Pathology University of Bern Bern SwitzerlandDepartment of Molecular Biology University of Geneva Geneva SwitzerlandDepartment of Clinical Research, Visceral Surgery and Medicine University of Bern Bern SwitzerlandDepartment of Clinical Research, Visceral Surgery and Medicine University of Bern Bern SwitzerlandAbstract The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two‐thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non‐regenerating livers. We provide pre‐clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non‐regenerative disorders.https://doi.org/10.15252/emmm.201506089aged liverHippo pathwayliver regenerationMSTRNAi
spellingShingle Giulio Loforese
Thomas Malinka
Adrian Keogh
Felix Baier
Cedric Simillion
Matteo Montani
Thanos D Halazonetis
Daniel Candinas
Deborah Stroka
Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
EMBO Molecular Medicine
aged liver
Hippo pathway
liver regeneration
MST
RNAi
title Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
title_full Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
title_fullStr Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
title_full_unstemmed Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
title_short Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2
title_sort impaired liver regeneration in aged mice can be rescued by silencing hippo core kinases mst1 and mst2
topic aged liver
Hippo pathway
liver regeneration
MST
RNAi
url https://doi.org/10.15252/emmm.201506089
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