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...
Main Authors: | , , , , , , , , |
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Language: | English |
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Springer Nature
2017-01-01
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Series: | EMBO Molecular Medicine |
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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. |
first_indexed | 2024-03-07T16:44:38Z |
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id | doaj.art-bb867698978741b1a93c15961be0af98 |
institution | Directory Open Access Journal |
issn | 1757-4676 1757-4684 |
language | English |
last_indexed | 2024-03-07T16:44:38Z |
publishDate | 2017-01-01 |
publisher | Springer Nature |
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series | EMBO Molecular Medicine |
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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