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EMBO Mol Med. 2017 Jan;9(1):46-60. doi: 10.15252/emmm.201506089.

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

Author information

1
Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
2
Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
3
Institute of Pathology, University of Bern, Bern, Switzerland.
4
Department of Molecular Biology, University of Geneva, Geneva, Switzerland.
5
Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland deborah.stroka@dkf.unibe.ch.

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.

KEYWORDS:

Hippo pathway; MST; RNAi; aged liver; liver regeneration

PMID:
27940445
PMCID:
PMC5210079
DOI:
10.15252/emmm.201506089
[Indexed for MEDLINE]
Free PMC Article

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