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

Loforese, Giulio; Malinka, Thomas; Keogh, Adrian; Baier, Felix; Simillion, Cedric André Marie; Montani, Matteo; Halazonetis, Thanos D; Candinas, Daniel; Keogh-Stroka, Deborah M. (2017). Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2. EMBO molecular medicine, 9(1), pp. 46-60. EMBO Press 10.15252/emmm.201506089

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Loforese, Giulio; Malinka, Thomas; Keogh, Adrian; Baier, Felix; Simillion, Cedric André Marie; Montani, Matteo; Candinas, Daniel and Keogh-Stroka, Deborah M.

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1757-4684

Publisher:

EMBO Press

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

01 Feb 2017 14:08

Last Modified:

08 Nov 2018 11:51

Publisher DOI:

10.15252/emmm.201506089

PubMed ID:

27940445

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.93387

URI:

https://boris.unibe.ch/id/eprint/93387

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