title: 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 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.
authors.affiliation: Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Giulio
authors.initials: G
authors.lastname: Loforese
authors.affiliation: Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Malinka
authors.affiliation: Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Keogh
authors.affiliation: Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Felix
authors.initials: F
authors.lastname: Baier
authors.affiliation: Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland.
authors.forename: Cedric
authors.initials: C
authors.lastname: Simillion
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Montani
authors.affiliation: Department of Molecular Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Thanos D
authors.identifier: 0000-0001-8384-5030
authors.initials: TD
authors.lastname: Halazonetis
authors.affiliation: Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Candinas
authors.affiliation: Department of Clinical Research, Visceral Surgery and Medicine, University of Bern, Bern, Switzerland deborah.stroka@dkf.unibe.ch.
authors.forename: Deborah
authors.identifier: 0000-0002-3517-3871
authors.initials: D
authors.lastname: Stroka
mesh_terms: D000375:Aging; D000818:Animals; D020869:Gene Expression Profiling; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008115:Liver Regeneration; D051379:Mice; D023421:Models, Animal; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D000099317:Hippo Kinases
chemical_list: D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; C082332:macrophage stimulating protein; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases
keywords: Hippo pathway; MST; RNAi; aged liver; liver regeneration