title: Hippo pathway activity influences liver cell fate.
abstract: The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration.
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Division of Gastroenterology and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Yimlamai
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Constantina
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Giorgio G
authors.initials: GG
authors.lastname: Galli
authors.affiliation: Department of Medicine, Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kilangsungla
authors.initials: K
authors.lastname: Yanger
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Pepe-Mooney
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Basanta
authors.initials: B
authors.lastname: Gurung
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Kriti
authors.initials: K
authors.lastname: Shrestha
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.affiliation: Department of Medicine, Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
authors.affiliation: The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: fernando.camargo@childrens.harvard.edu.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D054337:Cell Dedifferentiation; D022781:Hepatocytes / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D017346:Protein Serine-Threonine Kinases