TY - JOUR
T1 - Hippo pathway activity influences liver cell fate
AU - Yimlamai, Dean
AU - Christodoulou, Constantina
AU - Galli, Giorgio G.
AU - Yanger, Kilangsungla
AU - Pepe-Mooney, Brian
AU - Gurung, Basanta
AU - Shrestha, Kriti
AU - Cahan, Patrick
AU - Stanger, Ben Z.
AU - Camargo, Fernando D.
N1 - Funding Information:
We are grateful for stimulating discussions with the Camargo lab members, Barbara Trejo for help with IHC, Roderick Bronson for reviewing mouse liver pathology, and Ron Mathieu of the Stem Cell Program FACS facility. We thank G. Gu, T. Honjo, and M. Giovannini for use of Ck19-CreERT , RPBJ , and Nf2 mice, respectively. V. Factor generously donated A6 antibody for our use. This study was supported by awards from the Stand Up to Cancer-AACR initiative (FDC), grants from the National Institutes of Health (AR064036 and DK099559 to F.D.C.; DK083355 to B.Z.S.), a Department of Defense award (W81XWH-9) (to F.D.C.), and Junior Investigator funds from the Harvard Stem Cell Institute (to F.D.C.). D.Y. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (5T32 DK007477-27) and a Boston Children’s Hospital Career Development Award and is a George Ferry Young Investigator (NASPGHAN). G.G.G. is supported by an American-Italian Cancer Foundation postdoctoral research fellowship. B.P.-M. is supported by the National Science Foundation Graduate Research Fellowship Program (DGE1144152). F.D.C. is a Pew Scholar in the Biomedical Sciences.
PY - 2014/6/5
Y1 - 2014/6/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.03.060
DO - 10.1016/j.cell.2014.03.060
M3 - Article
C2 - 24906150
AN - SCOPUS:84902081616
VL - 157
SP - 1324
EP - 1338
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -