Hippo Pathway Activity Influences Liver Cell Fate

被引:690
作者
Yimlamai, Dean [1 ,2 ]
Christodoulou, Constantina [1 ,3 ,4 ]
Galli, Giorgio G. [1 ,3 ,4 ]
Yanger, Kilangsungla [5 ]
Pepe-Mooney, Brian [1 ,3 ,4 ]
Gurung, Basanta [1 ,3 ,4 ]
Shrestha, Kriti [1 ]
Cahan, Patrick [1 ]
Stanger, Ben Z. [5 ,6 ,7 ]
Camargo, Fernando D. [1 ,3 ,4 ]
机构
[1] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA
[2] Boston Childrens Hosp, Dept Med, Div Gastroenterol & Nutr, Boston, MA 02115 USA
[3] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[4] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[5] Univ Penn, Perelman Sch Med, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA
[6] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA
[7] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
BILE-DUCT DEVELOPMENT; EPITHELIAL-CELLS; TEAD/TEF FAMILY; YAP ONCOPROTEIN; ORGAN SIZE; STEM-CELLS; HEPATOCYTES; PROTEIN; GROWTH; INACTIVATION;
D O I
10.1016/j.cell.2014.03.060
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1324 / 1338
页数:15
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