Hippo Pathway Activity Influences Liver Cell Fate

By Dean Yimlamai, C. Christodoulou, G. Galli, Kilangsungla Yanger, Brian J Pepe-Mooney, Basanta Gurung, Kriti Shrestha, Patrick Cahan, B. Stanger, F. Camargo. Cell, 2014

798 citations recorded by the source corpus.

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 de-differentiate, 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.

Subfields: Biochemistry, Cell Biology

View Paper: https://www.semanticscholar.org/paper/ddf0ad52d054478dc57f071dba363b50462ee511

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In Cell Biology

1. K. Guan
2. Fa-Xing Yu
3. S. Piccolo
4. Bin Zhao
5. M. Cordenonsi
6. Z. Meng
7. Toshiro Moroishi
8. Duojia Pan

Citations in the corpus

• Mechanisms of Hippo pathway regulation (2016, positive): “…contribution of individual Hippo pathway components to tissue growth, cell differentiation, cell competition, and malignant transformation (Zhou et al. 2009; Cai et al. 2010; Barry et al. 2013; Chen et al. 2014, 2015b; Yimlamai et al. 2014; Imajo et al. 2015; Mamada et al. 2015; Shen et al. 2015).”
• The Hippo Signaling Pathway in Development and Disease (2019, background): “These phenotypes mirror the observation that YAP activation can cause trans-differentiation of hepatocytes into biliary epithelium (Yimlamai et al., 2014).”
• YAP/TAZ at the roots of cancer (2016, background): “Such ability of YAP/TAZ to induce transdifferentiation prior to tumorigenesis has been also noticed in YAP-expressing transgenic livers, turning hepatocytes into biliary progenitors (Yimlamai et al., 2014).”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, positive): “For instance, after partial hepatectomy, hepatocytes start to proliferate to restore liver mass in a few days, and in this process, YAP activity is induced and is most likely required for complete liver regeneration (Grijalva et al., 2014; Su et al., 2015; Wu et al., 2013; Yimlamai et al., 2014).”