Abstract

The presence of senescent, transformed or damaged cells can impair tissue function or lead to tumorigenesis; therefore, organisms have evolved quality control mechanisms to eliminate them. Here, we show that YAP activation induced by inactivation of the Hippo pathway specifically in damaged hepatocytes promotes their selective elimination by using in vivo mosaic analysis in mouse liver. These damaged hepatocytes migrate into the hepatic sinusoids, undergo apoptosis and are engulfed by Kupffer cells. In contrast, YAP activation in undamaged hepatocytes leads to proliferation. Cellular stresses such as ethanol that damage both liver sinusoidal endothelial cells and hepatocytes switch cell fate from proliferation to migration/apoptosis in the presence of activated YAP. This involves the activation of CDC42 and Rac that regulate cell migration. Thus, we suggest that YAP acts as a stress sensor that induces elimination of injured cells to maintain tissue and organ homeostasis.

Highlights

  • The presence of senescent, transformed or damaged cells can impair tissue function or lead to tumorigenesis; organisms have evolved quality control mechanisms to eliminate them

  • We examine the dynamics of YAP-activating hepatocytes by in vivo mosaic analysis in mouse and discover that the fate of YAP-expressing hepatocytes changes from proliferation to migration/apoptosis depending on the status of the liver sinusoidal endothelial cells (LSECs)

  • To examine how the Hippo pathway affects the fate of individual hepatocytes, we first established mosaic conditions by using hydrodynamic tail vein injection (HTVi) to introduce Myc-tagged YAP-wild type (WT), or one of three active YAP mutants (YAP (1SA), YAP (2SA) or YAP (5SA)), into mouse liver in vivo[19,20]

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Summary

Introduction

The presence of senescent, transformed or damaged cells can impair tissue function or lead to tumorigenesis; organisms have evolved quality control mechanisms to eliminate them. We show that YAP activation induced by inactivation of the Hippo pathway in damaged hepatocytes promotes their selective elimination by using in vivo mosaic analysis in mouse liver. These damaged hepatocytes migrate into the hepatic sinusoids, undergo apoptosis and are engulfed by Kupffer cells. YAP activation in undamaged hepatocytes leads to proliferation Cellular stresses such as ethanol that damage both liver sinusoidal endothelial cells and hepatocytes switch cell fate from proliferation to migration/apoptosis in the presence of activated YAP. We examine the dynamics of YAP-activating hepatocytes by in vivo mosaic analysis in mouse and discover that the fate of YAP-expressing hepatocytes changes from proliferation to migration/apoptosis depending on the status (healthy or damaged) of the LSECs

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