Deletion of the Hippo core kinases MST1 and MST2 by siRNA rescues liver regeneration in aged mice

The Hippo pathway controls organ size through cell proliferation and apoptosis through regulation of the co-transcription factor Yap1. The liver regenerates following the loss or damage of hepatic tissue, however in some... [ view full abstract ]

The Hippo pathway controls organ size through cell proliferation and apoptosis through regulation of the co-transcription factor Yap1. The liver regenerates following the loss or damage of hepatic tissue, however in some circumstances such as in aged livers, the ability of the liver to regenerate is impaired. We investigated how the Hippo pathway is regulated during the physiological process of liver regeneration after PH. Moreover, by using a regeneration impaired aged mouse model we aim to demonstrate that inhibition of the Hippo core kinases (MST1/2) has clinical potential to restore liver regeneration following PH. Knockdown of MST1/2 in the liver was achieved by siRNAs coupled with lysosomes.

Following a 2/3 PH in young (8-week) mice, there was increased activation of the core kinases MST1 and LATS1 during the hypertrophic phase of liver regeneration. The return of MST1 and LATS to a steady-state levels coincided with the activation of the YAP targets genes (Birc5, Cyclin B and Foxm1) and with the peak of hepatocytes proliferation. Following PH In aged mice (12-month), we observed an anomalous activation of the MST1 and LATS kinases and impairment of YAP target genes activation in the non-regenerating livers. Silencing the core kinases MST1 and MST2 by siRNA femoral vein injection provoked quiescent hepatocytes to re-enter proliferation and restored liver regeneration in aged mice after PH.

Our data suggest that the Hippo pathway is a component of the liver regenerative process and that targeting the Hippo core kinases MST1/2 could be used to restore impaired liver regeneration.