Abstract
The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two‐thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non‐regenerating livers. We provide pre‐clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non‐regenerative disorders.
Highlights
Due to its intrinsic capacity to regenerate—the liver has been at the forefront of clinical regenerative medicine and enables surgical treatments for numerous hepatic disorders
As the liver advanced into the proliferative phase (24–48 h post-partial hepatectomy (PH)), levels of p-MST1/2 and p-LATS1 decreased to steady state levels
YAP1 involvement in liver regeneration is in agreement with others (Wu et al, 2013; Grijalva et al, 2014); our data fine-tune the role of Hippo during the early hypertrophic and proliferative phases of the regenerative response
Summary
Due to its intrinsic capacity to regenerate—the liver has been at the forefront of clinical regenerative medicine and enables surgical treatments for numerous hepatic disorders. Patient recovery depends on the remnant liver mass to undergo compensatory growth to return to its original weight and functional capacity. Compensatory growth, or liver regeneration, following partial hepatectomy is a rapid and efficient process in which the normally quiescent hepatocyte population re-enters cell cycle and proliferates until the restoration of lost hepatic mass (Michalopoulos & DeFrances, 1997; Taub, 2004). Ageing is an adverse factor for liver regeneration; several studies in mice and humans demonstrated an age-dependent decline in the liver’s regenerative capacity following PH (Fry et al, 1984; Iakova et al, 2003; Ledda-Columbano et al, 2004; Schmucker & Sanchez, 2011). We investigated a potential targeted treatment to improve regeneration through inhibition of the Hippo pathway
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