Abstract
The ability of the liver to restore its original volume following tissue loss has been associated with the Hippo‐YAP1 pathway, a key controller of organ size. Yes‐associated protein 1 (YAP1)—a growth effector usually restrained by Hippo signaling—is believed to be of particular importance; however, its role in liver regeneration remains ill‐defined. To explore its function, we knocked down YAP1 prior to standard 70%‐hepatectomy (sHx) using a hepatocyte‐specific nanoformulation. Knockdown was effective during the major parenchymal growth phase (S‐phase/M‐phase peaks at 32 hours/48 hours post‐sHx). Liver weight gain was completely suppressed by the knockdown at 32 hours, but was reaccelerated toward 48 hours. Likewise, proliferative markers, Ccna2/b2 and YAP1 target gene expression were downregulated at 32 hours, but re‐elevated at 48 hours post‐sHx. Nonetheless, knockdown slightly compromised survival after sHx. When assessing a model of resection‐induced liver failure (extended 86%‐hepatectomy, eHx) featuring deficient S‐ and M‐phase progression, YAP1 was not induced at 32 hours, but upregulated at 48 hours post‐eHx, confirming its dissociation from M‐phase regulation. Therefore, YAP1 is vital to push hepatocytes into cycle and through the S‐phase, but is not required for further cell cycle progression during liver regeneration. The examination of YAP1 in human livers suggested its function is conserved in the regenerating mammalian liver.
Highlights
The vital functions of the liver require steady maintenance
At 48 hours after hepatectomy, Ki67 counts were similar and PCNA counts tended (P = 0.1) to increase in αYap1‐siRNA‐ vs αAhsa1‐siRNA‐treated mice, while phospho‐histone 3 (pH3) positivity and mitotic counts were reduced, but no more suppressed as at 32 hours, in Yap1‐deficient liver (Figure 3B). These findings suggest that Yes-associated protein 1 (YAP1) deficiency causes an initial proliferative block, which is followed by tardive, compensatory proliferation of hepatocytes independent of YAP1 at 48 hours post‐resection
To get better insight into the physiological role of YAP1 during liver regeneration, we examined its expression after extended hepatectomy
Summary
The vital functions of the liver require steady maintenance. the liver is equipped with a unique regenerative capacity and can regrow its original mass following extensive tissue loss. Massive resection (ie, 90%) of the liver causes 100% mortality within 2 days, while mortality is at ~30% following extended 86%‐hepatectomy (eHx), with survivors displaying metabolic liver dysfunction (hyperbilirubinemia, hypoalbuminemia, persisting steatosis) and a proliferative arrest in hepatocytes.[2,3] In humans, resection‐induced liver failure is known as the small‐for‐size syndrome (SFSS), likewise features metabolic as well as regenerative insufficiency,[3] and is the most frequent cause of postoperative death.[4] liver size is a key determinant of liver function, with an optimal volume for sound function and a minimal volume to sustain vital function under stress. The MST1/2 and downstream LATS1/2 kinases are the conserved regulators of yes‐associated protein 1 (YAP1) to restrain its activity via phosphorylation‐induced degradation Upon triggers such as the loss of cell‐cell contact, disturbed cell polarity, or mechanical stress, MST1/2‐LATS1/2 activities decline, and so does proteasomal degradation of YAP1. We compared outcomes with an established model of resection‐induced liver failure and validated findings in human liver tissue
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