The extent of liver injury determines hepatocyte fate toward senescence or cancer

Abstract

It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC.

Hallmarks of Aging in the Liver

“…Cell senescence-associated with telomere length shortening has been confirmed in livers of old human donors [136]. In addition to telomere shortening, changes to the nuclear size, DNA content, increased p21 [137,138], γ-H2AX [139] and β-galactosidase expression [140], formation of senescence-associated heterochromatin foci [141], genetic mutations of the telomerase enzyme complex [142] have all been confirmed to be features of senescence in human livers during normal aging and liver disease. In mice, the presence of increased senescent cells has been shown by the positive identification of (i) cellular markers [143,144]; (ii) senescence associated secretory phenotype [27], (iii) gene signatures of cellular senescence [145] and transcriptome phenotype markers [90].…”

High-Resolution 3D Fluorescent Imaging of Intact Tissues

“…This methodology could be adapted for 3D pathological assessments of disease state and for generating submicron-resolution whole organ atlases. Indeed, subcellular features are emerging as key markers for disease progression, such as multinucleation, sarcomere and T-tubule density and alignment, capillary density and alignment, and canaliculi dilation 27,[40][41][42][43][44][45][46][47] . In addition, recent tissue engineering approaches demonstrated cells and extracellular matrix can be bioprinted with micron-level resolution 48,49 , the datasets generated by this method will also be useful blueprints for engineering human tissues.…”

Diploid hepatocytes drive physiological liver renewal in adult humans

“…However, our data showed that at least 96% of all hepatocytes divide lifelong, providing no indication that a significant quiescent subpopulation of hepatocytes exists in the human liver. Accordingly, markers of permanent cell cycle arrest are physiologically not detectable in parenchymal liver cells (Aravinthan et al, 2013;Wang et al, 2018). Together, these observations suggest that virtually all hepatocytes participate in the organ's renewal over a life span.…”