Cell division of liver cells affects the physiology of the liver as an organ

What is it about?

Liver cells (hepatocytes) are thought to be mostly quiescent. Here we prevented hepatocytes from dividing by knocking out an essential cell cycle regulator (CDK1). The we investigated how this affects the physiology and function of the liver. We also verified that CDK1 was knocked out shortly after the mice were born. We found that this affected the polyploidy of hepatocytes (termed pathological polyploidy), which activated the DNA damage response. It also affected inflammation and fibrosis, especially early (around P14). We tested whether a similar phenotype would be seen by knocking out cyclin A2, one of the activators of CDK1. Although fibrosis and cell size was increased in the cyclin A2 knockout liver, instead of polyploidy there was aneuploidy. Finally, we tested whether knocking out CDK2 together with CDK1 would rescue some of the phenotypes. This prevented polyploidy, fibrosis, cell size increases, and the response to DNA damage indicating that these phenotypes are likely to be connected to "re-replication" of the DNA content in hepatocytes.

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Why is it important?

CDK1 and CDK2 are among the most important cell cycle regulators in proliferating cells. They have overlapping functions that are hard to deconvolute under normal experimental conditions. Here we took advantage of an organ where hepatocytes are mostly quiescent. We found that under these conditions, CDK1 is still important for several aspects of liver physiology including polyploidy. As a consequence, we observed a response to DNA damage, inflammation and fibrosis. The fact that in the CDK1CDK2 double knockout some of the phenotypes are rescued, indicates re-replication is important to prevent in hepatocytes.

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