Decoding Liver Cells: Hepatocyte Polyploidy Emerges as Vital Shield Against Aging

Liver cells, also called hepatocytes, stand out as a rare exception among human cells, as they are not strictly diploid (containing two sets of chromosomes) and frequently uphold multiple genome copies through a process termed polyploidization. Most importantly, the extent of polyploidization undergoes fluctuations both during aging and upon manifestation of chronic liver diseases. Currently, there are several, sometimes conflicting, main ideas as to how polyploidization may influence hepatocyte and liver function through periods of equilibrium, aging, and disease. Still, existing single-cell transcriptomic atlases overlook ploidy, despite its prevalent presence not only in hepatocytes but also in cardiomyocytes, osteoclasts, megakaryocytes, trophoblast giant cells, and mammary alveolar cells. Plus, the scientific community continues to debate the reasons behind hepatocyte polyploidization and the mechanisms governing it.

Insights from the Study

As polyploidy has been suggested as a mechanism for hepatocyte survival in response to lethal injuries, Celia P. Martinez-Jimenez and her team set to determine whether this mechanism similarly affects hepatocyte responses to milder perturbations, such as haploinsufficiency of liver-master regulators in phenotypically normal conditions. Exploring this in the context of Hnf4a and Cebpa haploinsufficient mice, the study demonstrates reduced liver steatosis (a medical condition characterized by the abnormal accumulation of fat within liver cells) and early polyploidization in young animals. Transcriptomic analysis further revealed ploidy-dependent gene expression changes, indicating that hepatocyte ploidy maintains liver homeostasis in response to single-gene copy deletion.

In addition, as polyploidization has been suggested as a universal method to maintain tissue balance, the team hypothesized that it could be a general response of the hepatocytes to genetic disturbances. Hence, the study extended its focus on investigating the role of early polyploidization in response to genetic perturbations via knockout of non-liver specific transcription factor CTCF, known to cause hepatosteatosis if absent. Ctcf^+/0 haploinsufficient mice indeed exhibited early tetraploidization and showed transcriptional buffering in response to the genetic perturbation, supporting the notion that hepatocyte ploidy protects against metabolic dysregulation.

Moreover, the study proposed a mechanism wherein tetraploid hepatocytes selectively enrich the wild-type allele in response to genetic perturbation, and conclusively confirmed that this non-random allele selection contributes to transcriptomic buffering, maintaining cellular homeostasis under genomic perturbation, particularly during aging.

Implications for Liver Health

While traditionally viewed as a terminal-differentiated cellular state, this study uncovers a previously unexpected adaptive role of hepatocyte polyploidization in response to genomic perturbation and aging. This was evidenced by the surprising discovery of polyploidization in young hepatocytes of haploinsufficient mice, which exhibited reduced age-associated liver steatosis. The findings suggest that hepatocyte ploidy serves as a universal genomic shield, buffering against transcriptional changes induced by genetic perturbations.

Importantly, the implications of hepatocyte polyploidy extend beyond its role in age-related challenges. The genomic shield appears to enrich for wild-type alleles during aging, presenting a novel perspective on liver health and potential therapeutic avenues in addressing aging-related diseases such as non-alcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma.