Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases

Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. Polyploid hepatocytes are characterized in terms of the number of nuclei per cell (cellular ploidy; mononucleate/binucleate hepatocytes) and the number of chromosome sets in each nucleus (nuclear ploidy; diploid, tetraploid, octoploid). The advantages and disadvantages of polyploidy in mammals are not fully understood. About 30% of the hepatocytes in the human liver are polyploid. In this review, we explore the mechanisms underlying the development of polyploid cells, our current understanding of the regulation of polyploidization during development and pathophysiology and its consequences for liver function. We will also provide data shedding light on the ways in which polyploid hepatocytes cope with centrosome amplification. Finally, we discuss recent discoveries highlighting the possible roles of liver polyploidy in protecting against tumor formation, or, conversely, contributing to liver tumorigenesis.

Blocking cell fusion inhibits age-induced polyploidy and maintains epithelial organization in Drosophila

A characteristic of normal aging and age-related diseases is the remodeling of a tissue's cellular organization through polyploid cell growth. Polyploidy arises from an increase in nuclear ploidy or the number of nuclei per cell. However, it is not known whether age-induced polyploidy is an adaption to stressors or a precursor to degeneration. Here, we find that the adult fruit fly's abdominal epithelium becomes polyploid with age through generation of large multinucleated cells that make up more than 40% of the tissue area. The syncytia arise by cell fusion, not endomitosis. Epithelial multinucleation is also a characteristic of macular degeneration, including Ctnna1tvrm5, a mouse model for pattern dystrophy. Similarly, we find that the knockdown of alpha-catenin enhances multinucleation in the fly epithelium. We further show that age-induced polyploidy can be suppressed by inhibiting cell fusion revealing a means to maintain tissue organization in older animals.

Robust Cytonuclear Coordination of Transcription in Nascent Arabidopsis thaliana Autopolyploids

Polyploidy is hypothesized to cause dosage imbalances between the nucleus and the other genome-containing organelles (mitochondria and plastids), but the evidence for this is limited. We performed RNA-seq on Arabidopsis thaliana diploids and their derived autopolyploids to quantify the degree of inter-genome coordination of transcriptional responses to nuclear whole genome duplication in two different organs (sepals and rosette leaves). We show that nuclear and organellar genomes exhibit highly coordinated responses in both organs. First, organelle genome copy number increased in response to nuclear whole genome duplication (WGD), at least partially compensating for altered nuclear genome dosage. Second, transcriptional output of the different cellular compartments is tuned to maintain diploid-like levels of relative expression among interacting genes. In particular, plastid genes and nuclear genes whose products are plastid-targeted show coordinated down-regulation, such that their expression levels relative to each other remain constant across ploidy levels. Conversely, mitochondrial genes and nuclear genes with mitochondrial targeting show either constant or coordinated up-regulation of expression relative to other nuclear genes. Thus, cytonuclear coordination is robust to changes in nuclear ploidy level, with diploid-like balance in transcript abundances achieved within three generations after nuclear whole genome duplication.

Polyploidy spectrum: a new marker in HCC classification

ObjectivesPolyploidy is a fascinating characteristic of liver parenchyma. Hepatocyte polyploidy depends on the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Which role can be assigned to polyploidy during human hepatocellular carcinoma (HCC) development is still an open question. Here, we investigated whether a specific ploidy spectrum is associated with clinical and molecular features of HCC.DesignPloidy spectra were determined on surgically resected tissues from patients with HCC as well as healthy control tissues. To define ploidy profiles, a quantitative and qualitative in situ imaging approach was used on paraffin tissue liver sections.ResultsWe first demonstrated that polyploid hepatocytes are the major components of human liver parenchyma, polyploidy being mainly cellular (binuclear hepatocytes). Across liver lobules, polyploid hepatocytes do not exhibit a specific zonation pattern. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumours. Remarkably, nuclear ploidy is specifically amplified in HCC tumours. In fact, nuclear ploidy is amplified in HCCs harbouring a low degree of differentiation and TP53 mutations. Finally, our results demonstrated that highly polyploid tumours are associated with a poor prognosis.ConclusionsOur results underline the importance of quantification of cellular and nuclear ploidy spectra during HCC tumorigenesis.