Cellular polyploidy in organ homeostasis and regeneration

Abstract

Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their diploid counterparts, including an increase in cell size, contributing to organ growth and tissue homeostasis, and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals. Here, we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid. Moreover, we discuss its crucial roles in cell growth and tissue regeneration in the heart, liver, and other tissues.

Keywords: cardiac regeneration; cellular polyploidy; liver regeneration; tissue regeneration.

Figure 1.

Molecular mechanisms trigger polyploidy formation. Different mechanisms are responsible for the genesis of different tetraploid cells. Cell fusion through receptor–ligand interactions or defective cytokinesis can form binucleated tetraploid cells. Endoreplication (cells skip mitosis) or mitotic slippage (cells exit mitosis without undergoing anaphase) generates mononucleated tetraploid cells. Note: Indicated mechanisms are only representative mediators and not a complete list.

Figure 2.

The formation of polyploid cardiomyocyte during postnatal development. Normally, cardiomyocytes can complete both mitosis and cytokinesis, leading to the formation of two diploid daughter cells (A). Once the cardiomyocyte completes only mitosis with defective cytokinesis, it will give rise to one binucleated cardiomyocyte (B). If the cardiomyocyte failed in both mitosis and cytokinesis, it would generate one polyploid cardiomyocyte nuclei (C)..

Figure 3.

Hepatocytes polyploidy during development. Gradual hepatocyte polyploidy emerges in rodent during postnatal growth and is nearly diploid in newborns (1 × 2n). During weaning, diploid hepatocytes can either complete the cell cycle and produce two diploid hepatocytes or undergo incomplete cytokinesis and generate binucleated tetraploid hepatocytes (2 × 2n). Two mononucleated tetraploid cells are formed when binucleated cells enter the next cell cycle with normal cytokinesis. This continued process results in the formation of mono- or binucleated tetraploid and octoploid (8n) hepatocytes and so on. In the adult, hepatocytes regulate its ploidy by responding to different signals. They can either increase (such as cytokinesis failure) or decrease ploidy state (multipolar spindle formation, a process called ploid reversal). During this ploidy reversal process, chromosome segregation errors could happen, which triggers the formation of aneuploid cells.

Figure 4.

Heart regenerative capacity in relation to cardiomyocyte polyploidy in different species with time. Zebrafish and newt cardiomyocytes are exclusively diploid and maintain robust cardiac regenerative capacity throughout life. In contrast, cardiomyocyte polyploidy in humans and mouse increases with time, accompanied by the loss of heart regeneration capacity, suggesting that the occurrence of polyploidy might be at the cost of regeneration capacity decline in mammals.