Figure 2. Polyploidy and developmental programming of adult diseases show similar properties.
Figure 2. Polyploidy and developmental programming of adult diseases show similar properties.
- Polyploidy helps to cope with the adverse environments via the augmentation of stress resistance and adaptation through epigenetic mechanisms . Furthermore, it is one of the most variable characteristics of somatic cells. The degree of polyploidization in homologous organs shows large across-species diversity. The percentage of cardiomyocytes with polyploid nuclei varies several folds in mammals of similar weight. For example, about 50% of human cardiomyocytes contain nuclei with 4, 8, 16, or even 32 genomes, whereas cardiomyocytes of the grey wolf or reindeer show only about 1% of cells with polyploid nuclei . Accordingly, cardiomyocyte ploidy also varies between individuals of the same species. The mean ploidy in the normal human heart varies from about 4× to 10× . Thus, polyploidy is characterized by the degree of biologic plasticity similar to the renowned factors of ontogenetic programming.
- Polyploid cells (e.g., cardiomyocytes, megakaryocytes, hepatocytes, pancreacytes, vascular epithelial cells, retina epithelium) appeared in the perinatal and early postnatal ontogenesis . These periods are characterized by high biological plasticity and coincide in time with the critical periods of development .
- Cells of slowly renewing organs, including neurons of neocortex and cerebellum, cardiomyocytes, and hepatocytes, which accumulate additional genomes in infancy, childhood, and pre-pubertant period, retain the increased genome amount throughout their lives, regardless of environmental conditions .
- Polyploidization is associated with a decrease in organ functional potential . This decrease probably originates from the involvement of polyploidy in the trade-off between proliferation and function that is also a sign of the developmental programming of adult diseases factor .
- The level of ploidy, particularly in cardiomyocytes, responds to the well-established stimuli of developmental programming (including adverse growth conditions, increased functional load, inflammation, and malnutrition) similarly in the various species and various cells . For example, in mammal hepatocytes, cardiomyocytes, retinocytes, and drosophila somatic cells, polyploidy is associated with the increased response to stress, activated pathways of morphogenesis and glycolytic metabolism, and the weakened aerobic metabolism and apoptosis .
- Polyploidy is associated with epigenetic changes at various levels of genome organization leading to chromatin remodeling and genome instability . The association between polyploidy and chromatin decompactization under stress was well documented for cardiomyocytes and hepatocytes . Polyploidy can alter global patterns of DNA methylation, microRNA expression, and histone modification in mammalian, insect, and plant cells . Polyploid cells show higher expression of bivalent genes, which harbor both activating (H3K4me3) and repressive (H3K27me3) chromatin domains, allowing rapid switching between cellular programs . Overall, ploidy-associated transcriptomic changes occur through the same epigenetic mechanisms as in the developmental programming of health and disease, including chromatin remodeling, DNA methylation, histone modification, and others.
- Excessive polyploidization can be associated with the diseases that usually originated from the developmental programming, including cardiovascular disease, hypertension, neurodegenerative disease, type 2 diabetes, metabolic syndrome, and others .
Experimental Studies Confirm the Role of Polyploidy in the Developmental Programming of Health and Disease
Recent experimental and clinical studies confirm that polyploidy can be involved in the developmental programming of adult diseases. The most convincing evidence was obtained for cardiovascular diseases that are the most susceptible to developmental programming. Thus, studies in sheep indicated that pre-term birth irreversibly increases the percentage of polyploid mononuclear cardiomyocyte and induces DNA damage, fibrosis, and lymphocytic infiltration . In humans, pathologic hemodynamic load during postnatal growth permanently increases cardiomyocyte ploidy and decreases cardiac performance . The inflammatory stress caused by gastroenteritis in the rat resulted in cardiomyocyte hyperpolyploidization, long-term atrophy, and cell remodeling . The experimental model of gastroenteritis was used as gastroenteritis triggers developmental programming factors, including inflammation, growth retardation, and malabsorption, and as gastroenteritis is a major cause of diseases in toddlers, infants, and children . Both types of neonatal gastroenteritis cause irreversible excessive polyploidization, long-term atrophy, and remodeling of cardiomyocytes . Altogether, these data indicate that polyploidy can be involved in developmental programming as it is irreversible, responds to programming stimuli during the critical period of development, changes cell phenotype, and weakens cell function, thus meeting all basic criteria of developmental programming.
3. Genome Duplication in Regeneration and Aging
Polyploidization is an important way to preserve cell function and survival under stressful conditions (e.g., necrosis, inflammation, toxic stress, aging, wound healing, and pathological stress) 
. This happens when it is impossible to restore the tissue by the proliferation of diploid cells (e.g., during regeneration and maintenance of organs consisting of terminally differentiated cells, including heart, liver, kidney, and brain). In these slowly renewing organs, polyploidy may be the only way to maintain functionality under stressful conditions 
The participation of polyploidy in regeneration is a part of an evolutionarily conservative response to damage 
. This may be due to the increased resistance and efficiency of polyploid cells compared to diploid ones, which is particularly important during restoration. When there is a need to quickly restore function, polyploidy helps to increase cell size (although often not proportionally to the number of genomes), bypassing the energy-consuming mitosis associated with the reorganization of cytoskeleton, disruption of intercellular contacts and tissue architecture 
. It is known that polyploidy is associated with the switching of metabolism to the energy-saving mode 
. This is especially evident in the heart, where polyploidy caused by stress and hyperfunction leads to the replacement of myosin heavy chain α (fast, adult, and ATP costly) with myosin heavy chain β (slow, embryonic, and ATP economical) 
. This relationship was confirmed in the experimental models of heart disease, as well as in hypertensive heart disease, dilated cardiomyopathy, myocardial infarction, and ischemia 
The ability of polyploid cells to maintain function in conditions of energy deficiency probably allows some species to adapt to extreme hypoxia. For example, about 80% of the cardiomyocyte nuclei in the naked mole rat (Heterocephalus glaber
) contain four or more genomes 
. Notably, this rodent lives under toxic conditions with a low oxygen concentration and has the longevity of 32 years, which is about tenfold greater than the mouse 
. At the same time, in other rodents of similar weight, cardiomyocytes contain almost diploid nuclei 
. Ducks and geese, which can fly without rest for about 10 h at an altitude of 8–10 km, with an oxygen concentration threefold lower than at sea level and air temperature of −40 °C, have cardiomyocytes with a high ploidy (6–8 genomes) 
. At the intraspecies level, the association between the early-stage hypoxia and the increased cardiomyocyte ploidy was found in humans with tetralogy of Fallot and other congenital heart defects that mix arterial and venous blood 
Regeneration may include the ability of certain types of multinucleated polyploid cells to enhance stem properties. In addition, in rapidly renewing tissues with high proliferative potential, the multinuclear and binuclear polyploid cells can give rise to lower ploidy cells with manifestations of stemness. For example, in drosophila ovaries and testes, stem cells appeared from the amitotic division of polyploid cells containing 4–16 genomes 
. The incentive for depoliploidization is stress, associated with starvation or aging 
. In a sponge, totipotent stem cells are formed from binuclear polyploid precursors of tezocytes 
. These data indicate that the relationship between polyploidy and stemness is evolutionary conserved. Notably, in evolution, the appearance of lower-ploidy cells from the amitotic division of a polyploid cell is considered as one of the mechanisms of the origin of multicellular organisms, called ‘cellularisation’ 
However, polyploidy-associated regeneration has also species-specific effects. For example, tetraploid cells of large mammals typically experience replicative aging after endoreplication errors, although tetraploid mesenchymal stem cells and heart interstitial cells of murine rodents (mouse, rat) avoid replicative aging 
. Murine rodents have weaker cell cycle control compared to larger mammals due to the evolutionary balance in rodents being biased in favor of the rapid development at the expense of accuracy and reliability of cellular processes 
. Therefore, they have a higher ability of regeneration due to the proliferation of tetraploid cells, however, this ability increases the likelihood of carcinogenesis.
Polyploidy can be an important regeneration mechanism during aging when the proliferative potential of diploid cells is insufficient to repair defects in DNA, cytoskeleton, mitochondria, and other cellular components resulting from the accumulation of molecular errors, oxidative stress, functional overloads, inflammation, and mechanical tissue damage. The relationship between polyploidization and aging was observed in the retinal epithelium, vascular epithelium, megakaryocytes, lymphocytes, neurons, and other cells 
. In some cases, damage-induced polyploidization is only temporary salvation in an emergency. For example, in the epicardium of Danio rerio
, after the completion of regeneration by polyploidization, the polyploid cells were purified by apoptosis and replaced by dividing epicardial cells 
In general, regeneration through polyploidization is most likely a necessary measure, which provides a safety margin when normal regeneration due to proliferation of diploid cells is not possible. It may be fraught with genomic instability leading to oncogenesis.