Somatic polyploidy was found in the tissues of all multicellular organisms (including algae, mosses, lichens, vascular plants, invertebrates, and vertebrates), which points to its adaptive value [3,5]^[1][2]. In human and warm-blooded animals, polyploidy can be a part of normal postnatal morphogenetic programs and can be a manifestation of response to pathological stimuli and diseases. Thus, polyploid cells arise in normal organogenesis of heart, neuronal glia, cerebellum, neocortex, retina, liver, placenta, blood vessels, skin, blood, and other organs [3,22,71,72,73,74]^{[1][3][4][5][6][7]} and in atherosclerosis, neurodegenerative disorders, cardiovascular diseases, wound healing, inflammation, diabetes, cancer, and other pathologies [1,7,8,72,74,75,76,77,78,79,80]^{[8][9][10][5][7][11][12][13][14][15][16]}. Despite the prevalence in normal physiology and pathology, the functional significance of polyploidy still is not clear. Contrary to the old hypothesis, polyploidy is not necessarily required for differentiation and does not have a strong effect on proliferation [81]^[17]. Moreover, polyploidy is far from always associated with the increase in protein cell content in proportion to the number of genomes, which makes its role in the regulation of cell and organ size ambiguous [81,82]^[17][18].

Some researchers believe that somatic polyploidy is harmful as it slows down proliferation, inhibits regeneration, reduces cell functionality and promotes genetic instability [69,83,84,85,86,87,88]^{[19][20][21][22][23][24][25]}. Others think that additional genomes are useful as they enhance cell function due to the acceleration of metabolic processes, protein synthesis, regenerative properties, and protect cells from oncogenic transformation [1,3,89,90]^{[8][1][26][27]}. There are also opinions that genomic duplications are neutral as polyploid cells can be an approximate equivalent to the corresponding number of diploid cells [91]^[28].

The lack of consensus may originate from the fact that polyploid cells exhibit different properties in tissues with different growth activity and differentiation states. For example, in the growing heart and liver, polyploidization of cardiomyocytes and hepatocytes occur as a result of restriction of the last cell cycle phases (cytokinesis and karyokinesis) and is associated with a slowdown of proliferation [72,92]^[5][29]. In the heart and liver of adult mammals, where the mitotic activity of cardiomyocytes and hepatocytes is extremely low, de novo polyploidization (stimulated by hyperfunction or stress) occurs due to cell cycle reactivation and DNA synthesis [72,77]^[5][13]. In this case, the cells also lose the last phases of the cell cycle, however, the cell cycle activity in these cells is higher than in the resting diploid cells [72]^[5].

Despite different manifestations of polyploidy in various biological contexts, there is one important common feature that was previously attributed only to polyploidy in pathology—the association between polyploidy and stress. Extensive analysis of the recent literature indicates that polyploidy is always associated with stress, both in physiologic and pathologic contexts. Thus, in normal mammalian tissues, genome accumulation coincides with critical periods of postnatal growth when cells are forced to combine proliferation and differentiation and to undergo physiological stress [2,7,9,72,93]^{[30][9][31][5][32]}. Cardiomyocytes accumulate genomes during metabolic maturation coinciding with ROS overproduction and genome instability due to lamina reorganization and transition to the oxygen-rich postnatal environment [94,95]^[33][34]. Macrophage polyploidization during inflammation is also caused by DNA damage [96]^[35]. Hepatocytes undergo polyploidization in development in the course of transition from liquid to solid food when the physiological microenvironment is particularly genotoxic [2]^[30]. Trophoblast cells duplicate genomes along with decidualization accompanied by the increase in secretory activity and invasiveness [97,98,99]^[36][37][38].

Stress promotes genome accumulation in quiescent, dormant, and proliferating cells. In quiescent cardiomyocyte and hepatocyte from the adult human and mouse and in the dormant cancer cells that survived treatment, stress induces DNA re-replication resulting in polyploid cell formation [2,77,79,100,101]^{[30][13][15][39][40]}. In the proliferating cells, physiological stress associated with genome instability can promote polyploidy via the premature cell cycle and disrupted cell differentiation [94]^[33]. This phenomenon was described in cardiomyocytes from the hypoplastic left ventricle in the human and neonatal mice [94,102]^[33][41]. It was also observed in cardiomyocytes and hepatocytes of neonatal rats that survived severe inflammatory stress [7^[9][31][11],9,75], and in drosophila epithelial cells involved in wound healing [1,103]^[8][42]. Thus, evidence coming from various objects and fields of research suggest that polyploidy is a way of adaptation to stress and related complications like increased ROS production and DNA instability.

A comparison of polyploidization in hepatocytes and cardiomyocytes of mammals and birds, which differ in functional potential of the heart and liver, indicated how polyploid cells can affect organ function [71,82,104]^[4][18][43]. For the heart, the functional potential was estimated by the organ mass relative to body mass (heart index), for the liver, by the metabolic scope (i.e., the difference between the basal and maximal metabolic rate). The investigation of 36 species of birds and 30 species of mammals showed that the most severe polyploidization of hepatocytes and cardiomyocytes was observed in the animals with a small metabolic scope and a low heart index, which means that polyploidization reduces the functional potential of the organ [71,82,104]^[4][18][43].

Paradoxically, organ functional potential in adults inversely correlated with its functional load in neonates. The data obtained with 30 species of wild mammals belonging to six orders indicated that an organ, which works intensively in the adult state, is subjected to a low workload during ontogenesis and plentifully furnished with resources [70]^[44]. On the contrary, an organ with low functional potential in the adult state starts to work intensively just after birth and experiences a shortage of resources during growth. This paradox can be explained by the assumption that an organ with high functional potential should be formed under beneficial conditions. Cell ploidy in the adult state positively correlated with the neonatal functional load (as polyploidization is caused by the overlapping of cell function with proliferation during growth). The data obtained with 36 bird species that are either mature or immature at hatching confirmed the positive correlation between adult cardiomyocyte ploidy, maturity and mobility at birth, and cardiac functional load during growth [104,105]^[43][45].

The best examples illustrating these relationships are the couples of sedentary and athletic species with similar weights and differences in the maturity at birth and the organ functional load during neonatal development (when polyploidization begins). Thus, in an excellent athlete wolf (Canis lupus), that is immature-born and has low cardiac functional load during active growth, the average cardiomyocyte ploidy is 4.1 n, and relative heart mass is 0.8%. The corresponding values for a sedentary swine (Sus scrofa) that is mature-born and mobile from birth, are 8.5 n and 0.25% [71,82]^[4][18]. Accordingly, an athletic Cooper’s hawk (that is immature and immobile at hatching, yet able to fly incessantly for 10 h in the adult state) has only 4.1 n per cardiomyocyte and a relative heart mass of about 1.0%, whereas the hen (that is mature and mobile at hatching and can be in the air only for a few seconds in the adult state) has 6.7 n per cardiomyocyte and a relative heart mass about 0.4%. The obtained data contradicted the widespread opinion that polyploidy enhances organ function.

In slowly renewing or terminally differentiated organs of warm-blooded animals (e.g., heart and liver), neonatal genome accumulation is irreversible [77,106]^[13][46]. The relationship between polyploidy and the decrease in the organ functional potential makes the factors regulating genome accumulation in somatic cells particularly important. To elucidate this point, the key features of early postnatal development (growth rate, degree of maturity at birth, type of development, metabolic rate) were compared in the large-scale studies of mammals and birds with different polyploidization of cardiomyocytes [71,82,104]^[4][18][43].

It is well established that neonatal genome accumulation is irreversible as the heart and liver cells are not replaced during the life span [77,106,107]^[13][46][47]. Recent studies using labeled isotopes (15N and 14C) have confirmed that in humans and mice, cardiomyocytes and hepatocytes can be of the same age as the individual himself [77,106]^[13][46]. The largest number of cells with an extreme life span has been found in the heart, where a complete set of cardiomyocytes is established in postnatal growth and remains stable throughout life [77,106]^[13][46]. Thus, in many mammalian species, cardiomyocytes accumulate genomes during the period of milk feeding (for example, in a rat from seven to fourteen days after birth, in a pig—from a week of age to two months), in birds cardiomyocyte genome accumulation proceeds during the interval from birth to maturation [71,82,104]^[4][18][43]. In humans, polyploidization occurred mostly from birth to 11 years [77,108]^[13][48]. Consequently, factors regulating this process in adult animals should be sought in early postnatal development (in childhood). The studies of cardiomyocyte ploidy in more than 80 species of birds and mammals indicated that the degree of polyploidization reflects cardiac functional load during growth [82,104,105,109]^{[18][43][45][49]}. Cardiomyocytes of precocious mammals and birds, which are relatively mature and mobile from hatching or birth, contain 1.6 fold more genomes than cardiomyocytes of altricious species of similar weight, which are helpless at hatching or birth and show weak mobility during growth [82,104]^[18][43]. Thus, cardiac functional load during critical developmental windows is important for polyploidization.