By Jessica Lu
Cardiomyocytes are the cells that make up cardiac muscle. Unlike typical cells which are diploid, almost all adult ventricular cardiomyocytes in mammals are polyploid. They can either have a single polyploid nucleus, multiple diploid nuclei or multiple polyploid nuclei (Gan, Patterson & Sucov, 2020). The physiological role of cardiomyocyte polyploidy is still unclear (Wouter & Olaf, 2020). This polyploidy is a major reason why adult mammalian cardiomyocytes have little capacity to divide, and therefore why mammalian hearts have very little ability to regenerate in the face of injury (Kadow & Martin, 2018).
Although cardiomyocyte polyploidy is abundant in adult mammals, this is not the case in foetal mammals. Throughout foetal development, the mammalian heart grows due to the replication of diploid cardiomyocytes. However, shortly after birth, there is a change the way in which the heart grows. From then on, growth occurs by enlarging existing cardiomyocytes (hypertrophy). This coincides with a period in which most cardiomyocytes increase their DNA content by multinucleation or polyploidisation (Wouter & Olaf, 2020). The polyploidisation is caused by endoreplication, which occurs when there is an interruption in the cell cycle after the genome of a diploid cell has already been replicated in the S-phase (Gan, Patterson & Sucov, 2020). It is still unclear whether polyploidy is a prerequisite or a consequence of hypertrophy (Wouter & Olaf, 2020).
The precise cues which initiate polyploidisation after birth in mammals are still unclear. The changes in polyploidisation coincide with an increase in blood pressure, ventricular pressure, cardiac wall stress, and energy metabolism. Metabolic processes themselves can induce polyploidisation. In the foetal heart, highly proliferative myocytes generally use glucose via glycolysis as a source of energy. This changes after birth, when fatty acid β-oxidation becomes the primary pathway for generating energy. It has been found that promoting β-oxidation leads to increased binucleation. Furthermore, molecular regulation of polyploidisation has been found to occur through the activity of many proteins, such as glycogen synthase kinase-3 (GSK3) and epithelial cell transforming-2 (Ect2). Cyclins also play a crucial role (Wouter & Olaf, 2020). For example, overexpression of cyclinG1 in neonatal mice cardiomyocytes promotes DNA synthesis whilst inhibiting cytokinesis, thus increasing the population of binuclear cardiomyocytes. On the other hand, inactivation of cyclinG1 reduces polyploidy and multinucleation in cardiomyocytes (Zhipei et al., 2010).
Unlike in mammals, cardiomyocytes remain diploid throughout life in most studied fish and salamander species, such as zebrafish and newt. Interestingly, these are also the species whose hearts can regenerate as adults (Wouter & Olaf, 2020). Transgenic zebrafish models with half polyploid hearts had reduced ability to regenerate, showing that it is indeed polyploidy which reduces this regeneration ability. However, questions still remain about how proliferation in polyploid cells is reduced in the heart. In contrast to cardiomyocytes, hepatocytes (the major cell type in the liver) are predominantly polyploid in adult mammals, and yet they still able to divide. Unlike the heart, the liver is able to regenerate after injury (Kadow & Martin, 2018).
There are a few ideas for why polyploidy in mammalian cardiomyocytes has evolved. One idea is that polyploidy evolved to prevent cell division. Cell division is potentially disruptive to heart function, as it requires the cardiomyocyte to break its attachment to its neighbours and at least partially disassemble its sarcomeres for cytokinesis. However, there are two counterarguments to this model. The first is that in the foetal heart, cardiomyocytes proliferate while the heart is actively and productively beating. The second is that the ability to proliferate does not necessarily mean cells will actively proliferate. In fact, in the neonatal mammalian heart before polyploidisation, there is little cardiomyocyte proliferation. This model does not explain why the ability to proliferate would be detrimental if it were only used sparingly (Gan, Patterson & Sucov, 2020).
Another possible reason for the evolution of polyploidy is that it provides protection against the reactive oxygen species generated in metabolically active cardiomyocytes. Polyploid cells have more copies of genes, and thus can suffer more DNA damage before a critical gene is damaged. It is possible that preventing critical damage in this way reduces the need for the heart to regenerate in the first place (Gan, Patterson & Sucov, 2020). A similar explanation for polyploidy has been applied to how the liver protects itself against cancer, despite its exposure to mutagens (Zhang et al., 2018). Primary cardiac tumours are rare (Leja, Shah & Reardon, 2011), and perhaps polyploidy in cardiomyocytes is one reason for this.
Overall, there are many questions which are yet to be answered regarding polyploidy in myocytes. For example, the physiological role of cardiomyocyte polyploidy is still unclear, as are the precise cues which induce it postnatally in mammals. Despite the evidence that cardiomyocyte polyploidy prevents heart regeneration in the face of injury, how this occurs specifically in the heart and not in organs such as the liver is unclear. Research on cardiomyocyte polyploidy could potentially be applied to discovering strategies to regenerate diseased or injured hearts.
Gan, P., Patterson, M. & Sucov, H. M. (2020) Cardiomyocyte Polyploidy and Implications for Heart Regeneration. Annual Review of Physiology. 82 (1), 45-61. Available from: doi: 10.1146/annurev-physiol-021119-034618.
Kadow, Z. A. & Martin, J. F. (2018) A Role for Ploidy in Heart Regeneration. Developmental Cell. 44 (4), 403-404. Available from: doi: 10.1016/j.devcel.2018.02.004.
Leja, M. J., Shah, D. J. & Reardon, M. J. (2011) Primary cardiac tumors. Texas Heart Institute Journal. 38 (3), 261-262. Available from: https://pubmed.ncbi.nlm.nih.gov/21720466
Wouter, D. & Olaf, B. (2020) Polyploidy in Cardiomyocytes. Circulation Research. 126 (4), 552-565. Available from: doi: 10.1161/CIRCRESAHA.119.315408.
Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H., Sehgal, A., Nguyen, L. H., Zhang, Y., Gopal, P., Tarlow, B. D., Siegwart, D. J. & Zhu, H. (2018) The Polyploid State Plays a Tumor-Suppressive Role in the Liver. Developmental Cell. 44 (4), 447-459.e5. Available from: doi: 10.1016/j.devcel.2018.01.010.
Zhipei, L., Shijing, Y., Xiaobo, C., Thomas, K. & Thomas, B. (2010) Regulation of Cardiomyocyte Polyploidy and Multinucleation by CyclinG1. Circulation Research. 106 (9), 1498-1506. Available from: doi: 10.1161/CIRCRESAHA.109.211888.