Solving the Polyploid Mystery in Health and Disease

Abstract

Polyploidy (the more than doubling of a cell's genome) frequently arises during organogenesis, tissue repair, and age-associated diseases. Despite its prevalence, major gaps exist in how polyploid cells emerge and affect tissue function. Studies have begun to elucidate the signals required for polyploid cell growth as well as the advantages and disadvantages of polyploidy in health and disease. This review highlights the recent advances on the role and regulation of polyploidy in Drosophila and vertebrate models. The newly discovered versatility of polyploid cells has the potential to provide alternative strategies to promote tissue growth and repair, while limiting disease and dysfunction.

Figure 1.. Generation of diploid and polyploid cells through division and growth.

The mitotic cell cycle generates either two diploid daughter cells (A) or two polyploid daughter cells (B) depending on whether the initiating cell is diploid (A) or polyploid (B). Incomplete cell cycles promote polyploid cell growth by either endomitosis (C), which results in a mono- or binucleated, polyploid cell or via the endocycle (D) resulting in a mononucleated polyploid cell. (E) Cell fusion also generates bi- and multinucleated polyploid cells independent of the cell cycle. Cell cycle markers do not discern polyploid vs diploid cell generation. A cell’s total ploidy (DNA content) has to be measured to rigorously distinguish between diploid (A) and polyploid (B-E) cell outcomes.

Figure 2.. The functional significance of polyploidy in health and disease.

Illustrations of recent discoveries of polyploidy in health and disease. (A) Development and function of the blood brain barrier in Drosophila requires a balance of mono- and multinucleated polyploid cells generated by endocycle and endomitosis. (B) Mammary gland lactation requires polyploidization of secretory cells by endomitosis. (C) Wound-induced polyploidization occurs in Drosophila and vertebrate tissues to promote repair. (D) Polyploid cells arise with age and may help to compensate for cell loss. (E) Polyploid cells can retain the capacity to divide yet are susceptible to error-prone division resulting in aneuploidy. (F) Polypoid cells can also restrict tumor growth.

Figure 3.. Mechanical tension is a driver for polyploid cell growth.

The zebrafish epicardium heals by cell division and polyploidization. The tissue is composed of mostly diploid cells (2C) prior to injury. During regeneration, higher tension (T_high) occurs at the leading edge and is sufficient to induce polyploid growth by boosting the endocycle and endomitosis.

Figure 4.. Organ size (mass) is determined by cell number or cell size.

Model illustrates how organ mass is restored by either cell proliferation (cell number) or polyploidization (cell size) following cell loss caused by various tissue insults, including injury or cell turnover as result of aging and disease. Polyploidization allows organ mass to be restored with fewer total cells as total ploidy of tissue remains unchanged.