Polyploidy in Tissue Repair and Regeneration

Abstract

Polyploidy is defined as a cell with three or more whole genome sets and enables cell growth across the kingdoms of life. Studies in model organisms have revealed that polyploid cell growth can be required for optimal tissue repair and regeneration. In mammals, polyploid cell growth contributes to repair of many tissues, including the liver, heart, kidney, bladder, and eye, and similar strategies have been identified in Drosophila and zebrafish tissues. This review discusses the heterogeneity and versatility of polyploidy in tissue repair and regeneration. Polyploidy has been shown to restore tissue mass and maintain organ size as well as protect against oncogenic insults and genotoxic stress. Polyploid cells can also serve as a reservoir for new diploid cells in regeneration. The numerous mechanisms to generate polyploid cells provide an unlimited resource for tissues to exploit to undergo repair or regeneration.

Figure 1.

Polyploid cells are generated by cell fusion and endoreplication. (A) Cell fusion generates a polyploid syncytium when individual cells fuse together. The syncytium's cellular ploidy (C) equals the sum of its nuclear ploidy. This process is mediated by cytoskeletal remodeling proteins, including Rac GTPase in both epithelial and muscle cell types. (B) Mitosis produces two identical daughter cells with 2C ploidy after completing cytokinesis. (C) An endocycle produces a polyploid cell by bypassing M phase and moving between G and S phases only. This generates a daughter cell with double the DNA content as the parent cell. Diploid nuclei (beige) and ≥4C polyploid nuclei (dark blue). (D) Endomitosis results in polyploid cells by failed karyokinesis (nuclear division) generating a mononucleated, polyploid daughter cell with double the ploidy or failed cytokinesis (cell division) creating a binucleated 4C polyploid daughter cell with two diploid nuclei. Cells may use one or more of these processes to form polyploid cells in tissue repair and regeneration. (This figure was created with BioRender.com.)

Figure 2.

Polyploid cell growth restores tissue mass and maintains organ size in fruit fly tissues and in mouse liver. Examples of tissues in the fruit fly and mouse where polyploidy has been demonstrated to precisely restore tissue mass. (A) Epithelial cells underlying the abdomen cuticle in the adult fruit fly heal a needle puncture wound by the endocycle and cell fusion. The endocycle boosts epithelial ploidy to >4C and cell fusion speed wound closure (Losick et al. 2013). (B) The hindgut pylorus region of the fruit fly intestine is made of diploid cells that endocycle to repair genetically induced apoptotic cell damage (Cohen et al. 2018). Pyloric cells can be switched to a mitotic cell cycle by knocking down frz to restore organ size. (C) Mammalian liver regeneration relies on a combination of diploid and polyploid division as well as endoreplication of its hepatocytes (Wilkinson et al. 2018; Zhang et al. 2018; Lin et al. 2020). The mouse liver is able to regrow and restore organ size by solely relying on diploid hepatocyte division or polyploid cell growth, as observed in Cdk1 and E2F8 mouse mutants (Diril et al. 2012; Pandit et al. 2012). Total tissue ploidy equals number of cells times each cell's ploidy. (This figure was created with BioRender.com.)

Figure 3.

Polyploidy heterogeneity: equal or not? (A) Illustration of many cellular mechanisms in which polyploid cells are generated and in turn generate diploid cells by amitosis, reductive division, or cytokinesis. Polyploid cells can also continue to grow increasing ploidy and cell size or mitotically divide as polyploid. (B) The enigma is whether cells with equivalent ploidy are equal in terms of their structure, gene expression, and physiological function or whether polyploidy and the mechanism used to generate polyploid cells dictates its output. Diploid nuclei (beige) and >4C polyploid nuclei (dark blue). (This figure was created with BioRender.com.)