Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy

Abstract

The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species.

Keywords: aneuploidy; cell fusion; polyploidy; stem cells; tissue regeneration.

Figure 1

Cell fusion induced polyploidy, aneuploidy, and genomic instability. Cell fusion first results in the origin of bi- or multinucleated heterokaryons (A), which could either remain in this state (B) or could undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST). Symmetric ploidy reduction/HST (C) gives rise to viable diploid daughter cells, whereby a random segregation of parental alleles to daughter cells can be possible. Multipolar ploidy reduction/HST (D) results in the origin of aneuploid/genomic unstable daughter cells, whereas merotelic attachments (E) during mitosis can cause lagging chromosomes and micronucleus formation in aneuploid/genomically unstable daughter cells. Aneuploidy/genomic instability concomitant with micronucleus formation is associated with further DNA damage, such as chromothripsis and translocations (not shown here). Most of these aneuploid/genetically unstable cells will be nonviable or will become senescent. However, it cannot be ruled out that some hybrid cells will survive and that aneuploidy/genomic instability concomitant with further DNA aberrations could ultimately lead to a malignant transformation of the cells.