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.
Highlights
Data showed that bone marrow-derived stem cells (BMSCs) could transdifferentiate into functional organ cells in accordance with the blueprint provided by the target tissue [24,25], suggesting that BMSCs could be administered to the desired tissue, and regeneration would run in a self-autonomous way
More thorough analyses revealed that transdifferentiation of BMSCs could be either induced by soluble factors secreted by cells [2,26,27] or could be due to the biological phenomenon of cell fusion [4,5,6,7,8,10,12,18,20,28,29,30,31,32,33]
BMSC-derived mononuclear cells were found in regenerated tissue, which were positive for both donor and recipient markers, indicating that such cells have truly originated from cell fusion [18,29,43,44]
Summary
20 years ago, the first papers were published demonstrating that bone marrow-derived stem cells (BMSCs), such as mesenchymal stem/stromal cells (MSCs) and hematopoietic stem cells (HSCs), possess a certain degree of plasticity/pluripotency and could be functionally differentiated into hepatocytes [1,2,3,4,5,6,7], neurons [6,8,9,10,11,12], cardiomyocytes [6,13,14], skeletal muscle [15,16,17], intestinal cells [18,19,20] or insulin-producing cells [21]. The finding that stem cells could adopt the properties of foreign tissue cells by merging with them was confusing. This referred to the process of cell fusion itself, which to date is still not well understood and to the fate of the hybrid cells that were originated. Ploidy reduction/HST of hybrid cells could either result in daughter cells with a normal diploid karyotype [37,42] or in aneuploid daughter cells that are genomically unstable [7,36,39,45,46,47,48]. We will summarize and discuss the role of cell fusion as an inducer of polyploidy and aneuploidy and the fate of such cell fusion-derived cells
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