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.

Cancer is one of the most common diseases worldwide, and treatment bears many challenges such as drug and radioresistance and formation of metastases. These difficulties are due to tumor heterogeneity, which has many origins. One may be cell fusion, a process that is relevant in both physiological (e.g., wound healing) and pathophysiological (cancer and viral infection) processes. In this study, we examined if cell fusion between mesenchymal stem/stromal cells (MSCs) and breast cancer (BC) cells occurs and if newly generated hybrid cells may exhibit cancer stem/initiating cell (CS/IC) characteristics. Therefore, several methods such as mammosphere assay, AldeRed assay, flow cytometry (CD24, CD44, CD104) and Western blot analysis (of epithelial to mesenchymal transition markers such as SNAIL, SLUG and Twist) were applied. In short, four different hybrid clones, verified by short tandem repeat (STR) analysis, were analyzed; each expressed an individual phenotype that seemed not to be explicitly related to either a more stem cell or cancer cell phenotype. These results show that cancer cells and MSCs are able to fuse spontaneously in vitro, thereby giving rise to hybrid cells with new properties, which likely indicate that cell fusion may be a trigger for tumor heterogeneity.

Regenerative medicine is concerned with the investigation of therapeutic agents that can be used to promote the process of regeneration after injury or in different diseases. Mesenchymal stem/stromal cells (MSCs) and their secretome – including extracellular vesicles (EVs) are of great interest, due to their role in tissue regeneration, immunomodulatory capacity and low immunogenicity. So far, clinical studies are not very conclusive as they show conflicting efficacies regarding the use of MSCs. An additional process possibly involved in regeneration might be cell fusion. This process occurs in both a physiological and a pathophysiological context and can be affected by immune response due to inflammation. In this review the role of MSCs and cell fusion in tissue regeneration is discussed.