What could abnormal syncytia do if they proliferate? While the published reports on COVID-19 discuss large syncytia, as these cells are the most noticeable products of cell fusion due to their size and numerous nuclei (thus often called multinucleated giant cells), they are not the only outcome of cell fusion. Cell fusion can produce binuclear or trinuclear cells, which are often more abundant in experimental systems than large syncytia but could go unnoticed in human tissues or not attributed to cell fusion because distinguishing them reliably from binuclear cells produced by failed mitosis is difficult or impossible with available tools (Gast et al., 2018 ). A syncytium, especially if it has only two or three nuclei, can also enter mitosis and produce mononuclear daughter cells, an outcome that might contribute to the pool of dysmorphic cells in the lung, another hallmark of COVID-19 (Bussani et al., 2020). Multipolar mitoses that are common in these mitoses are prone to produce aneuploid cells with chromosomal aberrations, adding another abnormal feature to the offspring of cell fusion (Duelli ets al., 2007), a phenomenon that may be particular relevant to patients with neoplastic lesions. Fusion of proliferating cells introduces additional abnormalities by combining cells that are at different phases of the cell cycle. Because nuclei united in one cell can progress through the cell cycle independently, one nucleus can force the others to enter mitosis prematurely, causing fragmentation of their chromatin in a phenomenon known as chromatin pulverization (reviewed in (Stevens et al., 2010)). The resulting fragments can incorporate into the chromatin of the hybrid (Pantelias et al., 2019). The common features of chromosomal aberrations in cell hybrids and cancer cells (Ogle et al., 2004; Duelli et al., 2007; Delespaul et al., 2019; Lartigue et al., 2020) along with the shared clonal heterogeneity of cancers and neoplastic cell hybrids, which enables their evolution (Miroshnychenko et al., 2021) has provided support for a long standing model that cell fusion is involved in cancer development, progression, recurrence, dormancy, and acquired drug resistance (reviewed in: (Duelli and Lazebnik, 2003; Parris, 2013; Shabo et al., 2020)). This model has been supported by recent reports of cell hybrids in human cancers (Gast et al., 2018; Laberge et al., 2019) and by multiple observations in animal models (reviewed in (Duelli and Lazebnik, 2003; Pawelek and Chakraborty, 2008; Noubissi and Ogle, 2016)). Whether any neoplastic hybrids found in humans are made by viral fusogens, as it has been suggested (Duelli et al., 2005; Parris, 2005; Duelli and Lazebnik, 2007), is yet to be learned.
