Cell fusion in the liver, revisited

Abstract

There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show “transdifferentiation”, but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral infections, carcinogenesis and aging, remains unclear.

Keywords: Cell fusion; Hepatocytes; TdTomato; Lineage tracing; Chimeras; Extracellular vesicles

Core tip: About 70% of hepatocytes are polyploid, arising either from genome duplication without division (endoreplication) or from cell fusion. Experiments with chimeric mice containing two cell populations each bearing a different genetic marker had shown that some liver cells express markers of both genomes, suggesting that cell fusion occurred. Here, we review the data in the literature and describe new experiments using a chimeric model that confirms that cell fusion contributes to liver polyploidy. We argue that the role of cell fusion in pathological conditions, such as viral hepatitis and neoplastic transformation, is worth further study.