Reprogramming lineage identity through cell–cell fusion

The conversion of differentiated cells to a pluripotent state through somatic cell nuclear transfer provided the first unequivocal evidence that differentiation was reversible. In more recent times, introducing a combination of key transcription factors into terminally differentiated mammalian cells was shown to drive their conversion to induced pluripotent stem cells (iPSCs). These discoveries were transformative, but the relatively slow speed (2-3 weeks) and low efficiency of reprogramming (0.1-1%) made deciphering the underlying molecular mechanisms difficult and complex. Cell fusion provides an alternative reprogramming approach that is both efficient and tractable, particularly when combined with modern multi-omics analysis of individual cells. Here we review the history and the recent advances in cell-cell fusion that are enabling a better understanding cell fate conversion, and we discuss how this knowledge could be used to shape improved strategies for regenerative medicine.