Cell fusion for reprogramming pluripotency: toward elimination of the pluripotent genome

Embryonic stem cell (ESC) technology should enable the generation of specific cell types for the study and treatment of human diseases. Therapeutic cloning provides a way to generate ESCs genetically matched to diseased individuals through nuclear reprogramming of the somatic genome. However, practical and ethical limitations associated with therapeutic cloning are calling for the development of oocyte- and-embryo-free alternatives for obtaining of autologous pluripotent cells for transplantation therapy. An alternative approach to reprogram the somatic genome involves fusion between somatic and pluripotent cells. Potential fusion partners with reprogramming activities include embryonal carcinoma cells, embryonic germ cells, and ESCs. Experimental evidence is now available, which demonstrates that mouse and human somatic cells can be reprogrammed by fusion to form pluripotent hybrid cells. Recent progress infusion-based reprogramming is reviewed with reference to the developmental potency of hybrid cells as well as genetic and epigenetic correlates of reprogramming. However, hybrid cells lack therapeutic potential because of their abnormal ploidy and the presence of nonautologous genes from the pluripotent parent. We discuss the potential of fusion-based reprogramming for the generation of diploid, autologous pluripotent cells using two alternative routes: the enucleation of ESCs and the fusion of such cytoplasts to somatic cell karyoplasts or intact somatic cells, and the selective elimination of the pluripotent genome following fusion to the somatic partner. Finally, these approaches are discussed in the light of recent progress showing that overexpression of embryonic transcription factors can restore a state of pluripotency to somatic cells.