We showed years ago by fusing two differentiated cell types in stable non-dividing heterokaryons that “terminally” differentiated human cells could be reprogrammed. The balance of regulators was critical in determining the direction of differentiation. We are now enlisting natural mechanisms to tip the balance of regulators and derive new mammalian cell sources for regenerative medicine: (1) by using heterokaryons to identify crucial early regulators of reprogramming to pluripotency (iPS); (2) by altering telomerase activity; (3) by mimicking cues of adult stem cell niches; and (4) by dedifferentiation like newts. Our experimental systems offer a means to explore regulatory networks. Elucidation of the logic underlying nuclear reprogramming via molecular timelapse snapshots (the “Kineticon) is revealing discrete steps in pathways of dedifferentiation and redifferentiation. These approaches provide fundamental mechanistic insights and are revealing common principles of nuclear reprogramming. The generation of novel cell sources should enable new clinical applications of cell therapies for regenerative medicine.
