Stem cell biologists sure play a mean pinball

Abstract

Mouse fibroblasts are reprogrammed to functional neurons by expression of a few transcription factors.

Figure 1. Pinball model of development and reprogramming

The basis of this model is that reprogramming from one cell fate to another requires a dedifferentiation step back to a more primitive state followed by a new path of differentiation. A zygote (‘ball’) is formed after a sperm enters the egg (bottom right). Totipotent stem cells are produced from the first few divisions of the fertilized egg and become either embryonic or extraembryonic cell types. As development progresses in the ‘ball launch lane’, embryonic stem cells emerge in the inner cell mass of the blastocyst. The embryonic stem cell expresses endogenous transcription factors (‘bumpers’) responsible for self-renewal and maintenance of pluripotency. As it moves forward, its developmental potential becomes increasingly restricted. Differentiation into one of the three major dermal lineages is influenced by the developmental guidance cues and epigenetic determinants (‘edges’) that the cell encounters. Endogenous transcription factors (bumpers) or exogenous transcription factors (‘flippers’) can drive differentiation forward or, in some cases, flip the cell upward to a less differentiated state (dotted red arrows). A terminally differentiated cell (brown) falling through ‘out lanes’ can be forced back to pluripotency through ‘return lanes’ to make iPS cells by overexpression of master regulators (bottom orange flippers) such as Oct4 and Sox2. The expression of other, less powerful transcription factors (smaller flippers) can only tap the cell within a small radius or across an epigenetic edge to another lineage via a transient more primitive state. In an alternative model, a differentiated cell can be pushed directly sideways to another cell type (transdifferentiation) without being flipped to a less differentiated state.