Mechanistic insights into reprogramming to induced pluripotency

Abstract

Induced pluripotent stem (iPS) cells can be generated from various embryonic and adult cell types upon expression of a set of few transcription factors, most commonly consisting of Oct4, Sox2, cMyc, and Klf4, following a strategy originally published by Takahashi and Yamanaka (Takahashi and Yamanaka, 2006, Cell 126: 663-676). Since iPS cells are molecularly and functionally similar to embryonic stem (ES) cells, they provide a source of patient-specific pluripotent cells for regenerative medicine and disease modeling, and therefore have generated enormous scientific and public interest. The generation of iPS cells also presents a powerful tool for dissecting mechanisms that stabilize the differentiated state and are required for the establishment of pluripotency. In this review, we discuss our current view of the molecular mechanisms underlying transcription factor-mediated reprogramming to induced pluripotency.

Figure 1. Landmark events on the path to induced pluripotency

It is thought that expression of the four reprogramming factors Oct4 (O), Klf4 (K), Sox2 (S), and cMyc (M) triggers a cascade of events within two to three weeks that leads to the iPS cell state. Stable and clonally expandable pre-iPS cells can also be generated as a by-product of this process and can enter the fully re-programmed state upon addition of indicated molecules.

Figure 2. Considering stochastic events in reprogramming

(A) Latency of faithful reprogramming. All cells have the potential to give rise to daughter cells that can faithfully reprogramming, but conversion to iPS cells occurs at divergent times - as early as two weeks (top) to as late as 18 weeks for pre-B cells (bottom). (B) Epigenetic barriers. Within a clonal populations, only a few daughter cells reach the iPS cell status due to epigenetic barriers that need to be overcome in a stochastic manner. (C)Pathways between reprogramming stages. It is thought that reprogramming occurs in defined steps (see Figure 1) but could use alternative pathways between these steps. The scenarios presented are not exhaustive, as other potential reprogramming profiles can exist.