Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

Abstract

Pluripotent stem cells, like embryonic stem cells (ESCs), have specialized epigenetic landscapes, which are important for pluripotency maintenance. Transcription factor-mediated generation of induced pluripotent stem cells (iPSCs) requires global change of somatic cell epigenetic status into an ESC-like state. Accumulating evidence indicates that epigenetic mechanisms not only play important roles in the iPSC generation process, but also affect the properties of reprogrammed iPSCs. Understanding the roles of various epigenetic factors in iPSC generation contributes to our knowledge of the reprogramming mechanisms.

Figure 1

The path from a somatic cell to a refined iPSC and the putative epigenetic barriers during the process. When reprogramming factors are introduced into a fibroblast, the reprogramming factors immediately drive the cell to overcome barrier 1, resulting in the acquisition of the epithelial properties through MET. A fibroblast that fails to conquer this barrier retains its cellular identity with either an accelerated or arrested proliferation status. After the cell gains epithelial properties, a subsequent barrier (2) to acquiring pluripotency is encountered. Intermediate epithelial cell that successfully overcomes the second barrier becomes a nascent iPSC, which can self-renew independently of introduced transcription factors. Otherwise, it is trapped in the intermediate stage and becomes a partially reprogrammed cell. For the nascent iPSC, additional barrier(s) (3) need to be overcome actively or destructed passively to achieve a bona fide pluripotency equivalent to that in ESCs. Processes that depend on the reprogramming factors are shown in solid arrows, whose thickness reflects the approximate propensity for the cell to undergo a specific transition. Dotted arrows represent the processes that require additional manipulations other than the induction of reprogramming factors. Putative epigenetic barriers in iPSC generation are numbered and shown in solid arcs. Other potential barriers are shown in dotted arcs.

Figure 2

Schematic presentation of a model explaining how iPSC generation can be facilitated by additional factors that act on different steps of the reprogramming process. Reprogramming is initiated at t₀ by introducing transcription factors Oct4, Sox2 and Klf4 (OSK), OSK plus Kdm2b, or OSK plus Nanog. Soon after reprogramming (t₁), some cells rapidly overcome the putative epigenetic barrier (1) to gain epithelial features. In the presence of Kdm2b, which facilitates the acquisition of epithelial status, more cells overcome this barrier, turning into intermediate epithelial cells. Overcoming this first barrier is depicted in a stochastic manner, although a deterministic mode is also possible. Intermediate cells subsequently encounter the barrier (2) to activating pluripotency circuitry. Overcoming the second barrier may take longer time (t₁ to t₂ to t₃) and the task remains incomplete for some cells, which become partially reprogrammed cells. Nanog, which is capable of driving intermediate cells to iPSCs, facilitates reprogramming at this step. At certain time points in reprogramming (e.g. from t₂ to t₃), the effect of Kdm2b or Nanog is manifested by the increased efficiency in iPSC generation. Different reprogramming factor combinations may also lead to different ratios of partially reprogrammed cells. Note that, cell proliferation and its potential effect on reprogramming are not considered in the figure, since neither Kdm2b nor Nanog enhances reprogramming by affecting the cell cycle^,. Cell fate transitions in the reprogramming process are illustrated in the box on the right with putative epigenetic barriers numbered. Bars at the bottom of the figure indicate the progression of iPSC-destined cells in overcoming individual barriers.