A developmental framework for induced pluripotency

Abstract

During development, cells transition from a pluripotent to a differentiated state, generating all the different types of cells in the body. Development is generally considered an irreversible process, meaning that a differentiated cell is thought to be unable to return to the pluripotent state. However, it is now possible to reprogram mature cells to pluripotency. It is generally thought that reprogramming is accomplished by reversing the natural developmental differentiation process, suggesting that the two mechanisms are closely related. Therefore, a detailed study of cell reprogramming has the potential to shed light on unexplained developmental mechanisms and, conversely, a better understanding of developmental differentiation can help improve cell reprogramming. However, fundamental differences between reprogramming processes and multi-lineage specification during early embryonic development have also been uncovered. In addition, there are multiple routes by which differentiated cells can re-enter the pluripotent state. In this Review, we discuss the connections and disparities between differentiation and reprogramming, and assess the degree to which reprogramming can be considered as a simple reversal of development.

Hemichordate models

“…However, these worms, like hydras and planarians, have amazing regenerative capabilities and they are able to form a complete animal from random portions cut from the body [54]. While iPS and stem cell research in mammals have made remarkable progress recently, regenerative studies in lower animals, especially planarians, have provided fascinating insights into the molecular gene circuitry involved in regeneration and totipotency [55,56]. Our group and Swalla's lab have just commenced molecular analyses of regeneration in the hemichordate, P. flava, and this work already shows significant promise [54,57,58].…”

Induced Pluripotent Stem Cells Meet Genome Editing

“…Yamanaka and Takahashi quickly demonstrated that their factors also worked in human cells (Takahashi et al, 2007). However, additional experiments over that last ten years in mouse and human cells also revealed that other sets of transcription factor combinations can be equally potent in reprogramming cells to a pluripotent state, providing valuable insights into the transcriptional pluripotency networks and how cells establish pluripotency (Buganim et al, 2012) (Apostolou and Hochedlinger, 2013; Park et al, 2008; Takahashi and Yamanaka, 2015; Yu et al, 2007). …”

Kinetic barriers in transdifferentiation

“…This model however, has great difficulties in explaining induced pluripotency, 1 where any somatic cells (with presumed low DG) can be reprogrammed epigenetically to pluripotent stem cells (with presumed high DG); nor the reestablishment of totipotency by the fusion of an egg and a sperm -two terminally differentiated cells. A first principle analysis suggests that epigenetic reprogramming is an isoenergetic process if we assume that epigenetic information of the original cell and the converted cell are similar.…”

“…2 Previous studies have shown that the p53 pathway serves as a barrier in the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). 1,4 The effects of p53 attenuation on epigenetic reprogramming and cell cycle progression go hand-in-hand in the derivation of iPSCs, a length process that requires many rounds of cell divisions. 5 In the conversion of a mitotic cell (fibroblast) to a postmitotic neuron, p53 attenuation exerts two opposing actionsit facilitates the transdifferentiation of receptive cells to postmitotic neurons and promotes the division of those fibroblasts that are unresponsive to conversion.…”