22 - Epigenetic consequences of somatic cell nuclear transfer and induced pluripotent stem cell reprogramming

Summary

Introduction and historical context

Work on amphibian embryos by Hans Spemann more than 80 years ago (see Chapter 1) raised the possibility that individual nuclei could maintain developmental integrity despite undergoing multiple cell divisions [1]. Subsequent work by Briggs and King amplified this concept through development and use of nuclear transfer to replace the nucleus of a frog oocyte with that of a later stage embryo [2]. While early blastula nuclei could support frog egg development, later nuclei did not, leading Briggs and King to conclude that nuclei lose their developmental potential as embryogenesis progresses [3]. Work by Gurdon, however, brought about a paradigm shift (see Chapter 1) from Briggs and King's view of decreasing nuclear potential to one of sustained nuclear potential, owing to his demonstration that fully differentiated tadpole intestinal nuclei could support Xenopus laevis development into a functional tadpole [4]. The possibility of sustained nuclear developmental potential was fully realized 35 years later when Wilmut and co-workers demonstrated that cultured cells derived from the adult sheep mammary gland could sustain development all the way to adulthood [5]. These insights into nuclear developmental potential were further amplified by the discovery of Yamanaka and co-workers that differentiated somatic cells could be reprogrammed into cells with developmental capacity equivalent to that of mouse embryonic stem cells (mESCs). This was achieved by administering to mouse fetal fibro-blasts a limited set of transcription factors that were known to be expressed in mESCs [6]. The following year, Yamanaka and others extended their compelling observation to human somatic cells, demonstrating that these could be similarly reprogrammed to a pluripotent state [7–9]. The award of the 2012 Nobel Prize in Physiology or Medicine jointly to Gurdon and Yamanaka emphasized the importance of these discoveries.

We have used this chapter to summarize recent studies on the epigenetic characteristics of embryos generated by somatic cell nuclear transfer (SCNT) and pluripotent stem cells induced by reprogramming, as compared to their fertilization-derived counterparts. A recent review has addressed similar issues [10], and others have delineated the epigenetic features that would distinguish SCNT embryos and reprogrammed pluripotent stem cells from their counterparts derived by normal fertilization [11–15]. Accordingly, we forego reiterating the detailed methods for epigenetic analysis, focusing rather on the results from recent studies and their implication for potential applications of SCNT or reprogrammed cells in regenerative medicine.