Accessing naïve human pluripotency

Abstract

Pluripotency manifests during mammalian development through formation of the epiblast, founder tissue of the embryo proper. Rodent pluripotent stem cells can be considered as two distinct states: naïve and primed. Naïve pluripotent stem cell lines are distinguished from primed cells by self-renewal in response to LIF signaling and MEK/GSK3 inhibition (LIF/2i conditions) and two active X chromosomes in female cells. In rodent cells, the naïve pluripotent state may be accessed through at least three routes: explantation of the inner cell mass, somatic cell reprogramming by ectopic Oct4, Sox2, Klf4, and C-myc, and direct reversion of primed post-implantation-associated epiblast stem cells (EpiSCs). In contrast to their rodent counterparts, human embryonic stem cells and induced pluripotent stem cells more closely resemble rodent primed EpiSCs. A critical question is whether naïve human pluripotent stem cells with bona fide features of both a pluripotent state and naïve-specific features can be obtained. In this review, we outline current understanding of the differences between these pluripotent states in mice, new perspectives on the origins of naïve pluripotency in rodents, and recent attempts to apply the rodent paradigm to capture naïve pluripotency in human cells. Unraveling how to stably induce naïve pluripotency in human cells will influence the full realization of human pluripotent stem cell biology and medicine.

Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis

“…Reversion of primed pluripotent to naive state that can grow in LIF with 2i condition has been attempted [115]. Studies on mouse EpiSCs and human ESCs/iPSCs have included forced expression or addition of extra factors such as Prdm14/Klf2 for mouse EpiSCs [116] and OCT4, KLF2, KLF4 [117], Rarg (RAR-gamma) and Lrh-1 (liver receptor homolog 1; Nr5a2) [118] and histone deacetylase inhibitors [119].…”

Cancer-like epigenetic derangements of human pluripotent stem cells and their impact on applications in regeneration and repair

“…As noted previously, the first isolated mouse ESC and iPSC showed full X reactivation (XaXa), in contrast to the XaXi status or the aberrant partially reactivated XaXerror state seen to date in most hESC and hiPSC. Subsequent work has revealed this discrepancy to be in part symptomatic of a larger divide in classes of pluripotent stem cells, between developmentally earlier “naïve” ground state PSC (as represented by the XaXa mouse naïve PSCs) and developmentally more mature “epiblast” PSC (as represented by XaXi mouse epiblast PSC and most previous human PSC) (extensively reviewed in [51]). Modifications of epiblast hPSC derivation can begin to shift the balance of X-inactivation status towards a more naïve-like ground state of pluripotency [52].…”

Stem cells and the evolving notion of cellular identity

“…Only when stem cells from the epiblast stage of mouse development were isolated and cultured did the distinctions become clear: human ESCs resembled more closely the epiblast-derived stem cells (EpiSCs) of slightly later stage embryos. Hence, murine EpiSCs appear to be a closer developmental equivalent to human ESCs than murine ESCs [5]. Vigorous recent efforts to isolate human ESCs under conditions that more closely mimic the mouse ESCs have yielded a large number of papers that report slightly different conditions and states of a putative 'naive' human stem cell.…”