Regulatory Principles of Pluripotency: From the Ground State Up

Abstract

Pluripotency is the remarkable capacity of a single cell to engender all the specialized cell types of an adult organism. This property can be captured indefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent an invaluable platform to investigate cell fate decisions and disease. Recent advances have revealed that manipulation of distinct signaling cues can render ESCs in a uniform "ground state" of pluripotency, which more closely recapitulates the pluripotent naive epiblast. Here we discuss the extrinsic and intrinsic regulatory principles that underpin the nature of pluripotency and consider the emerging spectrum of pluripotent states.

Functional and mechanistic studies of XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells

“…In the case of murine ESCs (mESCs), a minimal culture media supplemented with serum and LIF (leukemia inhibitory factor) can perpetuate the pluripotency state (1). Such culture conditions, among others, provide the external cues to counteract differentiation programs hardwired in ESCs [e.g., the autocrine FGF4 signaling (2)], by fueling an intricate network of transcription factors (TFs) at the core of which stands the autoregulated and self-sustained OCT4 (POU class 5 homeobox 1), SOX2 (sex determining region Y-box2), and NANOG (Nanog homeobox) circuit (3,4). These "core" pluripotency factors orchestrate ESC transcriptional programs in conjunction with "ancillary" TFs (e.g., ESRRB, KLF2, KLF4, SALL4, TBX3, TFCP2L1), various cofactors (5), noncoding RNAs (6), histone modifiers, and chromatin remodelers (7), ultimately conveying regulatory inputs to specialized basal transcriptional machineries (8)(9)(10).…”

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

“…This heterogeneity is a manifestation of the simultaneous possession of differentiation and self‐renewal potential within the ESC population (reviewed in Torres‐Padilla & Chambers, 2014). Indeed, ESCs cultured in LIF/FCS have been proposed to contain a mixture of pluripotent cells that have progressed to different extents toward a primed state (Hackett & Surani, 2014). Such a primed state can also be captured in vitro as EpiSC, by explantation and culture of post‐implantation epiblast cells (Brons et al , 2007; Tesar et al , 2007).…”

“…Such a primed state can also be captured in vitro as EpiSC, by explantation and culture of post‐implantation epiblast cells (Brons et al , 2007; Tesar et al , 2007). In contrast, ESCs cultured in LIF supplemented with inhibitors of both MEK and GSK3b (two inhibitors or 2i; Ying et al , 2008) may represent the opposite end of the range of pluripotent states that can be maintained in vitro (Hackett & Surani, 2014). Supporting the idea that heterogeneity is a direct physiological consequence of the balance between self‐renewal and differentiation, TF expression becomes uniformly high as a result of pharmacological treatment with PD0325901 (Wray et al , 2010).…”

The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane Localization and Activation

“…Although the transcriptional program that coordinates pluripotency has been progressively unveiled during the past few years (Hackett and Surani, 2014;Kumar et al, 2014), the signaling pathways that regulate early differentiation events are not completely understood.…”