The Current State of Naïve Human Pluripotency

Abstract

Naïve or ground state pluripotency is a cellular state in vitro which resembles cells of the preimplantation epiblast in vivo. This state was first observed in mouse embryonic stem cells and is characterized by high rates of proliferation, the ability to differentiate widely, and global hypomethylation. Human pluripotent stem cells (hPSCs) correspond to a later or “primed” stage of embryonic development. The conversion of hPSCs to a naïve state is desirable as their features should facilitate techniques such as gene editing and more efficient differentiation. Here we review protocols which now allow derivation of naïve human pluripotent stem cells by transgene expression or the use of media formulations containing inhibitors and growth factors and correlate this with pathways involved. Maintenance of these ground state cells is possible using a combination of basic fibroblast growth factor and human leukemia inhibitory factor together with dual inhibition of glycogen synthase kinase 3 beta, and mitogen‐activated protein kinase kinase (MEK). Close similarity between the ground state hPSC and the in vivo preimplantation epiblast have been shown both by demonstrating similar upregulation of endogenous retroviruses and correlation of global RNA‐seq data. This suggests that the human naïve state is not an in vitro artifact. Stem Cells 2015;33:3181–3186

Sirtuin 1 Promotes Deacetylation of Oct4 and Maintenance of Naive Pluripotency

“…It is clear that naïve cells are more robust than primed cells, both in their growth rate and in their ability to contribute to the differentiated cell population in injected blastocycts (Brons et al, 2007; Dodsworth et al, 2015; Silva et al, 2008; Tesar et al, 2007). Indeed, we found that knocking out SirT1 also slowed the growth of naïve cells and by some assays altered their morphology to resemble primed cells.…”

“…Several attempts have been made to stably reprogram human embryonic stem cells to the naïve state using both genetic (Takashima et al, 2014; Wang et al, 2011) and chemical methodologies (Chan et al, 2013; Duggal et al, 2015; Gafni et al, 2013; Hanna et al, 2010; Theunissen et al, 2014; Valamehr et al, 2014; Ware et al, 2014). These studies have been met with varying levels of success, but the robustness of these protocols with regards to the long term culture of the naïve state is still being evaluated (Dodsworth et al, 2015). …”

Live imaging of X chromosome reactivation dynamics in early mouse development can discriminate naïve from primed pluripotent stem cells

“…Our data suggest that the Momiji mouse strain will provide a powerful tool for tracing the reprogramming involved in establishing iPSCs (EpiSCs→iPSCs) and will help to clarify how XCR participates in this process. Clarification of the reprogramming processes, from a primed to a naïve state, will help in the effective establishment of naïve human iPSCs from primed ESCs (Dodsworth et al, 2015;Pera, 2014). …”

Cell‐Surface Expression Levels Are Important for Fine‐Tuning the Performance of Receptor Tyrosine Kinase‐Based Signalobodies

“…RTKs play pivotal roles in cell‐fate control of many cell types. For instance, basic fibroblast growth factor (bFGF) is essential for maintaining human embryonic stem cells, whereas vascular endothelial growth factor (VEGF) induces differentiation into endothelial cells . In neural stem cells, epidermal growth factor (EGF) and bFGF are required for self‐renewal, whereas nerve growth factor (NGF) and brain‐derived neurotrophic factor (BDNF) trigger differentiation into neurons .…”