Pluripotent stem cells: induction and self-renewal

Abstract

Pluripotent stem cells (PSCs) lie at the heart of modern regenerative medicine due to their properties of unlimited self-renewal in vitro and their ability to differentiate into cell types representative of the three embryonic germ layers-mesoderm, ectoderm and endoderm. The derivation of induced PSCs bypasses ethical concerns associated with the use of human embryonic stem cells and also enables personalized cell-based therapies. To exploit their regenerative potential, it is essential to have a firm understanding of the molecular processes associated with their induction from somatic cells. This understanding serves two purposes: first, to enable efficient, reliable and cost-effective production of excellent quality induced PSCs and, second, to enable the derivation of safe, good manufacturing practice-grade transplantable donor cells. Here, we review the reprogramming process of somatic cells into induced PSCs and associated mechanisms with emphasis on self-renewal, epigenetic control, mitochondrial bioenergetics, sub-states of pluripotency, naive ground state, naive and primed. A meta-analysis identified genes expressed exclusively in the inner cell mass and in the naive but not in the primed pluripotent state. We propose these as additional biomarkers defining naive PSCs.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.

Keywords: epigenetics; iPSC; naive; pluripotency; primed; urine.

Figure 1.

A gene signature defining the naive state. Genes expressed in the primed and naive state in deep sequencing data from Takashima et al. [129] were compared (a) and the most relevant over-represented KEGG pathways exclusively in naive, primed and common in naive and primed are listed in (b). ECM, extracellular matrix. Genes exclusively expressed in the naive state were compared to genes expressed in the inner cell mass (ICM) from Adjaye et al. [134] (c) and are proposed as the marker signature of the naive state (d).

Figure 2.

Gene ontology (GO) network of the gene signature defining the naive state. Significantly over-represented GOs for the naive state gene signature were determined via the R package GOstats [137] and summarized to a network via the REVIGO tool [138] and Cytoscape [139]. The colour reflects the significance of over-representation of a GO term. The darker the red of a GO term node, the lower is its p-value. GO terms determined as highly similar by the REVIGO tool are connected. In this network, embryonic placenta development emerges as a major hub connecting many other developmental GO terms such as bone development, lens development in the camera-type eye and multicellular organism development. (Online version in colour.)