Abstract
ABSTRACTHuman naïve pluripotent stem cells (PSCs) share features with the pre-implantation epiblast. They therefore provide an unmatched opportunity for characterising the developmental programme of pluripotency in Homo sapiens. Here, we confirm that naïve PSCs do not respond directly to germ layer induction, but must first acquire competence. Capacitation for multi-lineage differentiation occurs without exogenous growth factor stimulation and is facilitated by inhibition of Wnt signalling. Whole-transcriptome profiling during this formative transition highlights dynamic changes in gene expression, which affect many cellular properties including metabolism and epithelial features. Notably, naïve pluripotency factors are exchanged for postimplantation factors, but competent cells remain devoid of lineage-specific transcription. The gradual pace of transition for human naïve PSCs is consistent with the timespan of primate development from blastocyst to gastrulation. Transcriptome trajectory during in vitro capacitation of human naïve cells tracks the progression of the epiblast during embryogenesis in Macaca fascicularis, but shows greater divergence from mouse development. Thus, the formative transition of naïve PSCs in a simple culture system may recapitulate essential and specific features of pluripotency dynamics during an inaccessible period of human embryogenesis.
Highlights
Pluripotency refers to a flexible potential for individual cells to give rise to all lineages of the embryo
pluripotent stem cells (PSC) were aggregated in suspension in N2B27 medium for up to 14 days
The neural markers were not expressed in outgrowths from naïve PSC aggregates (Fig. S1A)
Summary
Pluripotency refers to a flexible potential for individual cells to give rise to all lineages of the embryo. The period varies from around 4 days in mouse and other rodents to 8-10 days or longer in primates, including Homo sapiens, and in many other mammals Over this time, pluripotent cells change in character from the initial naïve condition to a lineage-primed state poised for commitment (Morgani et al, 2017; Nakamura et al, 2016; Nichols and Smith, 2009; Smith, 2017). This dynamic transition is manifest at the cellular level by epithelialisation and molecularly by reconfiguration of transcriptome, epigenome and metabolism (Bedzhov and Zernicka-Goetz, 2014; Buecker et al, 2014; Kalkan et al, 2017; Mohammed et al, 2017; Zhou et al, 2012)
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