Abstract
SummaryAfter reprogramming to naive pluripotency, human pluripotent stem cells (PSCs) still exhibit very low ability to make interspecies chimeras. Whether this is because they are inherently devoid of the attributes of chimeric competency or because naive PSCs cannot colonize embryos from distant species remains to be elucidated. Here, we have used different types of mouse, human, and rhesus monkey naive PSCs and analyzed their ability to colonize rabbit and cynomolgus monkey embryos. Mouse embryonic stem cells (ESCs) remained mitotically active and efficiently colonized host embryos. In contrast, primate naive PSCs colonized host embryos with much lower efficiency. Unlike mouse ESCs, they slowed DNA replication after dissociation and, after injection into host embryos, they stalled in the G1 phase and differentiated prematurely, regardless of host species. We conclude that human and non-human primate naive PSCs do not efficiently make chimeras because they are inherently unfit to remain mitotically active during colonization.
Highlights
Human embryo-derived pluripotent stem cells (PSCs) and human induced PSCs exhibit biological and functional characteristics of primed pluripotency: (1) dependence on fibroblast growth factor 2 (FGF2)/extracellular signal-regulated kinase and activin A/SMAD signaling for self-renewal; (2) inactivation of the second X chromosome in female lines; and (3) a global transcriptome more similar to that of post-implantation epiblast in the gastrulation embryo (Chen and Lai, 2015; Davidson et al, 2015; Nakamura et al, 2016; Nichols and Smith, 2009)
We investigated the differential ability of mouse ESCs (mESCs), and rhesus monkey and human naive PSCs, to colonize both closely and distantly related host embryos
We explored the differential ability of mESCs, rhesus monkey PSCs, and human naive induced PSCs (iPSCs) to colonize rabbit and cynomolgus embryos, and drew conclusions on the inherent abilities of rodent and primate naive PSCs to colonize distantly related hosts
Summary
Human embryo-derived pluripotent stem cells (PSCs) and human induced PSCs (iPSCs) exhibit biological and functional characteristics of primed pluripotency: (1) dependence on fibroblast growth factor 2 (FGF2)/extracellular signal-regulated kinase and activin A/SMAD signaling for self-renewal; (2) inactivation of the second X chromosome in female lines; and (3) a global transcriptome more similar to that of post-implantation epiblast in the gastrulation embryo (Chen and Lai, 2015; Davidson et al, 2015; Nakamura et al, 2016; Nichols and Smith, 2009). PSC lines obtained from rhesus monkeys are less well characterized, they exhibit the essential characteristics of primed pluripotency (Wianny et al, 2008) In this respect, human and nonhuman primate PSCs differ from their murine counterparts, which exhibit biological and functional characteristics of naive pluripotency (Chen and Lai, 2015; Davidson et al, 2015; Nichols and Smith, 2009). PSCs under these culture conditions display characteristic features of naive-state pluripotency of mESCs with a reconfigured transcriptome and epigenome (Chen et al, 2015a; Huang et al, 2014; Nakamura et al, 2016), loss of FGF2 dependency (Chen et al, 2015a; Takashima et al, 2014), gain of STAT3 dependency (Chan et al, 2013; Chen et al, 2015a; Gafni et al, 2013; Takashima et al, 2014), reactivation of the second X chromosome (Fang et al, 2014; Takashima et al, 2014; Theunissen et al, 2014), and elevation of oxidative phosphorylation (Takashima et al, 2014; Ware et al, 2009)
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