Abstract
Pluripotent stem cells retain the developmental timing of their species of origin in vitro, an observation that suggests the existence of a cell-intrinsic developmental clock, yet the nature and machinery of the clock remain a mystery. We hypothesize that one possible component may lie in species-specific differences in the kinetics of transcriptional responses to differentiation signals. Using a liquid-handling robot, mouse and human pluripotent stem cells were exposed to identical neural differentiation conditions and sampled for RNA-sequencing at high frequency, every 4 or 10 minutes, for the first 10 hours of differentiation to test for differences in transcriptomic response rates. The majority of initial transcriptional responses occurred within a rapid window in the first minutes of differentiation for both human and mouse stem cells. Despite similarly early onsets of gene expression changes, we observed shortened and condensed gene expression patterns in mouse pluripotent stem cells compared to protracted trends in human pluripotent stem cells. Moreover, the speed at which individual genes were upregulated, as measured by the slopes of gene expression changes over time, was significantly faster in mouse compared to human cells. These results suggest that downstream transcriptomic response kinetics to signaling cues are faster in mouse versus human cells, and may offer a partial account for the vast differences in developmental rates across species.
Highlights
Pluripotent stem cells, due to their properties of self-renewal and potency, provide a unique model for studying early development and are of particular interest for their exciting potential in regenerative therapies [1]
A slow developmental clock operating in human pluripotent stem cells imposes severe obstacles to many pluripotent stem cell therapies
We found that responses occurred early across species, but expression patterns were prolonged in human cells and the rate of upregulation in gene expression was significantly faster in mouse cells
Summary
Pluripotent stem cells, due to their properties of self-renewal and potency, provide a unique model for studying early development and are of particular interest for their exciting potential in regenerative therapies [1]. The neural plate forms at embryonic day 7.5 in the mouse and requires only 2 additional days to fully close the neural tube in the embryo, growing roughly 2.6 mm in that short time [9]. It has been shown that pluripotent cells closely maintain their species-specific developmental rates ex utero, even in the absence of an intact embryo or the maternal environment [2,3,4,5,11,12,13,14]. This suggests the existence of a species-specific cell-intrinsic clock contributing to developmental timing, the mechanisms orchestrating developmental timing across vast differences in body size remain largely unknown [14,15]
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