Apoptosis, G1 Phase Stall, and Premature Differentiation Account for Low Chimeric Competence of Human and Rhesus Monkey Naive Pluripotent Stem Cells

• Published in: Stem cell reports Vol. 16; no. 1; pp. 56 - 74
• Main Authors: Aksoy, Irène, Rognard, Cloé, Moulin, Anaïs, Marcy, Guillaume, Masfaraud, Etienne, Wianny, Florence, Cortay, Véronique, Bellemin-Ménard, Angèle, Doerflinger, Nathalie, Dirheimer, Manon, Mayère, Chloé, Bourillot, Pierre-Yves, Lynch, Cian, Raineteau, Olivier, Joly, Thierry, Dehay, Colette, Serrano, Manuel, Afanassieff, Marielle, Savatier, Pierre
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2021; Elsevier
• Subjects: BCL2; human; interspecies chimera; Life Sciences; macaque monkey; mouse; naive pluripotency; non-human primate; pluripotent stem cells; rabbit; reprogramming; reprogramming; mouse; non-human primate; pluripotent stem cells; interspecies chimera; rabbit; BCL2; macaque monkey; naive pluripotency; human
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.12.004

After 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. [Display omitted] •Mouse ESCs are highly effective in colonizing rabbit and non-human primate embryos•Rhesus monkey and human naive PSCs ineffectively colonize rabbit and monkey embryos•Most rhesus/human naive PSCs differentiate prematurely upon injection into embryos•Rhesus monkey PSCs stall in the G1 phase after transfer into rabbit embryos Aksoy and colleagues report that mouse embryonic stem cells (mESCs) remained mitotically active after injection into rabbit and cynomolgus monkey embryos. In contrast, primate naive PSCs colonized rabbit and cynomolgus embryos with much lower efficiency. Unlike mouse ESCs, they died of apoptosis. The surviving cells slowed DNA replication, stalled in the G1 phase of the cell cycle, and differentiated prematurely, thus questioning their very nature.